Multiwavelength phototherapy devices, systems, and methods for the non-invasive treatment of damaged or diseased tissue.

Abstract

This invention provides systems and methods for multi-wavelength low-level phototherapy, multi-wavelength PBM, and other phototherapy. [Solution] A multiwavelength phototherapy apparatus for treating disorders or diseases, for improving and / or restoring the function of cells and / or tissues by the tuned and targeted delivery of two or more doses of light having different wavelengths to cells or tissues, includes a housing having an interior; an eyepiece disposed on the housing and configured and positioned for the placement of a patient's eye adjacent to the eyepiece; a first light source disposed within the housing that generates a first ray having a first therapeutic wavelength; and a second light source disposed within the housing that generates a second ray having a second therapeutic wavelength, wherein the second therapeutic wavelength differs from the first therapeutic wavelength by at least 25 nm.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This PCT international patent application, filed on September 9, 2015, claims the interests of U.S. Provisional Patent Applications No. 62 / 048,182, 62 / 048,187, and 62 / 048,211, filed on September 9, 2014, respectively. U.S. Provisional Patent Applications No. 62 / 048,182, 62 / 048,187, and 62 / 048,211 are incorporated herein by reference in their entirety.

[0002] (Field of invention) This disclosure generally relates to multiwavelength phototherapy, including photobiomodulation ("PBM"). More specifically, this specification discloses non-invasive phototherapy devices, systems, and methods in the ophthalmic field for improving or restoring the function of cells or tissues (e.g., cells or tissues of an injured or diseased eye) by tuned and targeted delivery of two or more light doses, each having a different wavelength peak, to cells or tissues. When light is guided in a tuned manner, two or more light doses modulate the activity of two or more photosensitive factors or photoreceptors, thereby promoting the healing of injured or diseased cells or tissues. [Background technology]

[0003] In methods generally referred to as photobiomodulation ("PBM") or low-level phototherapy, light can function in different mechanisms within cell tissues to stimulate or inhibit biological activity. PBM involves the use of visible to near-infrared (NIR) light (500-1000 nm) produced by lasers or non-coherent light sources, applied to the body surface to produce beneficial effects on a wide range of disease conditions. (Chung et al., Ann. Biomed. Eng (2011); Hashmi et al., PM.R.2:S292-S305 (2010); Rojas et al., Dovepress 2011:49-67 (2011); and Tata and Waynant, Laser and Photonics Reviews 5:1-12 (2010)). PBM requires the use of light at suitable intensity, energy, and wavelength without causing significant damage to cells.

[0004] The mechanism of PBM at the cellular level is thought to be due to the activation of the mitochondrial respiratory chain complex, which leads to the stabilization of metabolic function. There is growing evidence that cytochrome c oxidase (CCO) is an important photoreceptor in the spectral range from far-infrared to near-infrared light. Grossman et al., Lasers. Surg. Med. 22:212~218 (1998); Kara et al., J. Photochem. Photobiol. B. 27:219~223 (1995); Karu and Kolyakov, Photomed. Laser Surg. 23:355~361 (2005); Kara et al., Lasers Surg. Med. 36:307~314 (2005); and Wong-Riley et al., J. Biol. Chem. 280:4761~4771 (2005).

[0005] There are many disorders that can affect the eye, including trauma or disease. Eye diseases can include, for example, glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, central serous retinopathy (CRS), non-arteritic anterior ischemic optic neuropathy (NAION), Leber hereditary optic nerve disease, and uveitis. Other disorders can include physical trauma (e.g., cataract or lens surgery) or other causes of eye injury or degeneration. Eye degeneration can result from major destructive events (e.g., eye trauma or surgery) and can also include processes of cellular destruction resulting from persistent, delayed, and progressive cellular destruction mechanisms caused by major destructive or disease events. [Overview of the project] [Problems that the invention aims to solve]

[0006] It is desirable to develop methods and devices for the treatment of these eye diseases, disorders, or degenerations. It is especially desirable to develop methods and devices for treatment that may be less invasive or have fewer side effects than surgery or pharmaceutical treatment, or that can be used in conjunction with surgery or pharmaceutical treatment to aid in healing or treatment. [Means for solving the problem]

[0007] This disclosure provides multiwavelength phototherapy devices, systems, and methods for use in the non-invasive treatment of disorders or diseases associated with lost or reduced cellular or tissue function. Accordingly, the multiwavelength phototherapy devices, systems, and methods disclosed herein can be adapted for therapeutic use by tuned and targeted delivery of two or more different wavelengths to the cells or tissues of patients suffering from disorders or diseases, thereby enhancing reduced function, reducing hyperactivity, or modifying altered function in the cells or tissues associated with the disorder or disease, thereby reducing the symptoms or slowing the progression of one or more embodiments of the disorder or disease.

[0008] In certain embodiments, the present disclosure provides multi-wavelength phototherapy devices, systems, and methods for improving and / or restoring one or more functions of target cells. The systems and methods include tuned and targeted delivery of two or more different wavelengths of light to cells and / or tissues, thereby promoting the activity of two or more photosensitive factors or photoreceptors, thereby improving and / or restoring target cell function, particularly the function of target cells associated with impairment and / or disease.

[0009] In other embodiments, the Disclosure provides multiwavelength phototherapy apparatus, systems, and methods for providing a method for stimulating cytochrome c oxidase (CCO) activity in cells and / or tissues. The method comprises the regulated and targeted delivery of two or more photodose doses to cells having two or more photosensitive factors associated with and required for CCO activity. A first dose has a first wavelength that can activate a first photosensitive factor of CCO, and a second dose has a second wavelength that can activate a second photosensitive factor of CCO, thereby stimulating CCO activity. In certain embodiments of these embodiments, stimulating CCO activity improves and / or restores the function of target cells, particularly target cells in target tissue such as target tissue having one or more cells associated with injury and / or disease. Certain embodiments may also be reversed and / or their progression can be slowed by increasing intracellular CCO activity.

[0010] In further embodiments, the present disclosure provides multiwavelength phototherapy devices, systems, and methods for treating patients suffering from disorders and / or diseases associated with one or more lost or reduced cellular functions. The systems and methods include tuned and targeted delivery of two or more different wavelengths of light to one or more cells of a patient in order to restore lost and / or enhance reduced cellular functions, thereby treating disorders and / or diseases. In certain embodiments of these embodiments, lost or reduced cellular functions include intracellular functions such as intracellular CCO activity in target cells having two or more photosensitive factors associated with and required for the intracellular function.

[0011] In further embodiments, the present disclosure provides multiwavelength phototherapy devices, systems, and methods for treating patients suffering from ocular disorders and / or diseases associated with the loss and / or reduced function of one or more ocular cells. The systems and methods include tuned and targeted delivery of two or more different wavelengths of light to the patient's eye to restore and / or enhance the function of the lost and / or reduced ocular cells, thereby treating the disorders and / or diseases.

[0012] In certain embodiments of these devices, systems, and methods, the eye disorder and / or disease is an acute or chronic eye disorder and / or disease. It includes degenerative diseases of the eye (such as blurred vision or decreased visual acuity, visual impairment, inflammation, and decreased contrast sensitivity).

[0013] In other embodiments of these devices, systems and methods, the eye disorder and / or disease is an ocular syndrome (e.g., glaucoma, age-related macular degeneration (AMD) including atrophic or exudative forms, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber disease, ophthalmic surgery, uveitis, hypertensive retinopathy, or processes that impair the function of one or more eyes via vascular or neurological mechanisms, and optic neuritis).

[0014] In further embodiments of these devices, systems, and methods, the eye disorder and / or disease is an acute or chronic eyelid disease, including blepharitis, periorbital wrinkles, seborrhea, or other eyelid skin diseases (e.g., psoriasis and eczema).

[0015] In further other embodiments of these devices, systems, and methods, the ocular disorder and / or disease is an acute or chronic conjunctival or corneal disease of the eye, including acute injury (such as exposure keratitis or UV keratitis), dry eye, viral infection, bacterial infection, corneal detachment, corneal edema, surgical incision, penetrating wound, episcleritis or scleritis.

[0016] In other further embodiments of these devices, systems, and methods, the eye disorders and / or diseases are acute or chronic anterior chamber and vitreous diseases, including iritis, vitritis, and endophthalmitis (bacterial and sterile).

[0017] In at least some embodiments, the device is adapted to provide PBM treatment to subjects experiencing symptoms associated with one or more eye disorders or diseases, or to subjects diagnosed with one or more eye disorders or diseases caused by the subject's eye, along with any angular approach that provides access to opening and closing eyelids, sclera, or target tissue. The device may include a controller that can operate in response to signals from an independent, independent, or remote control system. The controller may activate one or more light sources suitable for delivering light to the subject's eye tissue.

[0018] In at least some embodiments, the apparatus, systems, and methods described herein can be used to treat or improve the effects resulting from or associated with eye conditions such as acute or chronic eye diseases. In at least some embodiments, the apparatus, systems, and methods described herein can be used to treat or improve symptoms or effects associated with degenerative eye diseases (such as blurred vision or decreased visual acuity, visual impairment, inflammation, ischemia, anatomical deposits (e.g., lipofusion, β-amyloid, or drusen), and decreased contrast sensitivity).

[0019] According to some embodiments, the apparatus, systems, and methods described herein can be used to treat or address subjects having or experiencing symptoms of acute or chronic ocular syndromes (e.g., glaucoma, atrophic or exudative age-related macular degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, central serous retinopathy (CRS), non-arteritic anterior ischemic optic neuropathy (NAION), Leber disease, ophthalmic surgery, uveitis, hypertensive retinopathy, or processes that impair the function of one or more eyes via vascular or neurological mechanisms, and optic neuritis).

[0020] The apparatus and methods described herein may also be used to treat or manage subjects with acute and chronic conjunctival or corneal diseases of the eye, including any acute injury (such as exposure keratitis or UV keratitis), dry eye, viral infection, bacterial infection, corneal detachment, corneal edema, surgical incision, penetrating wound, episcleritis, and scleritis. The apparatus and methods described herein may also be used to treat or manage subjects with acute or chronic anterior chamber and vitreous diseases, including iritis, vitritis, and endophthalmitis (bacterial and sterile). Classification is determined based on the affected area or etiology, and it should be understood that some disorders, diseases, or conditions may overlap between two or more classifications.

[0021] In one embodiment, the present disclosure provides a self-contained device for delivering phototherapy to a patient's eye tissue. The device includes a housing having an interior; an eyepiece disposed on the housing and configured and positioned for placement of a patient's eye adjacent to the eyepiece; a first light source disposed within the housing for generating a first ray having a first therapeutic wavelength; and a second light source disposed within the housing for generating a second ray having a second therapeutic wavelength, wherein the second therapeutic wavelength differs from the first therapeutic wavelength by at least 25 nm. The device is configured and positioned to direct the first and second rays through an aperture and the eyepiece to deliver phototherapy to the patient's eye.

[0022] In another embodiment, the present disclosure provides a self-contained device for delivering phototherapy to the ocular tissue of a patient's eye. The device includes a housing having an interior; an eyepiece disposed on the housing and configured and positioned for placement of a patient's eye adjacent to the eyepiece; a first light source disposed within the housing for generating a first ray having a first therapeutic wavelength; a second light source disposed within the housing for generating a second ray having a second therapeutic wavelength, the second therapeutic wavelength being at least 25 nm different from the first therapeutic wavelength; and a reflective filter disposed within the housing, configured and positioned to substantially allow light having the first therapeutic wavelength to pass through and to substantially reflect light having the second therapeutic wavelength. The device is configured and positioned to direct the first and second rays toward the reflective filter and then through the eyepiece to deliver phototherapy to the patient's eye.

[0023] In other embodiments, the present disclosure provides a wearable device for delivering PBM therapy to the ocular tissue of a patient's eye. Such a wearable device includes a frame, which includes an anterior piece and two earpieces extending from the anterior piece; a first light source, which generates a first ray having a first therapeutic wavelength and is disposed within or on the frame; and a second light source, which generates a second ray having a second therapeutic wavelength and is disposed within or on the frame, wherein the second therapeutic wavelength differs from the first therapeutic wavelength by at least 25 nm. When a patient wears the wearable device, at least some of the first and second rays are directed toward the patient's eye.

[0024] A related embodiment is a wearable device for delivering PBM therapy to the ocular tissue of a patient's eye. The device includes a frame comprising an anterior piece and two earpieces extending from the anterior piece; at least one light source disposed within the frame that generates a ray having a therapeutic wavelength; a spatial light modulator disposed within the frame and positioned to receive and modulate the ray to generate a modulated ray; and an optical directional element that, when the patient wears the device, receives the modulated ray and directs at least a portion of the modulated ray toward the patient's eye.

[0025] In further embodiments, this disclosure provides a method for providing phototherapy to a patient's ocular tissue using any of the instruments, apparatus, or systems described herein. In a particular embodiment, the method includes placing at least one of the patient's eyes in the eyepiece of the apparatus and directing at least one of a first therapeutic wavelength or a second therapeutic wavelength from the apparatus toward at least one of the patient's eyes to produce a therapeutic effect. In other embodiments, the method includes placing a wearable device on the patient and directing at least one of a first therapeutic wavelength or a second therapeutic wavelength from the device toward at least one of the patient's eyes to produce a therapeutic effect. [Brief explanation of the drawing]

[0026] These and other aspects of the present disclosure will be better understood in connection with the following drawings, which illustrate specific aspects of various embodiments. [Figure 1A] This is an oblique rear view of one embodiment of an ocular phototherapy device according to the present disclosure. [Figure 1B] Figure 1A is a front view of the eye phototherapy device in accordance with this disclosure. [Figure 1C] This is a side view of the eye phototherapy device shown in Figure 1A, in accordance with this disclosure. [Figure 1D] Figure 1A shows a side view of the eye phototherapy device and a patient, in accordance with this disclosure. [Figure 2] This is a side view of one embodiment of a second embodiment of an ophthalmic phototherapy device equipped with a chin rest, in accordance with the present disclosure. [Figure 3A] This is an oblique rear view of a third embodiment of an ocular phototherapy device having a removable patient interface, in accordance with the present disclosure. [Figure 3B] Figure 3A is an oblique side view of the eye phototherapy device in accordance with this disclosure. [Figure 4] This is a schematic cross-sectional view of one embodiment of a photoengine for use with a phototherapy device, in accordance with the present disclosure. [Figure 5] Figure 4 is a schematic cross-sectional view of one embodiment of an optical engine having additional optical components for use with a phototherapy device in accordance with the present disclosure. [Figure 6A] This is a side perspective view of one embodiment of an optical component for use with a phototherapy device, in accordance with the present disclosure. [Figure 6B] Figure 6A is a side perspective view of the optical components showing light directed toward the patient's left eye, in accordance with this disclosure. [Figure 6C] Figure 6A is a side perspective view of the optical components showing light directed toward the patient's right eye, in accordance with this disclosure. [Figure 7] This is a schematic block diagram of the components of one embodiment of a system for providing phototherapy in accordance with this disclosure. [Figure 8] This is a schematic block diagram of the use of a spatial light modulator in a phototherapy system in accordance with this disclosure. [Figure 9] This is a perspective side view of one embodiment of a wearable eye phototherapy device according to the present disclosure. [Figure 10A] This is a rear / oblique side view of a second embodiment of a wearable ocular phototherapy device in accordance with the present disclosure. [Figure 10B] Figure 10A is a rear view of the eye phototherapy device in accordance with this disclosure. [Figure 11A] This is an oblique posterior / side view of a third embodiment of a wearable ocular phototherapy device according to the present disclosure. [Figure 11B] Figure 11A is a front / side view of the ocular phototherapy device in accordance with this disclosure. [Figure 11C] Figure 11A is a rear view of the eye phototherapy device in accordance with this disclosure. [Figure 11D] This is a side view of the eye phototherapy device shown in Figure 11A, in accordance with this disclosure. [Figure 11E] Figure 11A is a cross-sectional view of the eye phototherapy device, showing the direction of light traveling to the wearer's eye, in accordance with this disclosure. [Figure 12A] This is an oblique posterior / side view of a fourth embodiment of a wearable ocular phototherapy device in accordance with the present disclosure. [Figure 12B] This is an oblique posterior / side view of a fifth embodiment of a wearable ocular phototherapy device according to the present disclosure. [Figure 12C] This is a plan view of the eye phototherapy device shown in Figure 12A or Figure 12B, indicating the direction of light traveling to the wearer's eye, in accordance with this disclosure. [Figure 13A] This is an oblique posterior / side view of a sixth embodiment of a wearable ocular phototherapy device according to the present disclosure. [Figure 13B] Figure 13A is a plan view of the eye phototherapy device in accordance with this disclosure. [Figure 13C] This is a side view of the eye phototherapy device shown in Figure 13A, in accordance with this disclosure. [Figure 13D] This is an enlarged view of the projection system of the ocular phototherapy device shown in Figure 13A, in accordance with this disclosure. [Figure 14A]This is an oblique posterior / side view of a seventh embodiment of a wearable ocular phototherapy device according to the present disclosure. [Figure 14B] Figure 14A is a plan view of the ocular phototherapy device in accordance with this disclosure. [Figure 14C] Figure 14A is a side view of the ocular phototherapy device in accordance with this disclosure. [Figure 14D] This is an enlarged view of the projection system of the ocular phototherapy device shown in Figure 14A, in accordance with this disclosure. [Figure 15] This is a schematic block diagram of the components of one embodiment of a system for providing phototherapy in accordance with this disclosure. [Figure 16] This bar graph shows the mean values ​​of contrast sensitivity at pre-treatment (0) and at 2, 4, 6, and 12 months (cpd; log units) for all patients undergoing multi-wavelength photobiomodulation therapy according to the system and methods of this disclosure (described in Example 1). N=18. Repeated measures ANOVA (1.5 cycles / degree): F(4,68)=4.39, p <0.0032 (i.e., statistically significant). [Figure 17] This bar graph of contrast sensitivity in 3cpd (log units) shows the mean contrast sensitivity values ​​for all patients undergoing multiwavelength photobiomodulation therapy according to the system and method of this disclosure (described in Example 1), pre-treatment (0) and 2, 4, 6, and 12 months post-treatment. N=18. Repeated measures of ANOVA of contrast sensitivity (3 cycles / degree): F(4,68)=11.44, p <0.0001 (i.e., statistically significant). [Figure 18] A bar graph of ETDRS visual acuity (in logMAR units) shows the mean LogMAR ETDRS values ​​for all patients undergoing multiwavelength photobiomodulation therapy according to the system and methods of this disclosure (described in Example 1), pre-treatment (0) and at 2, 4, 6, and 12 months post-treatment. N=18. Repeated measures ANOVA, output F(4.68)=18.86, p <0.0001 (i.e., statistically significant). [Figure 19]These are optical coherence tomography (OCT) data (described in Example 2 and summarized in Table 1) (representative of the data) showing retinal scans and locations (Figure 19A) and retinal thickness (Figure 19B) particularly in the central macula of a patient with atrophic adult-onset macular degeneration (atrophic AMD) who underwent a multi-wavelength photobiomodulation therapy process according to the system and methods of this disclosure. [Figure 20] This graph shows the percentage of eyes that achieved improvement in the visual acuity (VA) ETDRS line after 3 weeks of treatment, 3 times per week. A t-test comparison between baseline mean VA letter values ​​before treatment and mean VA letter values ​​after 3 weeks of treatment was statistically significant (p<0.05). N=41 eyes. [Figure 21] This graph shows the change in visual acuity (VA) letter values ​​(change from baseline) in individual patients after 3 weeks of treatment, 3 times per week. A t-test comparison between baseline VA letter values ​​before treatment and VA letter values ​​after 3 weeks of treatment was statistically significant (p<0.05). N=41 eyes. [Figure 22] This graph shows the anatomical and pathological reduction (drusen volume) following a photobiomodulation ("PBM") treatment protocol according to the method disclosed herein. Data were obtained from individual patients after 3 weeks of treatment, 3 times per week. A t-test comparison between baseline drusen volume before treatment versus drusen volume after 3 weeks of treatment was statistically significant; p<0.05. N=41 eyes. These data demonstrate the therapeutic effect of PBM treatment by the method disclosed herein. [Figure 23] This table summarizes the mean visual acuity, contrast sensitivity, and central drusen at baseline, 3 weeks, and 3 months after PBM treatment. The data presented are mean values ​​from the patient population + / - standard deviation (SD). [Figure 24] This is a schematic flowchart of one embodiment of a multiwavelength phototherapy system and method for improving or restoring the function of target cells, which promotes the activity of two or more photosensitive factors by tuned and targeted delivery of two or more different wavelengths of light to cells, thereby improving or restoring the function of target cells. [Figure 25]This is a schematic flowchart of one embodiment of a multi-wavelength phototherapy apparatus, system, and method for stimulating cytochrome c oxidase (CCO) activity in cells having two or more photosensitive factors associated with and required for CCO activity, by the controlled and targeted delivery of two or more light doses. The first light dose has a first wavelength that can activate a first photosensitive factor of CCO, and the second light dose has a second wavelength that can activate a second photosensitive factor of CCO, thereby stimulating CCO activity. [Figure 26] This is a schematic flowchart of one embodiment of a multiwavelength phototherapy apparatus, system, and method for treating patients suffering from disorders or diseases associated with one or more lost or reduced cellular functions, by tuned and targeted delivery of two or more different wavelengths of light to one or more cells of the patient, in order to restore lost or reduced cellular functions and thereby treat the disorder or disease. [Figure 27] This is a schematic flowchart of one embodiment of a multiwavelength phototherapy apparatus, system, and method for the treatment of patients suffering from eye disorders or diseases associated with the loss or reduction of cellular function of one or more cells of the eye. The system and method includes the tuned and targeted delivery of two or more different wavelengths of light to the patient's eye in order to restore and / or enhance the lost and / or reduced function of cells of the eye, thereby treating the eye disorder or disease. [Figure 28] This figure shows the principle measurement locations used in the cadaver test disclosed herein and detailed in Example 4. [Figure 29] This graph shows the average fluence rate (eyes open) obtained from the cadaver test disclosed herein and detailed in Example 4. [Figure 30] This graph shows the average fluence rate (eyes closed) obtained from the cadaver test disclosed herein and detailed in Example 4. [Figure 31] This is a graph of the peak wavelength shift as a function of case temperature (°C) for the red LED light source used in the cadaver test disclosed herein and detailed in Example 4. [Modes for carrying out the invention]

[0027] The multi-wavelength phototherapy devices, systems, and methods described in further detail herein are based on the discovery that specific cellular responses, including cellular responses within damaged and / or diseased tissue, can be facilitated by the tuned and targeted delivery to cells of light having two different wavelengths. A first dose of light having a first wavelength (or range of wavelengths) can stimulate a first intracellular activity, and a second dose of light having a second wavelength (or range of wavelengths) can stimulate a second intracellular activity. Further specific therapeutic effects can be achieved in patients suffering from damaged and / or diseased tissue by facilitating desired cellular responses that are involved in healing damaged tissue and / or reversing or slowing the progression of disease in diseased tissue.

[0028] Photobiomodulation ("PBM") is a non-invasive form of low-level phototherapy ("PBM"), including the treatment of light energy to a subject (e.g., human or animal). It uses lower irradiation intensities than those used in cutting, cauterizing, or excising biological tissue, while leaving undamaged tissue to produce the desired photobiomodulation effect. In non-invasive phototherapy, it is desirable to use a light source positioned outside the body to apply an effective amount of light energy to the internal tissue being treated (see, for example, U.S. Patents 6,537,304 and 6,918,922, both of which are incorporated herein by reference in their entirety).

[0029] Therapeutic effects can be achieved in patients suffering from damaged and / or diseased tissue by promoting one or more cellular responses within the cells of the damaged and / or diseased tissue. These cellular responses can be promoted by the regulated and targeted delivery of two or more light doses. A first light dose having a first wavelength or wavelength range can stimulate a first intracellular activity, and a second light dose having a second wavelength or wavelength range can stimulate a second intracellular activity. The regulated stimulation of the first and second intracellular activities promotes the desired cellular response, thereby facilitating the healing of damaged tissue and / or reversing or slowing the progression of disease in diseased tissue.

[0030] In the non-invasive or minimally invasive multiwavelength phototherapy devices, systems, and methods disclosed herein, an effective amount of light energy is delivered to internal tissue from one or more light sources, as exemplified herein, by eye tissue. The light sources are (1) located externally to the body (i.e., non-invasive) or subcutaneously within the body (i.e., minimally invasive), and (2) capable of generating light having different and specific wavelengths and / or frequency ranges. In particular, the multiwavelength phototherapy systems and methods disclosed herein use light having a first wavelength or range of wavelengths that can stimulate a first photosensitive factor, and light having a second wavelength or range of wavelengths that can stimulate a second photosensitive factor. Targeted and tuned delivery of light having the first wavelength and light having the second wavelength facilitates a cellular response within the target tissue, thereby facilitating the healing of damaged tissue and / or reversing or slowing disease progression in diseased tissue.

[0031] As will be described in more detail herein, when delivered alone, such multiwavelength phototherapy devices, systems, and methods provide therapeutic effects. The therapeutic effects can be further enhanced when these systems and methods are used in combination with one or more small molecule drugs and / or biological agents, and / or in combination with a second therapeutically suitable device and / or other treatment regimen. Drugs, biological agents, devices, and / or treatment regimens may be administered to the patient before, simultaneously with, and / or after the targeted and adjusted delivery of multiwavelength phototherapy.

[0032] Light exhibiting a single wavelength or frequency range, for example, red light with a wavelength of 600–700 nm, or near-infrared light ("NIR") with a wavelength of 800–900 nm, can be used to stimulate mitochondrial cytochrome c oxidase ("CCO") enzyme activity. As disclosed herein, the targeted and tuned use of two or more light sources, each having a different wavelength and intensity, can produce substantially improved, unique, additional, or synergistic therapeutic effects. In some embodiments, the therapeutic effect may be greater than the therapeutic effect of each wavelength of light alone when isolated and delivered to cells and / or tissues of interest, and / or when delivered in an untargeted, untuned manner.

[0033] More specifically, different wavelengths of light can stimulate structurally and functionally distinct regions within the protein of a target cell (e.g., the CuA and CuB portions of mitochondrial cytochrome c oxidase ("CCO")). It is recognized as part of this disclosure that by temporally adjusting the delivery of two or more wavelengths of light to the CuA and CuB portions of mitochondrial CCO, electron flow and oxygen binding mediated by the CCO enzyme can be optimized independently, sequentially, or in combination to (a) substantially improve overall CCO activity, (b) restore mitochondrial membrane potential ("MMP"), and (c) increase the level of ATP synthesis. Furthermore, such temporally adjusted and targeted delivery of multiple wavelengths of light substantially enhances the therapeutic efficacy of the aforementioned single-wavelength phototherapy systems and methods.

[0034] Therefore, the multi-wavelength phototherapy apparatus, systems, and methods of this disclosure can be advantageously used to restore the mitochondrial membrane potential (MMP) and / or increase ATP production in damaged and / or diseased tissues. Damaged and / or diseased tissues exhibit reduced properties in oxygen access.

[0035] As described in further detail herein, this disclosure envisions that targeted and tuned delivery of light having wavelengths, for example, about 640 nm to about 700 nm, activates the CCO CuB moiety, thereby detaching one or more CCO inhibitors (e.g., vasodilatory NO) occupying one or more CCO oxygen-binding sites. Thus, local release of NO from mitochondria can be used to improve local blood flow, thereby increasing O2 and nutrient levels in damaged and / or diseased tissues. Targeted delivery of light having wavelengths about 640 nm to about 700 nm can also be used to preferentially increase O2 binding affinity at the CCO active site, thereby stimulating ATP electron transport and aerobic synthesis.

[0036] As a further example, this disclosure also provides delivery of near-infrared ("NIR") light (i.e., light having wavelengths of approximately 800 nm to approximately 900 nm). NIR light exhibits therapeutic effects by facilitating photomediated electron transfer from cytochrome C to CCO, thereby improving the efficiency of electron flow and restoring mitochondrial membrane potential (MMP).

[0037] Accordingly, this disclosure provides apparatus, systems, and methods for using light having two or more different wavelengths or wavelength ranges. The systems and methods include tuned delivery. It includes both simultaneous and temporally tuned delivery of multiple wavelengths of light having predetermined optical parameters (e.g., duration of delivery, frequency of delivery, continuous delivery, pulsed delivery, and fluence level of delivery), thereby providing individualized therapeutic regimens. It is optimized to restore, promote, and / or enhance mitochondrial function, thereby facilitating the recovery of damaged tissue and / or reversing or delaying the progression of disease in diseased tissue.

[0038] As described herein, various embodiments of such multi-wavelength phototherapy devices, systems, and methods can be modified to affect key intracellular mediators (e.g., ATP, GTP, nitric oxide (NO), and / or reactive oxygen species (ROS)). Each is used by cells that transmit intracellular stimuli via one or more signaling pathways, thereby modulating downstream cellular activity / function.

[0039] The ability of the apparatus, systems, and methods of this disclosure to control this type of second messenger-mediated cellular pathway provides an opportunity to influence important regulatory mechanisms of cellular activity. For example, protein kinases represent a major type of enzyme that results in the phosphorylation of protein targets. ATP, the active substrate of protein kinases, transfers high-energy phosphorus bonds to protein targets. Thus, protein activity can be increased or decreased by phosphorylation of target proteins at one or more sites. As a result, enzyme activity and / or cellular pathways can be controlled by the effectiveness of ATP to the cell and the level of ATP within the cell. For example, this can be achieved by the suppression or activation of one or more protein targets by one or more protein kinases.

[0040] As part of this disclosure, we have found that the use of multiple wavelengths of light offers unique opportunities for treating damaged and / or diseased tissues by modulating signaling, mediating protein kinase activity, improving cellular performance, and restoring cellular function.

[0041] The multiwavelength phototherapy devices, systems, and methods disclosed herein can be readily adapted to modulate and control cellular gene expression and to restore cellular function in damaged and / or diseased tissues. Gene expression patterns are used by cells to modulate and control numerous pathways that subsequently affect cellular activity. For example, multiwavelength phototherapy systems and methods can be adapted for use in altering the gene expression patterns of multiple genes associated with cellular metabolism. In the regulation of multiple genes associated with electron chain transport, energy metabolism and oxidative phosphorylation can be utilized to restore cellular metabolic capacity and / or stimulate ATP production. It can stimulate other pleiotropic expression processes, collectively facilitating the long-term improvement and / or normalization of one or more cellular functions. In relevant embodiments, the multiwavelength phototherapy systems and methods disclosed herein can also be adapted to affect NFκβ, inflammatory pathways, and key cellular regulators of gene expression.

[0042] Based on these and other discoveries detailed herein, this disclosure provides: 1. A multi-wavelength phototherapy apparatus, system, and method for providing a method for stimulating cytochrome c oxidase (CCO) activity in cells and / or tissues. The method comprises the regulated delivery of two or more light doses to cells having two or more photosensitive factors associated with CCO activity. Each light dose has a different wavelength or frequency range. The wavelength of the first light can stimulate a first photosensitive factor, and the wavelength of the second light can stimulate a second photosensitive factor, thereby improving and / or restoring the function of one or more target cells, particularly target cells within a target tissue. 2. Multiwavelength phototherapy apparatus, systems, and methods for improving and / or restoring the function of one or more target cells. The system and method comprises tuned and targeted delivery of two or more different wavelengths of light to cells and / or tissues, thereby promoting the activity of two or more photosensitive molecules, thereby improving and / or restoring the function of one or more target cells, particularly target cells within target tissues. 3. Multiwavelength phototherapy apparatus, systems, and methods for the treatment of patients suffering from disorders and / or diseases associated with one or more lost and / or reduced cellular functions. The system and method comprises tuned and targeted delivery of two or more different wavelengths of light to one or more cells of a patient, thereby restoring lost and / or enhancing reduced cellular functions, thereby treating disorders and / or diseases. 4. Multiwavelength phototherapy apparatus, systems, and methods for the treatment of patients suffering from ocular disorders and / or diseases associated with the loss and / or reduced function of one or more ocular cells. The system and method comprises tuned and targeted delivery of two or more different wavelengths of light to the patient's eye to restore and / or enhance the function of the lost and / or reduced ocular cells, thereby treating the disorder and / or disease.

[0043] These and other aspects of this disclosure can be further understood by referring to the following non-limiting definitions.

[0044] definition While the following terms are expected to be readily understood by those skilled in the art, the following definitions are provided to facilitate the explanation of the contents disclosed herein.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the disclosures herein pertain. Any methods, apparatus, and materials similar or equivalent to those described herein may be used to carry out or test the disclosures herein, but representative methods, apparatus, and materials are described herein.

[0046] Unless otherwise indicated, all numerical values ​​used herein and in the claims, representing ingredient amounts, reaction conditions, etc., should be understood in all cases to be modified by the word “approximately.” Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximate values ​​that can be modified depending on the desired properties to be obtained by this disclosure. Where used herein, “approximately” means a value, or an amount of mass, weight, time, volume, concentration, or percentage, and means that the specified amount may include a difference of ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% in some embodiments, such differences being appropriate for carrying out the disclosed method.

[0047] Unless otherwise specified, terms are intended to be "open" (for example, the term "contains" must be interpreted as "contains, but not limited to," the term "has" must be interpreted as "has at least," and the term "includes" must be interpreted as "includes, but not limited to," etc.). For example, the phrases "at least one" and "one or more," as well as terms such as "a" or "an," both include singular and plural. When used in this application, including in the claims, according to long-standing patent law practice, the terms "a," "an," and "the" mean "one or more." That is, for example, a reference to "cells" includes multiple such cells, etc.

[0048] For example, conditional language such as “can,” “could,” “might,” and “may,” unless otherwise specified or understood within the context in which they are used, is typically intended to convey that a particular embodiment includes certain features, elements, and / or processes, but other embodiments do not. Therefore, such conditional language is generally not intended to mean that one or more embodiments necessarily include the logic for determining whether features, elements, and / or processes are required in any one or more embodiments, or whether they are included or performed in any particular embodiment, with or without user input or instructions.

[0049] If the characteristics or aspects of the disclosure are described in relation to the Markush group, it will be further understood that the disclosure is also intended to describe in relation to individual parts or subgroups of the Markush group.

[0050] All documents cited herein, including, but not limited to, patents, patent applications, patent publications, and all technical and / or scientific publications, whether in the United States, the PCT, or other foreign countries, are incorporated herein by reference in their entirety, whether mentioned above or below.

[0051] As used herein, the term “phototherapy” means the therapeutic delivery of light energy to a subject (e.g., human or other mammal) to achieve one or more therapeutic effects. The term “phototherapy” includes “low-level phototherapy” or “PBM,” which means the therapeutic delivery of light energy at an irradiation level that is or exceeds an irradiation level capable of promoting one or more desired biostimulatory effects, or below an irradiation level capable of cutting, cauterizing and / or excising biological tissue. See U.S. Patents 6,537,304 and 6,918,922, which are incorporated herein by reference in their entirety.

[0052] As used herein, the term “light source” means an element of a phototherapy device (also known as a phototherapy device) configured to provide an optical output (for example, to deliver light from the phototherapy device to a target tissue such as the eye tissue of a patient). As used herein, the term “red light” means light having a wavelength of approximately 640 nm to approximately 700 nm, and the term “near-infrared” or “NIR” means light having a wavelength of approximately 800 nm to approximately 900 nm.

[0053] As used herein, the terms “cytochrome c oxidase,” “CCO,” “complex IV,” and “EC1.9.3.1” refer to large transmembrane protein complexes that originate in mitochondria and are located within the mitochondrial membrane of eukaryotic cells. CCO is the final enzyme in the mitochondrial respiratory electron transport chain—receiving electrons from each of the four cytochrome c molecules, transferring them to oxygen molecules, and converting the molecular oxygen into two water molecules. CCO binds four protons from the inner aqueous phase to form water, translocates the four protons across the membrane, thereby establishing the electrochemical potential of the transmembrane protons, which are then used by ATP synthase in ATP synthesis.

[0054] As used herein, the terms “treatment,” “treatment,” “therapeutic regimen,” and “therapeutic regimen” mean therapeutic systems and methods that promote the healing of damaged tissue and / or reverse or slow the progression of disease in diseased tissue, which can be achieved by restoring the function of one or more cells in the damaged and / or diseased tissue. The terms “treatment,” “treatment,” “therapeutic regimen,” and “therapeutic regimen” include protocols and associated procedures used to provide a therapeutic system or method, and include one or more periods of irradiating one or more target cells and tissues, including ophthalmic cells and tissues, with light.

[0055] As used herein, the terms “target,” “target area,” and “target region” mean a specific area, region, location, structure, population, or projection of the eye within a tissue (e.g., the retina or optic nerve) to which light is delivered in connection with the treatment of a particular condition, disease, disorder, or injury (e.g., a condition, disease, disorder, or injury of the eye). In certain embodiments, the irradiation site of a tissue such as the eye may include all tissue. In other embodiments, the irradiation site of a tissue may include a target region of the tissue (e.g., a retinal region, macula, or cornea of ​​the eye).

[0056] As used herein, the term “degeneration” generally refers to the process of cellular destruction resulting from a major destructive event (e.g., trauma or surgery) and from persistent, delayed, and progressive destructive mechanisms by cells due to a major destructive or disease event.

[0057] As used herein, the term “major destructive event” means a disease process or a physical injury or invasive event, including surgery, but also includes other diseases and conditions. In the case of eye disorders and diseases, this may include glaucoma, age-related macular degeneration, diabetic retinopathy, CRS, NAION, Leber disease, ophthalmic surgery, uveitis, cerebral ischemia including focal optic nerve ischemia, and physical trauma, including any acute injury or invasive event resulting in contusion or compression injury to the ophthalmic nerve or retina or degeneration of the eye (e.g., contusion or compression injury to ocular tissue).

[0058] As used herein, the term “secondary disruption mechanism” means any mechanism, but not limited to, that leads to apoptosis, deficiency of cellular energy storage due to altered mitochondrial membrane permeability, release or failure of reuptake of excess glutamate, free radical damage, reperfusion injury, accumulation of insoluble proteins including lipofuscin and β-amyloid, and the generation and release of neurotoxic molecules, including complement, cytokine and inflammatory state activity.

[0059] As used herein, the term “cytoprotective effect” means a therapeutic strategy that slows or prevents other irreversible loss of target tissue, such as ocular tissue, due to degeneration following a major destructive event, regardless of whether the tissue degeneration loss is due to a disease mechanism associated with the major destructive event or a secondary destructive mechanism.

[0060] Both primary and secondary mechanisms contribute to the formation of "hazard zones," and tissues within these hazard zones that survive a primary destructive event remain at risk of death due to one or more processes with sequelae.

[0061] As used herein, the term “recovery” means an increase in the function of a cell (e.g., a cell from damaged and / or diseased tissue) to a level equal to or higher than that of a comparable normal cell (e.g., a cell from comparable undamaged and disease-free tissue, such as tissue from a healthy individual).

[0062] As used herein, the terms “significance” or “significant” mean a statistical analysis of the probability that there is a non-random association between two or more entities. To determine whether a relationship is “significant” or “significant,” statistical manipulation of the data may be performed to calculate a probability expressed as a “p-value.” Such a p-value below a user-defined cutoff point may be considered significant. In some embodiments, p-values ​​less than or equal to 0.05, in some embodiments less than 0.01, in some embodiments less than 0.005, and in some embodiments less than 0.001 may be considered significant.

[0063] As used herein, the term “diagnosed” means a determination made with respect to damaged and / or diseased tissue. A diagnosis may be made before using or performing this multiwavelength phototherapy system and method.

[0064] For example, conditional language such as “can,” “could,” “might,” and “may” is generally intended to convey that a particular embodiment includes a particular feature, element, or process, but other embodiments do not, unless otherwise specified or understood within the context in which they are used. Therefore, such conditional language is generally not intended to mean that one or more embodiments necessarily include the logic for determining whether a feature, element, or process is required in any one or more embodiments, or whether such features, elements, or processes are included or performed in any particular embodiment, with or without user input or instructions. The term “or” is inclusive unless otherwise specified.

[0065] light delivery device In certain embodiments, this disclosure provides multiwavelength phototherapy devices for the eye and associated treatment methods, including self-contained and wearable multiwavelength phototherapy devices for the eye. These devices and methods expose the eye to selected wavelengths of light that can promote the healing of damaged or diseased eye tissue. For example, self-contained devices or devices for use in a facility, or wearable devices for use at home or elsewhere, can deliver therapeutic, individually controlled multiwavelength combinations of low-level light to eye tissue. Treatment may include, for example, targeting damaged or diseased tissue with an ophthalmic device capable of delivering multiwavelength phototherapy on its own. Devices and sensors or other imaging techniques can be used to establish optimal spatial and tissue parameters of the eye to provide effective eye treatment. In at least some embodiments, multiwavelength devices are used in combination with other pharmaceuticals or devices to enhance or personalize phototherapy to eye tissue.

[0066] The tuning of selected wavelengths, their independent use, and the application of selected combinations of multi-wavelength PBMs can create highly targeted and beneficial cellular responses. In at least some embodiments, therapeutic approaches to treat ocular diseases or disorders can provide desired therapeutic utility by combining only two or more wavelengths, or by using one or more wavelengths in combination with a medical device and a biological agent or pharmaceutical.

[0067] The use of individual wavelengths (e.g., red light (640–700 nm) or near-infrared (NIR) light (800–900 nm)) can independently stimulate mitochondrial cytochrome c oxidase (CCO) enzyme activity, as found in both in vitro and in vivo experimental studies. However, individual wavelengths have been found to target different copper sites (e.g., CuA and CuB) within the multi-subunit of CCO, resulting in different biological responses. Therefore, the tuned use of both wavelengths in combination to target CuA and CuB, and to successively enhance both electron transfer and oxygen binding on the CCO enzyme, can improve the overall therapeutic effect of CCO in at least some embodiments. The efficiency of CCO activity, the restoration of mitochondrial membrane potential (MMP), and the improvement of adenosine triphosphate (ATP) synthesis may all be closely related. This multi-wavelength approach may be used in at least some embodiments to restore MMP or increase ATP production (e.g., in diseases or disorders where oxygen deficiency or limited utilization is observed).

[0068] In one embodiment, when blood flow is restricted, the use of a single wavelength (in the range of 640-700 nm over CuB) can first transfer inhibitors such as nitric oxide (NO) from oxygen-binding sites. NO is a potent vasodilator, and local NO release from mitochondria improves local blood flow by increasing O2 and nutrients in the diseased tissue area. Furthermore, stimulation with light having wavelengths in the range of 640-700 nm can stimulate electron transport and oxygenation (ATP) by preferentially increasing O2 binding affinity at the active site. In another example, when electron chain transfer from cytochrome C to CCO is dysfunctional, a more viable pathway to resolve ATP production can target CuA therapy by NIR at, for example, 810 nm (or in the range of 800-900 nm), which can provide improved efficiency of electron flow through photomediated electron transfer from cytochrome C and MMP recovery.

[0069] In some embodiments, the simultaneous or sequential use of predetermined optical parameters (e.g., duration, frequency, continuous or pulsed, fluence level, etc.) can provide a therapy for restoring mitochondrial function. The use of independently controlled multi-wavelength phototherapy can enable enhancement or optimization of therapeutic efficacy and can monitor or adjust to the impaired or diseased state.

[0070] The use of multiwavelength phototherapy can be adjusted as needed to achieve important intracellular mediation. ATP, guanosine triphosphate (GTP), NO, and reactive oxygen species (ROS) are all used by cells as active substrates for signal transduction, which is a known method for transmitting intracellular stimuli, thereby regulating numerous cellular pathways and subsequent cellular activities. The regulation of cellular pathways by specific secondary messengers can provide important regulatory mechanisms for cellular activity. Protein kinases represent the major type of enzyme that results in the phosphorylation of protein targets. ATP is the active substrate of protein kinases, which they use to transfer high-energy phosphorus bonds to target proteins. Protein activity can be increased or decreased by one or more phosphorylation sites. Therefore, enzyme or cellular pathway activity can be greatly regulated by the utilization of cellular ATP and ATP levels, and by the suppression or activation of specific protein targets by protein kinases.

[0071] The use of multiple light wavelengths can, for example, modulate signal transduction, mediate protein kinase activity, improve cellular performance, or restore cellular function in damaged or diseased tissue. The combined benefits of photons from one or more wavelengths facilitate the modulation of second messengers that influence specific pathways. For example, phototherapy, including the use of NO, ROS, or ATP monitoring in combination phototherapy, can establish properties suitable for photobiomodulation applications.

[0072] Separately, the use of multiple light wavelengths can be utilized to modulate and control gene expression in cells, thereby restoring cellular function in damaged or diseased tissues. Gene expression patterns are used by cells to modulate and control numerous pathways that affect subsequent cellular activity. Phototherapy (670 nm) is involved in altering gene expression patterns in multiple genes associated with cellular metabolism. In the regulation of multiple genes associated with electron chain transport, energy metabolism and oxidative phosphorylation are observed, thereby restoring cellular metabolic capacity and stimulating increased ATP production. This stimulates other pleiotropic expression processes, all of which lead to long-term improvement or normalization of cellular function. Phototherapy can affect NFκβ, inflammatory pathways, and major cellular regulators of gene expression. The combined benefits of photons from one or more wavelengths allow for the targeting and modulation of gene expression in specific pathways. Gene expression mapping in multi-wavelength phototherapy can be used to identify features suitable for photobiomodulation applications.

[0073] In at least some embodiments, the use of phototherapy in combination with gene therapy can stimulate, enhance, or control the regulation and expression of novel genes embedded in the nucleus by viral vectors or other gene therapy techniques. This differs from using light-activated gene products, as it utilizes selected wavelengths to naturally stimulate the cellular gene expression profile for newly implanted gene therapy. In at least some embodiments, the use of gene therapy can facilitate retinal tissue regeneration and provide gene therapy for mitochondrial genetic eye disorders (such as Leber optic neuropathy or AMD). In such cases, gene therapy combined with photobiomodulation that stimulates the expression of specific mitochondrial electron transport proteins can provide a better or optimized combination therapy approach.

[0074] Separately, RNA and protein expression patterns are used by cells to effectively regulate numerous pathways and subsequent cellular activity. Multiple light wavelengths can be used to indirectly regulate and improve RNA and protein expression, thereby restoring cellular function in damaged or diseased tissues. Protein mapping, in combination with phototherapy, can identify properties suitable for the application of photobiomodulation. AMD is considered a chronic inflammatory disease, and protein precipitates further exacerbate the inflammatory state and disease progression. Therefore, the use of multi-wavelength PBM can provide combination therapy. RPE cell experiments have shown that the use of 590 nm light suppresses VEGF expression, and therefore the use of 590 nm PBM (or another wavelength in the range of 500-650 nm) is useful in treating the exudative AMD subtype and can suppress local VEGF protein expression in ocular tissue.

[0075] VEGF antibody therapy (Lucentis®) is the currently approved drug treatment for exudative AMD. Separately, the use of 810 nm PBM (or other wavelengths in the 800-900 nm range) can improve mitochondrial function, reduce inflammatory markers, or prevent β-amyloid precipitation in mice with age-related Alzheimer's disease (or any combination of these effects). Furthermore, the use of 670 nm PBM (or other wavelengths in the 600-750 nm range) can reduce inflammatory markers such as complement C3 expression and precipitation in AMD mouse models, but does not affect β-amyloid precipitation. Both lipofusion and β-amyloid precipitation have been associated with the pathogenesis of diseased eyes in AMD patients. The multiwavelength PBM combination can be used alone or in combination with one or more agents (e.g., one or more anti-VEGF monoclonal antibodies (MAb) (Lucentis® and Avastin®)), anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs), anti-complement agents (e.g., Properidin, C3, MASP-2, C5 inhibitors), antioxidants or vitamins (e.g., AREDS supplements (Lipotriad Visonary®, Viteyes2®, ICaps® and PreserVision®, containing similar components in different ratios or with additional components)), or visual cycle disruptors (e.g., isomerase inhibitors (ACU-4429)).

[0076] In at least some embodiments, targeted use of phototherapy to improve mitochondrial function through increased CCO activity, MMP recovery, and regulation of ATP synthesis can be achieved using multiple wavelengths of light to generate local cellular responses favorable to injury or disease. Local cellular states in trauma and disease may differ in different tissue or organ regions and are under dynamic local regulation. For example, phototherapy of local CCO activity may lead to the release of inhibitory NO from O2 binding sites. NO is a potent vasodilator and signal transducer that can regulate local blood flow to target tissue. This may be useful in reversing local ischemia or restricted blood flow in injured or diseased tissue.

[0077] In at least some embodiments, the treatment may include targeting tissues such as the retina and associated surrounding ocular tissues with phototherapy. For example, it may be most beneficial for treating isolated focal optic nerve ischemia seen in non-arteritic ischemic optic neuropathy (NAION). In another example, it may be most beneficial to target anatomical islands of cellular deposition that may be inflammatory, ischemic, or disease-related lesions in atrophic AMD. In early-stage AMD, isolated cellular deposition of lipofusions or drusen can be confirmed in the retina by standard imaging techniques (OCT, fluorescence imaging). In such embodiments, the use of imaging techniques (e.g., OCT or fluorescence) can be used to target multiwavelength phototherapy to slow the disease, stop or reverse protein (e.g., lipofusions or β-amyloid) deposition, thereby reducing, slowing, or stopping disease progression.

[0078] The application of these targeted phototherapies provides a disease-modifying approach to chronic eye diseases. The devices can generate phototherapy alone or in combination with OCT or several other imaging devices (e.g., PET, MRI, ultrasound, Doppler, fluorescence, femtosensors, etc.) as an approach to enhance, optimize, or personalize patient treatment by identifying the isolation region of the boundaries of target and target cells or tissues, either alone or in combination with wavelengths.

[0079] In another such embodiment, imaging techniques (e.g., femtosensors that monitor local retinal O2 concentration) can be used to identify AMD patients with local hypoxia, improve treatment in combination with phototherapy, and monitor increased O2 concentration to restore mitochondrial retinal function.

[0080] In at least some embodiments, the selection of wavelength, light dose, and therapeutic parameters can be varied depending on the underlying disease or disorder. Individual targeting of multiple wavelengths of light can be used for one or more localized phototherapy, personalized patient phototherapy, promoting restored cellular performance, or slowing or stopping the propagation of eye disease. These approaches can be performed alone, in conjunction with existing diagnostic devices, or as a means of combining phototherapy and diagnostic methods.

[0081] In at least some embodiments, photobiomodulation involves the selection of wavelength and dose parameters. Different wavelengths have individual tissue absorption characteristics, which affect the depth of penetration and the optimal dose for clinical efficacy. The device may include components (e.g., a camera or other sensors) that can be used to capture features of the patient's orbit, including depth, size, skin color, or distance. This makes it possible to set the dose for each wavelength individually or in combination with default values ​​to enhance or optimize the treatment parameters. In at least some embodiments, the sensor can be used to assist in the selection of the dose based on eyelid opening and closing, for example, taking into account tissue color or thickness.

[0082] In at least some cases, there is some intervening tissue between the light source and the target tissue. In at least some embodiments, the wavelength of light can be selected so that absorption by the intervening tissue is less than damaging. Such embodiments use a low but effective irradiation intensity (e.g., about 100 μW / cm²) at the target tissue site. 2 ~about 10W / cm 2This may include setting the output of the light source (between 2 and 3), or setting the temporal profile of the light applied to the tissue (e.g., temporal pulse width, temporal pulse shape, duty cycle, pulse frequency), or setting the duration of application of the light energy (hundreds of microseconds to minutes) to achieve an effective energy density at the target tissue site being treated. Other parameters can also be varied in the use of phototherapy. These other parameters are useful for the light energy that is actually delivered to the treated tissue and can affect the effectiveness of the phototherapy.

[0083] In at least some embodiments, the target region of the tissue in question includes, for example, the area of ​​damage to the optic nerve and surrounding ocular tissue. In some embodiments, the target region includes a portion of the eye.

[0084] In at least some embodiments, the phototherapy apparatus and methods described herein are used to treat eye disorders. As used herein, an eye disorder can mean at least one feature of an ocular syndrome (including, but not limited to, glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber disease, ophthalmic surgery, uveitis, and further signs described throughout this application) or symptoms exhibiting such a feature.

[0085] In at least some embodiments, the phototherapy apparatus and methods described herein are used to treat physical trauma (e.g., cataract or lens surgery) or other causes of inflammation or degeneration of the eye, or to assist in the rehabilitation of the effects of ocular degeneration resulting from physical trauma. Ocular degeneration can include processes of cellular breakdown resulting from secondary delayed and progressive destruction mechanisms caused by cells, for example, from a major destructive event (such as eye trauma or surgery), as well as from the occurrence of a major destructive or disease event.

[0086] Major destructive events may include physical injury or injury, including disease processes or surgery, as well as other diseases and conditions (e.g., glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber disease, ophthalmic surgery, uveitis, cerebral ischemia including focal optic nerve ischemia, and physical trauma (e.g., cerebral ischemia including focal optic nerve ischemia and physical trauma (e.g., contusions or compression injuries to ocular tissue, including contusions or compression injuries to the ocular nerve or retina, or any acute injury or invasiveness resulting in degeneration of the eye)).

[0087] Secondary disruption mechanisms may include, but are not limited to, any mechanisms leading to apoptosis, deficiency of cellular energy storage due to altered mitochondrial membrane permeability, release or failure of excessive glutamate reuptake, free radical damage, reperfusion injury, deposition of insoluble proteins including lipofuscin and β-amyloid, and the generation and release of neurotoxic molecules, including complement, cytokine, and inflammatory state activity. Both primary and secondary mechanisms contribute to the formation of “danger zones” in ocular tissue, where the tissue in these zones survives at least temporarily after the primary disruption event, but is at risk of death due to the lingering effects of the process.

[0088] In at least some embodiments, the apparatus and methods described herein are used to provide cytoprotective effects. Cytoprotective effects may include therapeutic strategies that slow or prevent other irreversible loss of ocular tissue due to degeneration after a major destructive event, regardless of whether the tissue degeneration loss is due to a disease mechanism associated with a major destructive event or a secondary destructive mechanism.

[0089] In at least some embodiments, the apparatus and methods described herein are used to improve eye function, provide eye enhancement, prevent or slow the progression of eye function loss, restore previously lost eye function, or any combination thereof. Eye function may include visual acuity function and contrast sensitivity function.

[0090] Diseases or conditions affecting the function of the eye include, but are not limited to, major destructive events, disease processes, or physical injuries or traumas (including age-related macular degeneration, as well as other diseases and conditions such as glaucoma, stroke, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber disease, ophthalmic surgery, uveitis, cerebral ischemia including focal optic nerve ischemia, and physical trauma (including cerebral ischemia including focal optic nerve ischemia and physical trauma, such as contusions or compressive injuries to ocular tissue, or any acute injury or invasiveness that causes degeneration of the eye)).

[0091] As used herein, the terms “therapeutic regimen” and “treatment regimen” mean protocols and associated procedures used to provide therapeutic treatment, comprising one or more periods during which light is irradiated onto one or more target areas of the eye. As used herein, the terms “target,” “target area,” and “target region” mean a specific area, region, location, structure, population, or projection (e.g., within the retina or optic nerve) of the eye to which light is irradiated in connection with the treatment of a particular eye condition, disease, disorder, or injury. In at least some embodiments, the irradiated area of ​​the eye may be the entire eye. In other embodiments, the irradiated area of ​​the eye is a target area of ​​the eye (e.g., a retinal region, macula, or cornea).

[0092] In at least some embodiments, the apparatus and methods described herein can be used to promote the proliferation, migration, and transfer of endogenous progenitor retinal stem cells for retinal or ocular diseases. Stem cells have both the ability to autogenerate and to produce postmittal cells. The retinal pigment epithelium (RPE) is a monolayer of cells that underlies and supports the neural retina. It begins as plastic tissue and, in some species, produces the lens and retina, but differentiates early in growth and usually remains nonproliferative throughout life. However, a subpopulation of adult RPE cells can be activated in vitro into autogenerating cells, retinal pigment epithelial stem cells (RPESCs) that lose the RPE marker, can proliferate extensively, and redifferentiate into a stable, cobblestone-like RPE monolayer. Clonal studies have demonstrated that RPESCs are pluripotent and, under certain conditions, can produce neural and mesenchymal offspring. This plasticity explains human pathology, where the fate of mesenchymal cells is seen in the eye, for example, in proliferative vitreoretinopathy (PVR) and ocular atrophy. Available human CNS-derived pluripotent stem cells, RPESCs, are useful in research on fate selection, replacement therapy, and disease modeling.

[0093] In at least some embodiments, the apparatus and methods described herein can be used to promote the proliferation, migration, and regenerative cellular properties, and subsequent proliferation of stem cells, for use in retinal or ocular diseases. Stem cell-centered therapies are being studied in the treatment of retinal degenerative diseases. Retinal stem cells have been isolated from several mammalian species, including humans. However, transplantation of these cells has been minimally successful due to the limited ability of the cells to migrate and integrate into the host retina. Bone marrow-derived stem cells may be a possible alternative, but bone marrow contains multiple types of differentiateable / pluripotent cells, including hematopoietic stem cells, mesenchymal stem cells, and a heterogeneous population of non-hematopoietic cells that differentiate into mesenchymal tissue but may also differentiate into other tissue types.

[0094] In at least some embodiments, the methods and apparatus described herein can be used in combination with compositions and methods applicable to cell-centered or regenerative therapies for retinal diseases and disorders. In at least some embodiments, the methods and apparatus described herein can be used in combination with pharmaceutical compositions, apparatus and methods for the regeneration or repair of retinal tissue using stem cells (e.g., very small emryonic-like stem cells (VSELs), mesenchymal stem cells, ectodermal stem cells, etc.).

[0095] For example, the methods and apparatus described herein can be used in a method of treating retinal disorders with PBM after administering an ectodermal stem cell population to an individual in need of it, and after intravenously administering a mesenchymal stem cell population to an individual. The ectodermal stem cells may be derived from fetal neural tissue. In at least some embodiments, the methods and apparatus described herein can be used in obtaining a mesenchymal stem cell population from a source selected from at least one of umbilical cord blood, adult bone marrow, and placenta. In at least some embodiments, the methods and apparatus described herein can be used to treat one or more diseases or disorders, including, but not limited to, macular degeneration, retinitis pigmentosa, diabetic retinopathy, glaucoma, or corneal marginal epithelial cell deficiency. In at least some embodiments, the cells are induced in vitro and differentiated into cells or epithelial hematopoietic cells before administration and pre-prepared with PBM. In other embodiments, the cells are administered together with at least one other agent (e.g., an agent for eye treatment, or other beneficial adjuvants (e.g., anti-inflammatory agents, anti-apoptotic agents, antioxidants, or growth factors)). In these embodiments, PBM therapy can be performed simultaneously with, before, or after postpartum cell administration. PBM can be used to promote the regeneration of stem cells, to adjunct beneficial adjuvant therapies, or both.

[0096] Another embodiment involves cell lysates prepared from mesenchymal or ectodermal stem cells treated with PBM. The cell lysates can be separated into a membrane-enriched fraction and a soluble cell fraction. This disclosure features in vitro PBM treatment of cells before the preparation of the cell lysates, before administration to the patient, and after transplantation to the patient.

[0097] The phototherapy methods for treating eye conditions described herein and in U.S. Patent Provisional Application No. 62 / 048,211 can be carried out using various phototherapy systems. U.S. Patent Provisional Application No. 62 / 048,211, filed September 9, 2014, titled Multi-Wavelenth Phototherapy Systems and Methods for the Treatment of Damaged or Diseased Tissue, is incorporated herein by reference in their entirety.

[0098] In one embodiment, the device is configured for facility-centered use. The device may be freestanding or can be attached to existing equipment. The device can be expanded to incorporate other diagnostic or therapeutic capabilities related to eye disorders, or to form a system with other devices.

[0099] The device described herein is designed to be wearable. This device can be extended to incorporate other diagnostic or therapeutic capabilities related to eye disorders, or to form a system with other devices.

[0100] The light delivery device or apparatus may be a unit based on a floor, desk, cart, or table. The apparatus includes one or more illumination engines containing one or more light sources for delivering light of one or more selected wavelengths. The light from the light sources can be combined using, for example, photo-shaping optical elements, optical filters, optical conduits, or a combination thereof, to achieve a desired spatial and spectral illumination pattern in the eye. Other optical components may be included to guide the light from the light engine to the eye. In at least some embodiments, the apparatus output is substantially spatially fixed, and as a result, proper exposure of the target area requires the patient's position to be manipulated and optimized. Such patient manipulation can be assisted with an adjustable chin rest or forehead rest or both. Fine spatial adjustment of the output can be achieved, for example, by using a moving element within the apparatus (e.g., a folding mirror) that is operated manually or electrically. In other embodiments, the apparatus output is substantially spatially adjustable, in which case the apparatus may include a forehead rest or chin rest or both as a patient interface, and the apparatus output can be adjusted to expose the target area. Large-scale spatial adjustments can be achieved with one or more optical elements (e.g., lenses, folding mirrors, etc.) that translate or rotate to redirect light to a target area. The adjustment function can cover the expected positional range for a single eye, or it can cover the expected positional range for both eyes, eliminating the need to readjust the patient when treating both eyes in turn.

[0101] If the device is suitable for an office environment, it is expected that many patients will operate the device, and measures can be taken to limit cross-contamination between individuals. In at least some embodiments, the removable forehead or chin rest can be provided as washable or disposable. In at least some embodiments, the forehead or chin rest can be protected by a washable or disposable barrier.

[0102] In at least some embodiments, the device includes an interface that allows a user (physician, practitioner, or patient) to initiate control. This may include a touchscreen or keyboard for selecting various treatment methods, entering or extracting data, and performing device diagnostic procedures.

[0103] Figures 1A to 1D show one embodiment of the phototherapy device 100. The device 100 includes a housing 102, a patient interface surface 104, and at least one eyebox or eyepiece 106. The device also optionally includes a user interface 108, a power switch 110, a locking mechanism 112, and a ray positioning mechanism 114. As will be described in detail below, the housing 102 holds the optical engine and other optical elements. The illustrated housing 102 is an example of a housing, and it will be understood that other housing configurations may be used, including housings that attach to or support other optical devices.

[0104] The patient interface surface 104 is positioned so that the patient is correctly positioned for irradiation of the patient's eye or both eyes in phototherapy. The patient interface surface can be adjusted to roughly fit the contours of the patient's face and may include disposable or washable surfaces to prevent or reduce cross-contamination of the patient.

[0105] The eyebox or eyepiece 106 can accommodate both eyes of the patient or only one eye. In some embodiments, there may be separate eyeboxes or eyepieces for the left and right eyes. The eyebox or eyepiece 106 may have a peripheral area intended to contact the area around the patient's eye, or the patient interface surface 104 may be sufficient to properly position the patient for phototherapy. The eyebox or eyepiece 106 may also be an opening into which the patient positions their eye, or the eyebox or eyepiece may include a lens or other optical component.

[0106] Any user interface 108 can be incorporated into the device and may be any suitable interface, including, but not limited to, a touchscreen interface, a keyboard and a display, etc. Alternatively or additionally, the device 100 may include or allow the connection of an external user interface (e.g., an external computer, keyboard, mouse or joystick) by wire or wireless. The user interface 108 is normally operated by a physician or other practitioner, but in some embodiments, there may be a user interface portion that can be operated by the patient, for example, a button or other element to stop or start phototherapy. The user interface 108 can be used to input treatment parameters, patient information, operate the device 100, or for any other suitable use. In some embodiments, the user interface 108 may also be connected to a built-in camera (e.g., camera 754 in Figure 7) so that the practitioner can see the patient's eyes to assist in diagnosis or phototherapy.

[0107] Any power switch 110 can have any preferred form. Any locking mechanism 112 can be provided to allow the user to lock the operation of the device 100. Any ray positioning mechanism 114 can be used to move the ray to act on the patient's eye or both eyes and may include, but is not limited to, a joystick, trackball, or touchscreen.

[0108] Figure 2 shows another embodiment of the device 200, which includes a housing 102, a patient interface surface 104, at least one eyebox or eyepiece 106, an optional user interface 108, an optional power switch 110, an optional locking mechanism 112, an optional ray positioning mechanism 114, and a chin rest 116. The chin rest 116 can have any preferred shape and can have a disposable or washable surface for receiving the patient's chin. Preferably, the height of the chin rest in relation to the rest of the device is adjustable.

[0109] Figures 3A and 3B show yet another embodiment of the apparatus 300, which includes a housing 102, a patient interface surface 104, at least one eyebox or eyepiece 106, an optional user interface 108, an optional power switch 110, an optional locking mechanism 112, and an optional ray positioning mechanism 114. In this embodiment, the patient interface surface 104 is removable so that it can be cleaned or replaced, as shown in Figures 3A and 3B.

[0110] Figure 4 shows an example of a lighting engine 420 used with the apparatus 100 (see Figure 1A) and positioned within the housing 102 of the apparatus 100 (see Figure 1A). The lighting engine 420 may include an engine housing 421, one or more light sources 422a, 422b, 422c, one or more light-directing components 424a, 424b, an optional lens 426, and an optional heat exchanger or radiator 428. The light emitted from the light sources 422a, 422b, 422c forms light rays 430a, 430b, and 430c, respectively.

[0111] In this embodiment, or any other embodiment described herein, any suitable light source may be used, including but not limited to light-emitting diodes (LEDs), laser diodes, lamps, lasers, and the like. In at least some embodiments, one or more light-emitting diodes are used. In other embodiments, one or more laser diodes are used. One or more laser diodes may be, for example, gallium-aluminum-arsenide (GaAlAs) laser diodes, aluminum-gallium-indium phosphide (AlGaLnP) laser diodes, diode-excited solid-state (DPSS) lasers, or vertical-cavity surface-emitting laser (VCSEL) diodes.

[0112] In at least some embodiments where multiple light sources are used, the light sources can be coupled to one or more optical fibers. Other light sources that produce or emit light having a suitable wavelength and intensity can also be used. In some embodiments, combinations of multiple types of light sources can be used. Each light source may optionally include one or more of the following: lenses (e.g., lenses 423a, 423b, 423c), diffusers, waveguides, or other optical elements associated with the light source.

[0113] In some embodiments, the device may also include one or more non-optical energy sources (e.g., magnetic energy sources, radio frequency energy sources, DC electric field sources, ultrasonic energy sources, microwave energy sources, mechanical energy sources, electromagnetic energy sources, etc.). For example, phototherapy can be combined with OCT, PET, MRI, femtosensors, etc. to provide the device with therapeutic, diagnostic, tracking, and enhanced targeting capabilities.

[0114] In at least some embodiments having two or more light sources, individual light sources can be selected to produce light of different wavelengths. The wavelength or range of wavelengths delivered to the eye is produced by the light sources but can be filtered to remove some or all of the other wavelengths of light. In at least some embodiments, a first light source provides light of a first wavelength (which may be delivered together with light of adjacent wavelengths or filtered to remove other light), and a second light source provides light of a second wavelength. In at least some embodiments, the first and second wavelengths differ by at least 25, 50, 75, 100, 150, 200, 250, 300, 400, or 500 nm. In some embodiments, a third light source provides light of a third wavelength, which differs from the first and second wavelengths by at least 25, 50, 75, 100, 150, 200, 250, 300, 400, or 500 nm.

[0115] The lighting engine 420 includes one or more optical directional elements 424a, 424b. In the illustrated embodiment, the optical directional elements 424a, 424b are reflective filters. Optical directional element 424a is selected to allow light from a ray 430a having a first wavelength, generated by the first light source 422a, to pass through, and to reflect light from a ray 430b having a second wavelength, generated by the second light source 422b. Optical directional element 424b is selected to allow light from the ray 430a having the first wavelength and light from a ray 430b having a second wavelength, generated by the second light source 422b, to pass through. Optical directional element 424b reflects light from a ray 430c having a third wavelength, generated by the second light source 422c. Optical directional element 424b directs the desired wavelength of light towards the lens 426.

[0116] Other optical directional components may include, but are not limited to, optical fibers, absorption filters, reflectors or absorbers, and beam splitters. In some embodiments, the device operates so that two or more light sources generate light simultaneously. In other embodiments, the device operates to deliver light from a single light source at a predetermined time, although the light sources can be turned on / off in any preferred light delivery sequence. Lens 426 may be a single lens or a combination of lenses and may include other optical components (e.g., diffusers, apertures, filters, etc.).

[0117] Figure 5 shows the illumination engine 420 of Figure 4, with additional optical components including an aperture 530 and a relay structure 532. The aperture 530 receives light from the lens 426 and limits the light directed toward the patient's eye. The relay structure 532 directs light from the light engine 420 toward the patient and may include any number of preferred components, for example, one or more mirrors 534 and one or more lenses 536.

[0118] Figures 6A–6C show additional components of the apparatus for delivering light from the illumination engine 642 to the patient. Part of the apparatus can use the actuator 642 to adjust the direction of the ray 644 (Figures 6B and 6C) by rotating part of the relay structure 532 (or part of the illumination engine 420), which includes the housing 102, flow mirror 640, and actuator 642. Figure 6B shows the position of the ray directed towards the patient's left eye, and Figure 6C shows the position of the ray directed towards the patient's right eye. In some embodiments, the actuator 642 may have only two positions. In other embodiments, the actuator 642 allows for finer adjustment of the ray position. In at least some embodiments, the actuator 642 is connected to a user interface 108 or a ray positioning mechanism 114 or both.

[0119] In at least some embodiments, the amount of light emitted is selected to provide a predetermined dose at the target eye tissue. The target tissue may be an area of ​​the eye affected by disease or trauma as confirmed using standard medical imaging techniques, it may be a part of the eye known to be affected by a particular disease, it may be a part of the eye known to control a certain function or process, or it may be any area of ​​the eye. To obtain the desired dose at the level of the target eye tissue, the selection of an appropriate dose of light emitted from the emitting surface preferably includes, from many other factors, the wavelength or multiple wavelengths of the selected light, the type of disease (if any), the clinical condition of the subject, and the distance to the subject area.

[0120] In at least some embodiments, where there are multiple light sources, certain light sources emit light with a higher or lower intensity compared to others. Therefore, the output of the light sources can be adjusted as needed, depending on the thickness of the eyelid, cornea, or other intervening tissue between the light source's emission surface and the target ocular tissue. The parameters of the light emitted by the light sources will be described in more detail later.

[0121] In some embodiments, the apparatus may include a spatial light modulator to use light from a light source to generate an image or to facilitate targeting of light to a specific part of the eye (e.g., the retina or a part of the retina). Figure 8 shows an array of light sources 822 (including multiple) and light directed towards a spatial light modulator (SLM) 860 that adjusts the light to direct a modulated ray towards the patient. The spatial light modulator 860 may be, for example, a micromirror array, scanning mirror, or any other suitable device capable of reflecting light, such as a liquid crystal on a silicon (LCOS) display, a liquid crystal display (LCD), a digital light processor (DLP), and may optionally be used to form an image. The spatial light modulator may also include additional projection optics (e.g., lenses). In at least some embodiments, the apparatus may also utilize the lens of the patient's eye to facilitate image formation.

[0122] The spatial light modulator may be reflective, as shown in Figure 8, or transmissive, so that light passes through the SLM and is adjusted. The spatial light modulator can be inserted at any suitable location along the optical path. For example, a reflective SLM can be positioned at the location of the bent mirror 534 in the embodiment shown in Figure 5, or in any other suitable part of the device. A transmissive SLM can be positioned before or after the lens 426 or aperture 530 in the embodiment shown in Figure 5, or in any other suitable part of the device.

[0123] In at least some embodiments, targeting a light source over a specific portion of a patient's eye can be done using a spatial light modulator, a camera (which observes the patient's eye and allows manual or automatic adjustment of the direction of the ray, pupil tracking sensor, or any combination thereof).

[0124] Figure 7 shows one embodiment of a system for operating a device for the treatment of eye diseases, disorders, degeneration, etc. The system includes a controller 750, a user interface 708 (e.g., user interface 108 in Figures 1A to 3A), an actuator 742 (e.g., actuator 642 in Figures 6A to 6C), a light source 722 (e.g., light sources 422a, 422b, 422c in Figures 4 and 5), a memory 752, one or more sensors / cameras 754, and a power supply 756. These components are described in more detail below. It should be understood that other systems may include more or fewer components, and those components may be coupled together in a different arrangement than that shown in Figure 7. For example, the spatial light modulator 860 in Figure 8 may also be coupled to the controller 750 in Figure 7. Furthermore, any coupling between components may be wired, wireless, or any combination thereof.

[0125] In certain embodiments of this disclosure, the optical delivery device is wearable, thereby promoting portability and enabling the option of use outside of conventional ophthalmic facilities (e.g., at home, at work, or during recreational activities and travel). Accordingly, the wearable devices described herein offer advantages such as reducing the burden of travel for the patient and providing convenience to the patient when choosing a time for treatment delivery.

[0126] Since the purpose is to expose only one eye to phototherapy, the wearable device may be monocular or binocular, in which case the device can treat both eyes simultaneously, sequentially, or in a specified order. Binocular devices are described in detail herein, and the design issues, parameters, and structures disclosed herein are also applicable to monocular devices.

[0127] A wearable device may include one or more light sources of one or more wavelengths. In at least some embodiments, the device includes an array of light sources directed toward the eye and arranged at specific intervals to produce a desired spatial and spectral irradiation on the eye. In at least some embodiments, optical components can be used to redirect light from the light sources toward the wearer's eye. Intermediate optical components (e.g., lenses, filters, diffusers) may further form the output of the device as needed.

[0128] In at least some embodiments, the light source is positioned away from the line of sight of the eye, and the light is directed to the eye via an optical conduit or waveguide, or any other suitable component. The waveguide can function to mix multiple wavelengths or to homogenize the device output. The waveguide can incorporate integrated lenses, coatings, or diffusers to form rays at the inlet and outlet of the waveguide. In at least some embodiments, the waveguide is transparent, resulting in the user having a largely unobstructed field of view while wearing the device. Planar optical elements (e.g., volume phase holograms, surface relief holograms, diffraction gratings, or similar components) can be placed on or incorporated within the waveguide to direct the light and form the output, while keeping the waveguide substantially transparent.

[0129] In at least some embodiments, the light source is positioned away from the line of sight of the eye, and the light is directed to the eye via reflection from a surface. A coating can be placed on the surface to enhance reflection. The surface may be flat, or it may be curved in one or more directions, if possible, as the curve is defined to form the light output of the device. The surface may reflect mainly at the angle of incidence of light, or transmit mainly at the perpendicular incidence, resulting in little obstruction to the wearer's field of vision. The coating can be applied to the surface so as to reflect only certain wavelengths while transmitting others.

[0130] In at least some embodiments, the device is connected to an external control unit wirelessly or by wire. The external unit may include control electronics, associated drivers, software, etc., or any combination thereof. It may be cabled to a wearable device equipped with fiber optic cables for light transmission. In at least some embodiments, the control unit is connected to the wearable device by cables supplying signals or power. In at least some embodiments, the control unit is connected to the wearable device wirelessly. The control unit and / or the wearable device may be powered by one or more batteries or via an external power supply.

[0131] In at least some embodiments, the light source and the built-in programmable controller are powered by a power supply within the device. In at least some embodiments, the power supply is located away from the device. The power supply may include one or more electronic components (e.g., capacitors, diodes, resistors, inductors, transistors, regulators, batteries, fuel cells, or any other suitable energy storage device). The power supply may also use any type of device, component, or system configured to store electromagnetic energy. In at least some embodiments, the power supply includes a zinc-air battery, similar to those used in hearing aids.

[0132] In certain embodiments of these embodiments, the power supply is rechargeable. For example, the power supply may include a lithium vanadium pentoxide battery, a lithium manganese dioxide battery, a nickel-cadmium battery, a nickel-metal hydride battery, a lithium-ion battery, or any other suitable rechargeable battery chemistry. In at least some embodiments, the power supply may include an induction coil and a charging circuit that can be inductively charged by an external charging station. In at least some embodiments, the power supply may also be an RF power supply that can be charged by radio frequency (RF) energy. In at least some embodiments, an external power supply may optionally be used to drive the device.

[0133] In at least some embodiments using a rechargeable power supply, the power supply's charge capacity is sufficient to last through at least one treatment session. The required duration and frequency of treatment vary depending on the severity of the associated eye disease. In at least some embodiments, the charge capacity is required to be sufficient to power the programmable controller and light source for 5 to 30 minutes. In at least some embodiments, the treatment duration is at least 20 minutes. For subjects requiring prolonged and / or frequent treatment, some embodiments use two, three or more power supplies connected to the programmable controller and light source to provide sufficient power for longer or more frequent treatment sessions. In at least some embodiments, a single high-capacity power supply can be used. In at least some embodiments, the power supply may include a combination of one or more capacitors and one or more batteries.

[0134] Figure 9 shows one embodiment of a wearable phototherapy device 900. The device 900 includes a frame 902, an anterior piece 104 that is placed in front of the patient's eyes, and two earpieces 906.

[0135] Figures 10A and 10B show one embodiment of a wearable phototherapy device 1000, which includes a frame 1002, a front piece 1004, earpieces 1006, left and right arrays 1008 of light sources 1010a, 1010b, and 1010c, and one or more frame cases 1012 in which electronic equipment or batteries can be housed. The earpieces 1006 are an example of an additional element of the frame 1002 that is attached to the front piece 1004 to hold the device 1000 on the wearer. Examples of other additional elements include, but are not limited to, headbands, helmets, masks, or combinations thereof. The light sources 1010a, 1010b, and 1010c may be the same or different. One or more frame casings 1012 may contain a controller, light source electronic equipment, a battery, or any combination thereof within the case. In at least some embodiments, a portion of the frame casing 1012 or other frame 1002 may also incorporate at least one button or other user input element that can be used to start, end, or change the operation of the device 1000. Alternatively or additionally, wireless or wired connections to ports on the frame may allow the device to be started or ended, or optical delivery parameters to be entered or changed.

[0136] Other light sources that generate or emit light at suitable wavelengths and doses can also be used. In some embodiments, combinations of multiple types of light sources can be used. Each light source may optionally include one or more lenses, diffusers, filters, or other optical elements associated with the light source. In at least some embodiments, the frequency, power, pulse length, pulse width, wavelength, or any other emission parameter of each light source, or any combination of these parameters, can be controlled or adjusted independently of other light sources.

[0137] In at least some embodiments relating to two or more different light sources 1010a, 1010b, 1010c, the individual light sources are selected to produce light of different wavelengths. For example, the array 1008 of the apparatus 1000 may be an array of three different light sources 1010a, 1010b, 1010c, which may be any preferred arrangement. For example, a repeating arrangement of light sources 1010a, 1010b, 1010c along rows, columns, or both, or along diagonals; an arrangement of light source 1010a in rows, columns, or diagonals (which may be repeatable), followed by an arrangement of light source 1010b in rows, columns, or diagonals, followed by an arrangement of light source 1010c in rows, columns, or diagonals; or any other preferred regular or irregular arrangement. It will also be understood that the number of light sources emitting different wavelengths is not limited to three, but may be two, four, five, six or more different light sources emitting different wavelengths of light. In other embodiments, all of the light sources 1010a, 1010b, and 1010c can emit the same wavelength(s) of light.

[0138] For example, in at least some embodiments, a first light source 1010a provides light of a first wavelength (which may be delivered together with light of adjacent wavelengths or filtered to remove other light), and a second light source 1010b provides light of a second wavelength. In at least some embodiments, the first and second wavelengths differ by at least 25, 50, 75, 100, 150, 200, 250, 300, 400, or 500 nm. In some embodiments, a third light source 1010c provides light of a third wavelength, which differs from the first and second wavelengths by at least 25, 50, 75, 100, 150, 200, 250, 300, 400, or 500 nm.

[0139] Figures 11A to 11E show another embodiment of the wearable phototherapy device 1100, which includes a frame 1102, a front side piece 1104, an earpiece 1106, left and right arrays 1108 of light sources 1110a, 1110b, and 1110c, and one or more frame cases 1112 in which electronic equipment or batteries can be housed. Unless otherwise specified, all design issues, characteristics, and descriptions provided for elements of the same name in other embodiments are also applicable to the elements of the device 1100. For example, the light sources 1110a, 1110b, and 1110c may be the same or different, or there may be one, two, three, four or more different light sources that produce different wavelengths of light.

[0140] This embodiment also includes one or more visual ports 1105 through which the wearer can see. These visual ports are open or optionally incorporate glass or plastic that forms a lens. In at least some embodiments, the visual ports 1105 incorporate a prescription lens selected based on the wearer's visual acuity.

[0141] In particular, as shown in Figures 11A and 11C, the light sources 1110a, 1110b, and 1110c are positioned around three sides of the visual port 1105. In other embodiments, the light sources can be positioned around one, two, four or more sides (when the port has four or more sides) of the visual port. As shown in Figure 11E, the light sources 1110a, 1110b, and 1110c are positioned to produce light 1114 directed at least partially towards the wearer's eyes. In at least some embodiments, the light sources can include at least one optical element (e.g., a lens or reflector) that can be directed towards the wearer's eyes, or that directs or redirects light towards the wearer's eyes. In other embodiments, the light sources simply produce light in a conical direction, some of which reaches the wearer's eyes.

[0142] Figure 12A shows another embodiment of the wearable phototherapy device 1200, which includes a frame 1202, a front piece 1204, an earpiece 1206, a light source 1210, and one or more frame cases 1212 capable of housing electronic equipment or a battery. Unless otherwise specified, all design issues, characteristics, and descriptions provided for elements of the same name in other embodiments are also applicable to the elements of the device 1200.

[0143] The light source 1210 can provide different wavelengths of light directed by the light source 1210 by using separate light-generating elements (e.g., LEDs, laser diodes, etc.) within the frame. Alternatively or additionally, there may be multiple light sources 1210 arranged on the frame in rows, columns, or other arrangements. Although a single light source is shown on the left earpiece, it will be understood that a similar light source may be present on the right earpiece, as shown in Figure 12C.

[0144] A reflector 1216 is provided on the frame to receive light from the light source 1210 and redirect at least some of the light to the wearer's eyes. The reflector 1216 may be any suitable reflector, including, but not limited to, mirrors, reflective filters, reflective polarizers, beam splitters, etc., that redirect at least some of the light to the wearer's eyes. The reflector 1216 may also include one or more scattering elements, such as a light scattering mechanism, which diffuses the redirected light.

[0145] Figure 12B shows a similar embodiment of the wearable phototherapy device 1200, which includes a frame 1202, an earpiece 1206, a light source 1210, and one or more frame cases 1212 capable of housing electronic equipment or a battery. Unless otherwise specified, all design issues, characteristics, and descriptions provided for elements of the same name in other embodiments are also applicable to the elements of device 1200.

[0146] In the embodiment shown in Figure 12B, the reflector 1216 is partially transparent, and as a result partially reflects light and partially transmits light. For example, this reflector 1216 could be a partial mirror, reflective polarizer, or reflective filter that reflects light of a specific wavelength or wavelength band and transmits light of other wavelengths. The reflector 1216 redirects at least some of the light from the light source to the wearer's eyes. The reflector 1216 may be part of a lens or disposed on top of it. The reflector 1216 may also include one or more scattering elements, such as a light scattering mechanism, which diffuses the redirected light.

[0147] Figures 13A to 13D show yet another embodiment of the wearable phototherapy device 1300, which includes a frame 1302, a front piece 1304, an earpiece 1306, a light source 1310, and one or more frame cases 1312 capable of housing electronic equipment or a battery. Unless otherwise specified, all design issues, characteristics, and descriptions provided for elements of the same name in other embodiments are also applicable to the elements of the device 1300. The light source 1310 can provide different wavelengths of light by using separate photogenerating elements (e.g., LEDs, laser diodes, etc.) within the light source 1310.

[0148] The apparatus 1300 includes a projection system 1318 and a reflective prism 1320 to provide the wearer with phototherapy in the form of light rays or images. Figure 13D shows the projection system 1318 in more detail, including a light source 1310, a spatial light modulator (SLM) 1322, a beam splitter 1324, an illumination optical element 1326, and a projection optical element 1328. The spatial light modulator 1322 may be, for example, a micromirror array, scanning mirror, or any other suitable device capable of reflecting light, such as a liquid crystal on a silicon (LCOS) display, a liquid crystal display (LCD), a digital light processor (DLP), and may optionally be used to form an image. The illumination optical element 1326 and the projection optical element 1328 may include, for example, one or more lenses, diffusers, polarizers, filters, etc.

[0149] At least a portion of the light generated from the light source 1310 passes through the illumination optical element 1326 and is redirected to the spatial light modulator 1322 by the beam splitter 1324. The light is reflected by the spatial light modulator, which can use the light to form an image or adjust the received light and return to the prism 1320 by the beam splitter 1324 and projection optical element 1328. As shown in Figure 5B, at least a portion of the light entering the prism 1320 is redirected to the wearer's eyes.

[0150] Figures 14A to 14D show yet another embodiment of the wearable phototherapy device 1400, which includes a frame 1402, a front piece 1404, an earpiece 1406, a light source 1410, and one or more frame cases 1412 capable of housing electronic equipment or a battery. This device 1400 includes a projection system 1418 and a waveguide 1430 to provide phototherapy to the wearer in the form of light or images. Figure 14D shows the projection system 1418 in more detail, which includes a light source 1410, a spatial light modulator (SLM) 1422, a beam splitter 1424, an illumination optical element 1426, and a projection optical element 1428. Unless otherwise specified, all design issues, characteristics, and descriptions provided for elements of the same name in other embodiments are also applicable to the elements of device 1400. The light source 1410 can provide different wavelengths of light using separate photogenerating elements (e.g., LEDs, laser diodes, etc.) within the light source 1410.

[0151] In contrast to the embodiments shown in Figures 13A to 13D, the embodiments shown in Figures 14A to 14D use a waveguide 1430 to deliver at least some of the light to the wearer's eyes, as shown in Figure 14B. The waveguide 630 may include an internally coupled diffractive optical element 1432 or other array that receives light from the projection system 1418, and an externally coupled diffractive optical element 1434 or other array that directs the light from the waveguide to the wearer's eyes. The waveguide 1430 and prism 1320 are examples of light directing elements that receive modulated rays from spatial light modulators 1322, 1422 and direct the light to the wearer's eyes.

[0152] Figure 15 shows another embodiment of a system 1570 that operates a device for treating eye diseases, disorders, degenerations, etc. The system 1570 may include a controller 1550, a user interface 1560, a power supply 1556, a memory 1552, and one or more wearable devices 1500 (e.g., any of the wearable devices 900, 1,000, 1,100, 1,200, 1,300, 1,400 described above). The wearable device 1500 includes a light source(s) 1510 (e.g., the light sources 910a, 910b, 910c, 1010a, 1010b, 1010c, 1110a, 1110b, 1110c, 1210, 1310, 1410 described above), an optional built-in controller 1556, one or more optional sensors(s) / cameras 1554, a memory 1564, and a power supply 1562. Alternatively or additionally, sensors / cameras 1554 may be external to the device 1500 but can provide information to an external controller 1550 or an internal controller 1556. These components are described in more detail below. Other systems may contain more or fewer components, and it should be understood that these components are connected together in a different arrangement than that shown in Figure 15. Furthermore, any connections between components may be wired, wireless, or any combination thereof.

[0153] The exemplary system 1570 includes an external controller 1550 that can connect to the built-in controller 1556 of the wearable device 1500 wirelessly or via a wired connection (or any combination thereof) and program the built-in controller. In at least some embodiments, the external controller 1550 is used solely to program the built-in controller 1556 that operates the device 1500. In some embodiments, only healthcare professionals can access the external controller 1550. In other embodiments, a user can also access the external controller or another external controller to modify, start, or end treatment. It will be understood that any function described herein performed by one of the external or built-in controllers may, in other embodiments, be performed by the other one of the external or built-in controllers.

[0154] In other systems, wearable devices may include a user interface that is on the device, attachable to the device, or wirelessly connectable to the device, thus eliminating the need for an external controller. A healthcare professional, or optionally a user, can use this user interface to directly program the built-in controller 1556.

[0155] In some embodiments, the device may include one or more non-optical energy sources, or the device may be used in conjunction with another device that generates one or more non-optical energy sources (e.g., magnetic energy sources, radio frequency sources, DC electric field sources, ultrasonic energy sources, microwave energy sources, mechanical energy sources, electromagnetic energy sources, etc.). For example, phototherapy can be combined with OCT, PET, MRI, femtosensors, etc., to provide the device with therapeutic, diagnostic, tracking, and enhanced targeting capabilities.

[0156] Programmable controller To adjust one or more of the light energy emission, light energy intensity, light energy duration, frequency, area, or sequence, or other therapeutic parameters of the application of light energy to the target eye tissue, at least some embodiments include, or can be connected to a user interface, or can be separately connected to the device, a programmable controller (e.g., controller 750 in Figure 7, or the built-in controller 1550 in Figure 15, which may be part of the user interface 708, directly connected to the user interface 1560, or connected to an external controller 1550) for application of light energy to the target eye tissue. The programmable controller executes a set of program instructions stored in memory to accomplish a task or operation, such as operating one or more light sources according to a particular therapeutic regime, communicating with an external device, monitoring the status of elements such as light sources and power supplies, and storing parameters or program instructions in memory.

[0157] For example, a programmable controller can be used to emit light to a specific target area of ​​the eye according to a treatment regimen. For example, a programmable controller can execute a treatment program that includes a set of activation times or periods in which each light source is in an emitting state, and a set of non-activation times or periods in which the light sources are in a non-emitting state. In certain embodiments, the programmable controller includes a general-purpose or special-purpose microprocessor. In at least some embodiments, the programmable controller may include an application-specific integrated circuit (ASIC) or a logic-programmable device (FPGA).

[0158] In at least some embodiments, the programmable controller can communicate with internal memory (e.g., memory 752 in Figure 7 or memory 1564 in Figure 15) to retrieve or store data or program instructions for software or hardware. In at least some embodiments, the programmable controller includes a central processing unit (CPU). The programmable controller may further include memory (random access memory (RAM) or flash memory as primary storage for information, read-only memory (ROM), EPROM memory, or EEPROM memory as persistent storage for information).

[0159] In at least some embodiments, the memory may remain programmable after the initial programming. Furthermore, the programmable controller may include a real-time clock, one or more timers, an analog-to-digital (A / D) converter, a digital-to-analog (D / A) converter, and a serial communication interface (e.g., I 2The power supply may include a C or serial peripheral interface, a communication interface, or a pulse-width modulation (PWM) generator. The power supply provides power to the programmable controller, which in turn can drive one or more light sources. In at least some embodiments, the programmable controller drives one or more light sources via a light source driver. The light source driver can energize one or more light sources by applying a suitable current or voltage level. When the programmable controller generates a control signal to drive the light sources, light is emitted from the emitting surface. Conversely, when the light sources do not receive a control signal from the programmable controller to generate light, the emitting surface is in a non-emitting state. The light sources may be configured to emit light continuously or periodically according to various treatment regimens.

[0160] In at least some embodiments, the programmable controller is pre-programmed (e.g., before implantation) with a desired set of therapeutic parameters for a given target. For example, the desired frequency of light energy emission (e.g., every 24 hours), the duration of light energy emission (e.g., 5 minutes), the dose of light energy emission (e.g., 1 mW to 10 mW), the irradiation pattern or sequence of light source emission (e.g., a series of light energy emissions in these embodiments involving multiple light sources), and other parameters can be pre-programmed within the programmable controller. For pulsed dosimetry, the therapeutic parameters may also include the duty cycle per pulse of pulsed dosimetry, pulse shape, repetition rate, pulse width, or dose.

[0161] In at least some embodiments utilizing multiple light sources, a programmable controller can be programmed to activate a subset of light sources at a focal point on a specific target area. In at least some embodiments, the programmable controller can be programmed to activate light sources according to a predetermined treatment regimen, sequence, template, or order. For example, the treatment regimen may follow a pattern similar to the sequence described in paragraphs

[0203] to

[0228] of U.S. Patent Application Publication 2009 / 0254154, incorporated herein. The treatment regimen may also be adjustable by a physician (e.g., via telemetry or a wireless or wired network interface).

[0162] In at least some embodiments, the programmable controller can be dynamically reprogrammed via a communication interface. The communication interface may include an antenna configured to receive RF communication from an external telemetry device. The communication interface may also be configured to transmit information to the external telemetry device. Other types of wireless communication may also be available. In at least some embodiments, a physician can adjust treatment parameters in response to alarms or warnings generated by the phototherapy device. The physician can reprogram the programmable controller wirelessly via the communication interface.

[0163] In at least some embodiments, the programmable controller can automatically reprogram itself or readjust its therapeutic parameters in response to a control signal received from a feedback sensor (e.g., sensor 754 in Figure 7). The sensor can provide feedback on the parameters of the phototherapy or the physiological parameters of the subject (e.g., the patient). The sensor (e.g., sensor 754 in Figure 7) may include biomedical sensors, biochemical sensors, temperature sensors, etc. In at least some embodiments, the sensor may be an invasive sensor that can be inserted into the body or at least temporarily attached to the body. In at least some embodiments, the sensor may include a non-invasive or minimally invasive sensor.

[0164] The sensors can be used to measure, for example, adenosine triphosphate (ATP) concentration or activity, optic nerve output wave (e.g., using an ERG sensor system), mitochondrial activity (e.g., by measuring NADH or NADPH concentration), nitric oxide (NO) production or consumption, cytokines (such as IL-6 interleukin and tumor necrosis factor (TNF)), apoptosis labels (such as BAX and Bcl-2), evoked reaction optical scanning (EROS) responses, oxygen consumption levels, membrane potential, glycolytic activity, or pH levels. For example, increased cellular ATP concentration and a greater decrease in intracellular ATP levels are both related to cellular metabolism and are considered signs that the cell is viable and healthy. Increased concentrations of NADH in target eye tissue and a corresponding improvement in the redox state of the target tissue reflect both cellular metabolic activity and health.

[0165] diffusion In at least some embodiments, the light source or device includes a diffuser suitable for diffusing the light before it reaches the eye or ocular tissue and advantageously homogenizes the rays. Typically, the intervening tissue of the cornea is highly scattering, which can reduce the effects of a non-uniform ray intensity distribution on the illumination of the retina of the subject. However, a substantially heterogeneous or non-uniform ray intensity distribution can result in some parts of the subject's eye being heated more than others (e.g., localized heating where "hot spots" of rays act on the subject's eye).

[0166] In at least some embodiments, the light source or other components within the device conveniently homogenize the light rays, reducing non-uniformity. The exemplary energy density profile of the light before it originates from the light source peaks at a particular emission angle. In at least some embodiments, after diffusion by the light source or other components of the device, the energy density profile of the light does not have a substantial peak at any particular emission angle, but is distributed substantially uniformly within a range of emission angles. By diffusing the light, the light source or other components within the device distribute the light energy substantially uniformly over the irradiated area, thereby controlling, inhibiting, preventing, minimizing, or reducing “hot spots” that would otherwise cause an increase in temperature in the eye. Therefore, by diffusing the light, the temperature of the irradiated area of ​​the target eye is lower than if the device did not diffuse the light. For example, by diffusing the light, the temperature of the irradiated area of ​​the target eye may be higher than the temperature of the unirradiated area of ​​the target eye, but lower than the temperature of the irradiated area of ​​the target eye that was not diffused. Furthermore, by diffusing the light before it reaches the eye, the device can effectively increase the spot size of the eye over which the light acts, thereby conveniently reducing the amount of light irradiated to the eye.

[0167] In at least some embodiments, the light source or other components of the device provide sufficient light diffusion so that the amount of light irradiated is below the maximum permissible level for the eye or other eye tissue. For example, the maximum permissible level in a particular embodiment is the level at which the subject experiences discomfort or pain, while in a particular other embodiment, the maximum level is the level at which the subject's eye or eye tissue is damaged (e.g., thermal injury or burn). In at least some embodiments, the device provides sufficient light diffusion so that the amount of light irradiated is equal to the therapeutic value for the target tissue. For example, the device may include, but is not limited to, holographic diffusers such as those available from Physical Optics Corp. (Torrance, California) and Display Optics P / N SN1333 from Reflexite Corp. (Avon, Connecticut.).

[0168] targeting Phototherapy can be performed through closed eyelids, and it can be expected that most of the light will scatter over a relatively wide area of ​​the retina, or it can be performed with eyes open. With eyes open, most of the therapeutic light is expected to be delivered to the retina through the lens and pupil of the eye with minimal scattering. In certain embodiments, the device includes the ability to target a specific area of ​​the retina through the pupil. This can be achieved by incorporating a spatial light modulator (SLM) for precisely forming and controlling the exposed area on the retina. The SLM may be an LCOS panel, a scanning mirror, a deformable mirror array, or other modulator.

[0169] In at least some embodiments, the SLM, in combination with illumination and image optics, provides still or moving images to the patient. The images can be used to direct the patient's gaze, thereby helping to control the focus and direction of the eye being treated during treatment, or they can function to increase the usability of the device by providing visual entertainment to the patient during treatment. In certain embodiments, the illumination source of the SLM is solely an image display, while treatment is provided by a second light source(s). In other embodiments, the SLM illumination source(s) provides treatment.

[0170] feedback In at least some embodiments, the programmable controller includes a logic circuit, a clock connected to the logic circuit, and an interface connected to the logic circuit. In at least some embodiments, the clock provides timing signals to the logic circuit so that the logic circuit can monitor and control the timing interval of the applied light. Examples of timing intervals include, but are not limited to, the total treatment time, the pulse width time of the applied light pulses, and the time interval between pulses of the applied light. In at least some embodiments, the light source can be selectively turned on / off to reduce the thermal load on the eye or ocular tissue and to deliver a selected dose to a specific area of ​​the eye or other ocular tissue.

[0171] In at least some embodiments, the interface provides signals to a logic circuit, which uses them to control the applied light. The interface may include a user interface or an interface to a sensor that monitors at least one parameter of the treatment (e.g., sensor 754 in Figure 7 or sensor 1554 in Figure 15). In at least some embodiments, the programmable controller preferably adjusts the treatment parameters to optimize the measured response in response to signals from the sensors. Thus, the programmable controller can provide closed-loop monitoring and adjustment of various treatment parameters to enhance or optimize phototherapy. Signals provided by the user through the interface indicate parameters including, but are not limited to, individual target characteristics for practical light (e.g., eyelid skin type, fat percentage), selected applied dose, target time interval, and applied light dose / timing profile.

[0172] In at least some embodiments, the logic circuit is connected to a light source driver, which is connected to a power source (e.g., power source 756 in Figure 7 or power source 1562 in Figure 15), which in at least some embodiments is a battery or a capacitive energy storage device, and in other embodiments includes an AC current source. The light source driver is also connected to a light source. The logic circuit sends control signals to the light source driver in response to signals from a clock and user inputs from a user interface. In response to the control signals from the logic circuit, the light source driver adjusts and controls the power applied to the light source. In at least some embodiments, the control circuit can be used to provide real-time positive or negative feedback.

[0173] In at least some embodiments, the logic circuit responds to signals from sensors that monitor at least one parameter of the treatment and control the applied light. For example, at least some embodiments include a temperature sensor for heat transfer with the skin or eyelid to provide the logic circuit with information about skin temperature. In at least some embodiments, the logic circuit transmits a control signal to a light source driver in response to information from the temperature sensor to adjust the parameters of the applied light to maintain the skin or eyelid temperature below a predetermined level. Other examples of suitable sensors include, but are not limited to, other biomedical sensors including blood flow sensors, blood gas (e.g., oxidation, femtosensor) sensors, ATP production sensors, or cell activity state sensors. Such biomedical sensors can provide real-time feedback information to the logic circuit.

[0174] For example, if ATP production or mitochondrial activity levels are below a certain threshold level, the logic circuit can generate a control signal to the light source(s) to adjust the therapeutic parameters of the applied light (e.g., treatment time, wavelength, irradiation level, or other parameters). In at least some embodiments, the logic circuit preferably adjusts the parameters of the applied light to enhance or optimize the measured response in response to a signal from a sensor. In other embodiments where the logic circuit can provide automatic closed-loop monitoring and adjustment of various parameters of the applied light to enhance or optimize phototherapy, the control circuit may be configured to provide manual closed-loop feedback. The sensors (e.g., sensor 754 in Figure 7 or sensor 1554 in Figure 15) may also include biochemical sensors, EEG sensors, EROS sensors, photosensors, or other sensors. Any sensor or combination of sensors can be used.

[0175] In at least some embodiments, the device provides a method for imaging the sclera, cornea, retina, or other parts of the eye of a patient. Such images can be obtained by directing the patient's gaze to a designated location or other area, and then viewing or capturing an image of a desired area of ​​the eye. In at least some embodiments, this is performed by a device that automatically adjusts focus, exposure, size, or image position in an automated manner. In at least some embodiments, the user manually determines one or more images that capture parameters. In at least some embodiments, information from the images is then used by the user of the device to identify and determine a specific treatment or target area of ​​the eye. In at least some embodiments, the user manually adjusts the device output so that a desired dose is delivered to the target area. In at least some embodiments, the target area is programmed within the device, and a logic circuit can then dynamically adjust the device output to deliver the desired treatment to the identified area.

[0176] In at least some embodiments, the logic circuit responds to a signal indicating the spatial position or orientation of the patient's eye (e.g., where the patient is looking). This can be achieved using one or more cameras (e.g., camera 754 in Figure 7 or camera 1554 in Figure 15) and associated software algorithms. An infrared or other wavelength auxiliary emitter may be used as an illumination source to facilitate target tracking. Alternatively, commercially available target tracking components or algorithms can be partially or fully incorporated into the device. In at least some embodiments, the logic circuit can utilize the eye orientation signal to spatially adjust the device output to maintain proper exposure over a previously identified target area. In at least some embodiments, the signal can be used to adjust the intensity of the device output. Such intensity modulation may include increasing or decreasing the device output to maintain proper exposure to a given area, or it may include temporarily suspending treatment.

[0177] In at least some embodiments, the device actively monitors the state of the patient's eyelids (e.g., open / closed) during treatment. In at least some embodiments, a signal is used as an interlock for a logic circuit to temporarily stop the device's output when a specific eyelid state is detected. In at least some embodiments, the signal is used by the logic circuit to increase or decrease the power output of the device. The logic circuit may include measuring the cumulative time that a specific eyelid state is present throughout the treatment process. The total treatment time can then be automatically adjusted to deliver the entire desired dose. In at least some embodiments where treatment is delivered nominally with eyes closed, whenever an open-eye state is detected, the logic circuit may temporarily halt the treatment or temporarily reduce the device output to maintain the dose on the retina or other part of the eye. In at least some embodiments where treatment is delivered nominally with eyes open, whenever a closed-eye state is detected, the logic circuit may temporarily halt the treatment or temporarily increase the device output to maintain the dose on the retina or other part of the eye.

[0178] In at least some embodiments, the device includes one or more cameras (e.g., camera 754 in Figure 7 or camera 1554 in Figure 15) and associated software algorithms for measuring the patient's pupil diameter. Alternatively, one or more cameras may be external to the device but provide information directly or indirectly. This measurement can be performed once, periodically, or continuously. The logic circuit can then use the pupil diameter measurement signal to adjust treatment parameters to obtain a desired irradiation dose on the retina.

[0179] In at least some embodiments, the device includes sensors (e.g., sensor 754 in Figure 7 or sensor 1554 in Figure 15) to monitor the spatial or temporal irradiation pattern delivered to the patient. In some embodiments, such as the wearable devices disclosed herein, one or more sensors may be external to the device but directly or indirectly provide information to the device.

[0180] The sensor may include an array of one or more photodiodes, a camera with suitable wavelength and time sensitivity, or another sensor capable of measuring the spatial and temporal irradiation profile of the delivered treatment. The resulting “beam profile” is then analyzed by software within the device to measure the characteristics of the delivered treatment, which include one or more of the following: diameter (defined by the relative in-circle energy metric or relative intensity metric), uniformity, pulse frequency, total power, and maximum intensity. In at least some embodiments, the logic device uses the beam profile data as feedback to adjust the output of the device to obtain the desired dose.

[0181] In at least some embodiments, the device includes one or more cameras (e.g., camera 1554 in Figure 15) and associated software algorithms for measuring the patient's pupil diameter, or one or more cameras may be external to the device but directly or indirectly provide information to the device. This measurement can be performed once, periodically, or continuously. A logic circuit can then use the pupil diameter measurement signal to adjust treatment parameters to obtain a desired irradiation dose on the retina.

[0182] In at least some embodiments, the device includes one or more sensors (e.g., sensor 1554 in Figure 15) to monitor the spatial or temporal irradiation pattern delivered to the patient, or one or more sensors may be external to the device but directly or indirectly provide information to the device. The sensors may include arrays of one or more photodiodes, cameras of suitable wavelength and temporal sensitivity, or other sensors capable of measuring the spatial and temporal irradiation profile of the delivered treatment. The resulting “beam profile” is then analyzed by software within the device to measure the characteristics of the delivered treatment, which include one or more of the following: diameter (defined by relative in-circle energy metric or relative intensity metric), uniformity, pulse frequency, total power, maximum intensity, etc. In at least some embodiments, the logic device uses the beam profile data as feedback to adjust the output of the device to obtain a desired dose.

[0183] Pupillary dilation monitoring In addition to tracking eye movements, targeting the retina, aiming the light beam, and confirming eyelid position, monitoring pupil diameter may be used to ensure that the selected beam diameter is not obstructed by the pupil during treatment. If the pupil constricts, the expected dose may not reach the target tissue. Applying pupillary dilation solutions is undesirable in this treatment. Controlling pupil diameter via ambient light may be unreliable or impractical in this application, as a given intensity of visible light is part of the treatment. Estimating a single value for the smallest pupil diameter across the entire patient population is impractical or does not allow access to all target tissues through the pupil.

[0184] A light intensity sensor that maps the application of light to a target surface. In at least some embodiments, the device can include a composite measurement and algorithm for monitoring light intensity. The verification measurement can be a careful risk mitigation. For example, the beam profile exiting the device can be measured to confirm that the parameters (beam diameter, intensity map) selected for the target are applied as desired. In at least some embodiments, the device can reflect the light beam with a "leakage" mirror before exiting the device. A small amount of light transmitted through the "leakage" mirror is sampled by a sensor array (e.g., sensor 754 of FIG. 7 or 1554 of FIG. 15) to measure the selected parameters. In at least some embodiments, a camera (e.g., camera 754 of FIG. 7 or 1554 of FIG. 15) can monitor the light reflected from the patient. The reflected light can be sampled to confirm the beam profile applied to the patient.

[0185] To control, suppress, prevent, minimize or reduce damage or discomfort to the subject due to heating of the skin or eye tissue by light, the various parameters of the light beam emitted from the emission surface are selected to provide treatment. As described separately, these various parameters described below can be combined with each other within the values disclosed according to the embodiments described herein.

[0186] Wavelength In at least some embodiments, light in the visible to near-infrared wavelength range is used to irradiate the target skin or eye tissue. In at least some embodiments, the light from a particular light source is substantially monochromatic (i.e., light having one wavelength or light having a narrow band of wavelengths). In at least some embodiments, the desired beneficial or therapeutic biological response is obtained at one or more selected wavelengths. In at least some embodiments, the light includes one or more wavelengths between 550 nm and 1064 nm, or between 590 nm and 980 nm. In at least some embodiments, multiple wavelengths are used (e.g., applied simultaneously or sequentially). In at least some embodiments, the light of a particular desired wavelength has a wavelength distribution that peaks at a peak wavelength and has a line width of less than ±10 nm from the peak wavelength. In at least some embodiments, the light of a particular desired wavelength has a line width of less than 4 nm at 90% energy full width. In at least some embodiments, one or more selected wavelengths are chosen from 590nm±10%, 670nm±10%, 810nm±10%, and 1064nm±10%, with a spectral linewidth of less than 4nm and a total width at 90% energy. In at least some embodiments, light of a particular desired wavelength has a wavelength distribution that peaks at the peak wavelength and has a linewidth of less than ±40nm from the peak wavelength at 50% energy. In at least some embodiments, one or more selected wavelengths are chosen from 590nm±10%, 670nm±10%, 810nm±10%, and 1064nm±10%, with a spectral linewidth of less than 40nm and a total width at 50% energy.

[0187] In at least some embodiments, the selected wavelength is in the range of 800 - 900 nm, including, for example, a range of 850 nm ± 10, 15, or 30 nm. In at least some embodiments, the selected wavelength is in the range of 600 - 700 nm, including, for example, a range of 660 ± 10, 15, or 30 nm. In at least some embodiments, the selected wavelength is in the range of 550 - 650 nm, including, for example, a range of 590 ± 10, 15, or 30 nm. In at least some embodiments, the device generates multiple wavelength ranges of light, including but not limited to any combination of the wavelengths or wavelength ranges identified in this paragraph or the previous paragraph.

[0188] In at least some embodiments, each pre - selected wavelength of light is selected to be at or near a transmission peak (or at or near an absorption minimum) with respect to the intervening tissue. In at least some embodiments, one wavelength corresponds to the peak of the tissue transmission spectrum or to 820 nm (NIR). In at least some embodiments, one wavelength corresponds to the peak of the tissue transmission spectrum or to 670 nm (red visible).

[0189] In at least some embodiments, the light source includes at least one GaAlAs laser diode that continuously emits light having a wavelength selected from the aforementioned list. In at least some embodiments, the light source includes at least one LED that each provides non - coherent light having a wavelength selected from the aforementioned list.

[0190] In at least some embodiments, one or more wavelengths are selected to function with one or more photoreceptors within the target tissue. Without being bound by theory or a particular mechanism, but as more fully described elsewhere, for example, irradiation of one or more CCO photoreceptors is thought to increase ATP production in the target tissue or to control, inhibit, prevent, minimize or reduce apoptosis of damaged tissue, thereby producing a beneficial effect. Other wavelengths may be selected to function with photoreceptors to control, inhibit or stimulate different biological responses of the target tissue.

[0191] Some photoreceptors (such as water or hemoglobin) are ubiquitous and absorb light to such an extent that little or no penetration of light energy into the tissue occurs. For example, water absorbs light above about 1300 nm. Thus, energy in this range has little ability to penetrate tissue due to its water content. However, water passes or nearly passes wavelengths between 300 and 1300 nm. Another example is hemoglobin, which absorbs heavily in the range of 300 to 670 nm but is moderately transparent above 670 nm. Based on such broad assumptions, an "IR window" within the body can be defined. There are certain wavelengths that may somewhat penetrate the window.

[0192] Irradiance or power density In at least some embodiments, the light source is 0.005 mW / cm 2 ~10 W / cm 2 、0.01 mW / cm 2 ~5 W / cm 2 、0.01 mW / cm 2 ~1 W / cm 2 、1 mW / cm 2 ~500 mW / cm 2 、500 mW / cm 2 ~1 W / cm 2The light source emits a ray having a time-averaged dose or power density at the emission surface between (e.g., on the retinal surface) or in the overlapping area thereof. In at least some embodiments, the time-averaged dose to the target tissue is at least 0.001 mW / cm² of the target tissue level. 2 ~Maximum 1W / cm 2 In at least some embodiments, the time-averaged surface irradiation dose of the target tissue is at least 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mW / cm². 2 That's all; it depends on the desired clinical outcome.

[0193] In pulsed light, the time-averaged dose is averaged over a long period compared to the temporal pulse width of the pulse (for example, over a very short time, or over 1 second, or several seconds). In continuous wave (CW) light with time-variable dose, the time-averaged dose may be the average of instantaneous doses averaged over a period longer than the characteristic period of the light's variation. In at least some embodiments, duty cycles in the range of 1% to 80% and 10% to 30% are used for 0.001 mW / cm². 2 ~1W / cm 2 , 0.01 mW / cm 2 ~500mW / cm 2 , 10 mW / cm 2 ~100mW / cm 2 or 25 mW / cm 2 ~125mW / cm 2 It can be used as the peak irradiation dose for the target tissue. For example, in at least some embodiments, a 20% duty cycle and 50 mW / cm² are used. 2 A pulsed dose meter is used, which has the following characteristics: In at least some embodiments, the pulsed light beam is 0.001 μJ / cm 2 ~150J / cm 2 During this period, 0.01 μJ / cm 2 ~5J / cm 2 During this period, 0.1 μJ / cm 2~1J / cm 2 During this period, 0.01 μJ / cm 2 ~100mJ / cm 2 During this period, 100 mJ / cm² 2 ~1J / cm 2 The emission surface of the light source has energy or fluence per pulse (e.g., peak irradiation dose multiplied by the temporal pulse width) between or in the overlapping range thereof.

[0194] The cross-sectional area of ​​a ray (e.g., a multimode ray) in at least some embodiments can be approximated using an estimate of the ray intensity distribution. For example, as fully described below, the measured value of the ray intensity distribution is a Gaussian (1 / e 2 The ray intensity distribution can be approximated by measured values ​​or by a "crown" distribution, and a selected outer edge of the ray intensity distribution can be used to define the boundary of the ray area. In at least some embodiments, irradiation of the emitting surface is selected to provide a desired irradiation dose in the target tissue.

[0195] The amount of light emitted is preferably controllably variable, so that the emitted light energy can be adjusted to provide a selected dose to the tissue being treated. In at least some embodiments, the light emitted from the emitting surface is continuous with a total radiated power in the range of 4 watts to 6 watts. In at least some embodiments, the radiated power of the light is 5 watts ± 20% (CW). In certain embodiments, the peak power of the pulsed light is in the range of 10 watts to 30 watts (e.g., 20 watts). In at least some embodiments, the peak power in the pulsed light multiplied by the duty cycle of the pulsed light produced an average radiated power in the range of 4 watts to 6 watts (e.g., 5 watts).

[0196] In at least some embodiments, the amount of light irradiation is selected to provide a predetermined irradiation dose in the target tissue (e.g., at the depth of the pigmented epithelium of the retina). The selection of an appropriate amount of light irradiation from the emitting surface used to obtain the desired irradiation dose in the target tissue preferably includes considering scattering by other intervening tissues. Further information regarding light scattering by tissues is provided in U.S. Patent No. 7,303,578 and V. Tuchin in "Tissue Optics: Light Scattering Methods and Instruments for Medical Diagnosis," SPIE Press (2000), Bellingham, WA, pp. 3-11, which are incorporated herein by reference.

[0197] Phototherapy for the treatment of eye conditions (e.g., glaucoma, AMD, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber's disease, ophthalmic surgery, and uveitis) can depend, at least to some extent, on the dose or power density applied to the tissue (i.e., power per unit area or number of photons per unit area per unit time) and the energy density of the light energy (i.e., power per unit area or number of photons per unit area) when determining the relevant effectiveness of phototherapy. This may be particularly applicable with respect to treating and saving surviving but endangered cells in the danger zone surrounding the major damage. In at least some embodiments, given a selected wavelength of light energy, it is the amount or energy density of light delivered to the tissue (as opposed to the total power or total energy delivered to the tissue) that can determine the relative effectiveness of phototherapy.

[0198] Although not constrained by theory or specific mechanisms, light energy delivered within a specific range of irradiation dose and energy density provides desired biostimulatory effects to the intracellular environment, resulting in the restoration of proper function to previously dysfunctional or underfunctioning mitochondria in compromised cells. These biostimulatory effects may include interactions with target photoreceptors within target tissues, some of which promote ATP production or control, suppress, prevent, minimize, or reduce apoptosis in damaged cells experiencing disease, aging, or reduced blood flow (e.g., ischemia).

[0199] In at least some embodiments, delivering a cellular protective dose of light energy involves selecting surface irradiation of light energy on the eyelid or corneal surface corresponding to a predetermined dose at a target area of ​​the eye (e.g., the retina). As described above, light spreading through tissue is scattered and absorbed by the tissue. The calculation of the dose applied to the eyelid or corneal surface to deliver a predetermined dose to a selected target area can take into account the attenuation of light energy as it spreads through intervening tissue. Factors known to affect the attenuation of light spreading from the skin to the eye include, but are not limited to, skin thickness, the age and sex of the subject, and the location of the target area of ​​the eye, particularly the depth of the area associated with the skin or corneal surface.

[0200] The dose of light selected to be applied to the target area of ​​the eye may depend on, but is not limited to, many factors, including the wavelength of the applied light, heating issues, and the clinical condition of the subject, including the affected tissue area. The dose or power density of light energy delivered to the target area of ​​the eye may be adjusted to be combined with any other therapeutic agent or drug, in particular a pharmaceutical neuroprotective agent, to obtain the desired biological effect. In such embodiments, the selected wavelength and dose may also depend on the additional therapeutic agent or drug selected.

[0201] Temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and dose per pulse A general temporal profile of a pulsed ray, according to at least some embodiments, is described herein. The temporal profile is a combination of multiple pulses (P1, P2...P i ) and each pulse has a temporal pulse width, during which the instantaneous intensity or dose I(t) of the pulse is substantially non-zero. For example, in a pulsed light ray, pulse P1 has a temporal pulse width from time t=0 to time t=T1, and pulse P2 has a temporal pulse width from time t=T2 to time t=T3. and pulse P i is time t = T i ~time t=T i+1 The pulses have a temporal pulse width. The temporal pulse width can also be called the “pulse ON time”. The pulses are spaced temporally apart from each other by a period of time, during which the instantaneous intensity or dose of the light is substantially zero. For example, pulse P1 is spaced temporally apart from pulse P2 by time t = T2 - T1. The time between pulses can also be called the “pulse OFF time”. In at least some embodiments, the pulse ON times of the pulses are substantially equal to each other, while in other embodiments, the pulse ON times are different from each other. In at least some embodiments, the pulse OFF times between pulses are substantially equal to each other, while in other embodiments, the pulse OFF times between pulses are different from each other. As used herein, the term “duty cycle” has its broadest reasonable interpretation and includes, but is not limited to, the pulse ON time divided by the sum of the pulse ON time and pulse OFF time. In a pulsed light ray, the duty cycle is less than 1. The values ​​of the duty cycle and temporal pulse width specify the repetition rate of the pulsed light ray in detail.

[0202] Each pulse can have a temporal pulse shape that describes the instantaneous intensity or dose of pulse I(t) as a function of time. For example, the temporal pulse shape of the pulsed light beam is irregular and not the same for various pulses. In at least some embodiments, the temporal pulse shape of the pulsed light beam is substantially the same for various pulses. For example, the pulse can have a square temporal pulse shape, where each pulse has a substantially constant instantaneous dose over the pulse ON time. In at least some embodiments, the peak doses of the pulses are different from each other, while in other embodiments, the peak doses of the pulses are substantially equal to each other. Various other temporal pulse shapes (e.g., triangular, trapezoidal) are further compatible in at least some embodiments. In at least some embodiments, the rise time and fall time can be expressed in relation to a particular fraction of the peak dose of the pulse (e.g., the rise / fall time for 50% of the peak dose of the pulse).

[0203] In at least some embodiments, the peak dose of pulse P i can be the maximum value of the instantaneous dose I(t) within the temporal pulse width of the pulse. In at least some embodiments, the instantaneous dose varies within the temporal pulse width of the pulse, while in other embodiments, the instantaneous dose is substantially constant within the temporal pulse width of the pulse.

[0204] In at least some embodiments, the pulse dose of pulse P i is the integral of the instantaneous dose I(t) of pulse P

[0205] [Number] over the temporal pulse width of the pulse. i

[0206] [Number] ​In at least some embodiments, the total irradiation dose I TOTAL This can be the total pulsed irradiation dose.

[0207]

number

[0208]

number

[0209]

number

[0210] For example, different pulsed irradiation doses

[0211]

number

[0212]

number

[0213] The pulsed dose and duty cycle can be selected to provide a predetermined time-averaged dose. In at least some embodiments, where the time-averaged dose is equal to the dose of continuous wave (CW) light, the pulsed light and the CW light have an equal number of photons or fluxes. For example, 5 mW / cm². 2 A pulsed light beam with a pulsed irradiation dose and a duty cycle of 20% has a pulsed irradiation dose of 1 mW / cm². 2 This provides the same number of photons as a CW (continuously warm) beam with the same irradiation dose. However, in contrast to a CW beam, the parameters of a pulsed beam can be selected to deliver photons in a way that yields results unattainable with a CW beam.

[0214] In at least some embodiments, one or more of the temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and pulse dose of the pulsed light are selected so that no part of the tissue is heated to a temperature above 60°C, above 55°C, above 50°C, or above 45°C. In at least some embodiments, one or more of the temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and pulse dose of the pulsed light are selected so that no part of the tissue is heated to a temperature above 30°C, above 20°C, or above 10°C above its baseline temperature. In at least some embodiments, one or more of the temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and pulse dose of the pulsed light are selected to monitor a target in which no part of the tissue is heated to a temperature above 5°C, above 3°C, or above 1°C above its baseline temperature. In at least some embodiments, the baseline temperature is the temperature that the tissue would have if it were not irradiated with light. In contrast to previous low-level phototherapy, pulsed light has an average radiant power ranging from 1 watt to 10 watts, or from 4 watts to 6 watts.

[0215] In at least some embodiments, pulsed irradiation can provide a more effective treatment. Pulsed irradiation provides a higher peak dose in a shorter time, thereby allowing more power to be applied to the target tissue, while at the same time allowing thermal relaxation of interstitial tissue and blood between pulses to avoid overheating the interstitial tissue. The time scale for thermal relaxation is typically in the range of 2 to 3 milliseconds. For example, the thermal relaxation time constant of human skin (e.g., the time it takes for tissue to cool from high temperature to half high temperature) is about 3 to 10 milliseconds, while the thermal relaxation time constant of human hair follicles is about 40 to 100 milliseconds.

[0216] However, while pulsed light on this timescale conveniently reduces heating of intercellular tissues and blood, it does not provide the optimal amount of the intended effect compared to other timescales. In at least some embodiments, the eye or eye tissue in question is not optimized to reduce the effects of heat, but instead is irradiated with pulsed light having parameters selected to stimulate, excite, induce, or support one or more intercellular or intracellular biological processes related to the persistence, regeneration, or recovery of cellular performance or viability.

[0217] Therefore, in at least some embodiments, the selected temporal profile can result in a temperature of the irradiated tissue that is higher than that resulting from other temporal profiles, but is more effective than other temporal profiles. In at least some embodiments, the pulse parameters are selected to exploit the dynamics of biological processes rather than optimizing thermal relaxation of the tissue. In at least some embodiments, the pulsed light has a temporal profile (e.g., peak dose per pulse, temporal pulse width, and pulse duty cycle) selected to modulate the membrane potential in order to enhance, restore, or activate the cellular survival, cellular function, or both of the irradiated cells after an eye disease or injury.

[0218] For example, in at least some embodiments, pulsed light has a temporal profile that supports one or more intercellular or intracellular biological processes related to the survival or regeneration of retinal cells, but does not optimize thermal relaxation of the irradiated tissue. In at least some embodiments, cells survive longer after irradiation compared to their survival in the absence of irradiation. For example, in at least some embodiments, light can have a protective effect on cells or can induce cell regeneration processes.

[0219] In at least some embodiments, the temporal profile (e.g., peak dose, temporal pulse width, and duty cycle) is selected to maintain the irradiated tissue below a predetermined temperature while taking advantage of the dynamics of biological processes. This predetermined temperature is higher than the temperature obtained with other temporal profiles (e.g., other values ​​of peak dose, temporal pulse width, and duty cycle) and it limits or minimizes the temperature rise of the surrounding tissue due to irradiation.

[0220] For example, 10 W / cm² 2 The temporal profile with a peak irradiation dose and a 20% duty cycle is 2 W / cm². 2 It has a time-averaged irradiation dose of 2 W / cm². Such pulsed light has a pulsed dose of 2 W / cm². 2 It provides the same number of photons to the irradiation surface as a continuous wave (CW) beam with the same irradiation dose. However, due to the "dark time" between pulses, pulsed beams can result in a lower temperature increase than CW beams.

[0221] To reduce or minimize the temperature rise at the irradiated site of tissue, the temporal pulse width and duty cycle can be selected so that most of the heat generated per pulse dissipates before the next pulse reaches the irradiated site. In at least some embodiments, instead of optimizing the ray temporal parameters to minimize the temperature rise, the temporal parameters are selected to effectively correspond to, or closely approximate, the timing of the biomolecular processes involved in photon absorption, providing increased effectiveness. Instead of having temporal pulse widths on the order of hundreds of microseconds, at least some embodiments utilize temporal pulse widths that do not optimize the thermal relaxation of the irradiated tissue (e.g., milliseconds, tens of milliseconds, hundreds of milliseconds). Because these pulse widths significantly exceed the thermal relaxation timescale, the resulting temperature rise is greater than that of smaller pulse widths, but less than that of CW ray due to heat dissipation between pulses.

[0222] Numerous studies have investigated the effects of in vitro irradiation of cells using pulsed light in various cellular configurations. A study of the mechanism of action of non-coherent pulsed irradiation at a wavelength of 820 nm (pulse repetition frequency of 10 Hz, pulse width of 20 ms, dark period between pulses of 80 ms, and duty factor of 20%) on in vitro cell adhesion found that pulsed infrared light at 820 nm increases cell matrix binding. (Karu, Lasers in Surgery and Medicine 29:274~281 (2001), this entire work is incorporated herein by reference). This study hypothesized that the regulation of monovalent ion bundles across the plasma membrane and the release of arachidonic acid were related to the cellular signaling pathway activated by irradiation at 820 nm. A study of photo-induced changes in membrane conductance of abdominal photoreceptor cells revealed pulse parameter-dependent behavior exhibiting two photo-induced membrane processes. Lisman et al., J.Gen.Physiology 58:544~561 (1971), this entire work is incorporated herein by reference. Studies of laser-activated electron injection into cytochrome c oxidase observed that the kinetics and some of its thermodynamic properties establishing the reaction sequence of the proton pump mechanism have time constants on the order of milliseconds. Belevich et al., Proc.Nat'l Acad.Sci.USA 104:2685~2690 (2007) and Belevich et al., Nature 440:829~832 (2006), this entire work is incorporated herein by reference. In vivo studies of neuronal activation based on pulsed infrared radiation have proposed a photothermal effect from transient tissue temperature changes, resulting in direct or indirect activation of transmembrane ion channels that cause the propagation of action potentials. Wells et al., Proc. SPIE 6084:60840X (2006), is incorporated herein by reference in its entirety.

[0223] In at least some embodiments, the temporal profile of a pulsed ray includes a peak dose, temporal pulse width, temporal pulse shape, duty cycle, and pulse repetition rate or frequency. In at least some embodiments in which the pulsed ray penetrates the eye region, at least one of the peak dose, temporal pulse width, temporal pulse shape, duty cycle, and pulse repetition rate is 0.01 mW / cm² across the ray cross-section. 2 ~1W / cm 2 During that time, 10 mW / cm² 2 ~10W / cm 2 During this period, 100 mW / cm² 2 ~1000mW / cm 2 During this period, 500 mW / cm² 2 ~1W / cm 2 Between or 650 mW / cm² 2 ~750mW / cm 2 The light source emission surface is selected to impart a time-averaged dose (averaged over time, including multiple pulses). In at least some embodiments, the time-averaged dose to the retinal tissue being treated is 0.01 mW / cm². 2 Larger.

[0224] In at least some embodiments, the temporal pulse shape is typically rectangular, triangular, or any other shape. In at least some embodiments, the pulse has a rise time of less than 1% of the pulse ON time (e.g., 10% to 90% of the peak irradiation dose) or a fall time of less than 1% of the pulse ON time (e.g., 90% to 10% of the peak irradiation dose).

[0225] In at least some embodiments, the pulse has a temporal pulse width (e.g., pulse ON time) in the range of 0.001 milliseconds to 150 seconds, 0.01 milliseconds to 10 seconds, 0.1 milliseconds to 1 second, 0.5 milliseconds to 100 milliseconds, 2 milliseconds to 20 milliseconds, or 1 millisecond to 10 milliseconds. In at least some embodiments, the pulse width is 0.5, 1, 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 milliseconds. In at least some embodiments, the temporal pulse width is in the range of 0.1 milliseconds to 150 seconds.

[0226] In at least some embodiments, the time between pulses (e.g., pulse OFF time) is in the range of 0.01 milliseconds to 150 seconds, 0.1 milliseconds to 100 milliseconds, 4 milliseconds to 1 second, 8 milliseconds to 500 milliseconds, 8 milliseconds to 80 milliseconds, or 10 milliseconds to 200 milliseconds. In at least some embodiments, the time between pulses is 4, 8, 10, 20, 50, 100, 200, 500, 700, or 1000 milliseconds.

[0227] In at least some embodiments, the pulse duty cycle is in the range of 1% to 80%, or 10% to 30%. In at least some embodiments, the pulse duty cycle is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0228] In at least some embodiments, the peak irradiation dose and pulse energy density per pulse across the ray cross-section at the emission surface of the light source are 0.01 mW / cm². 2 ~1W / cm 2 , 10 mW / cm 2 ~10W / cm 2 , 100mW / cm 2 ~1000mW / cm 2 500mW / cm² 2 ~1W / cm 2 650mW / cm² 2 ~750mW / cm2 , 20 mW / cm 2 ~20 W / cm 2 , 200 mW / cm 2 ~2000 mW / cm 2 , 1 W / cm 2 ~2 W / cm 2 , 1300 mW / cm 2 ~1500 mW / cm 2 , 1 W / cm 2 ~1000 W / cm 2 , 10 W / cm 2 ~100 W / cm 2 , 50 W / cm 2 ~100 W / cm 2 , or, 65 W / cm 2 ~75 W / cm 2 is in the range of.

[0229] In at least some embodiments, the pulse energy density or energy density can be calculated as the time-averaged power density divided by the pulse repetition rate or frequency. For example, the minimum pulse energy density occurs at the minimum average power density and the fastest pulse repetition rate, where the pulse repetition rate is the duty cycle divided by the temporal pulse width, and the maximum pulse energy density occurs at the maximum average power density and the slowest pulse repetition rate. For example, at a time-averaged power density of 0.01 mW / cm 2 and a frequency of 100 kHz, the pulse energy density is 0.1 μJ / cm 2 , and at a time-averaged power density of 10 W / cm 2 and a frequency of 1 Hz, the pulse energy density is 10 J / cm 2 . For example, at a time-averaged power density of 0.01 mW / cm 2 and a frequency of 100 kHz, the pulse energy density is 0.1 μJ / cm 2 , and at a time-averaged power density of 10 W / cm 2 and a frequency of 1 Hz, the pulse energy density is 1 μJ / cm 2 . As yet another example, at a time-averaged power density of 700 mW / cm 2 and a frequency of 100 Hz, the pulse energy density is 7 mJ / cm 2 .

[0230] Beam size and beam profile In at least some embodiments, the light rays emitted from the light source have a nominal diameter in the range of 10 to 40 millimeters, 20 to 35 millimeters, or equal to 30 millimeters. In at least some embodiments, the cross-section is a circle with a radius typically in the range of 1 cm to 2 cm. In at least some embodiments, the light rays emitted from the emitting surface are 2 cm from the emitting surface of the light source. 2 Over, or 2cm 2 ~20cm 2 It has a cross-sectional area within the range of [this range].

[0231] Eyebox or eyepiece The beam diameter is at least 1 / e of the maximum intensity of the ray. 2 At an intensity of 1 / e, it can be defined as the maximum chord around the area of ​​the eye illuminated by the ray. In at least some embodiments, the ray periphery used to measure the beam diameter is such that the ray intensity is 1 / e of the maximum intensity of the ray. 2 The point is that, in at least some embodiments, the maximum effective diameter is limited by the size of the orbital region of the target and by heating of the orbital region of the target by irradiation. In at least some embodiments, the minimum effective diameter is limited by heating and by the total number of treatment sites that would actually be performed. For example, treating the target eye with a small beam diameter ray uses a corresponding number of treatment sites. In at least some embodiments, the irradiation time per treatment site can be adjusted accordingly to obtain the desired dose.

[0232] Identifying the total luminous flux within a circular aperture of a specific radius that is concentrated at the exit aperture ("intracircular energy") is a method for determining the force (irradiation) distribution on the light rays emitted from the emission surface. "Intracircular energy" can be used to ensure that the light rays are not too concentrated, too large, or too small. In at least some embodiments, the light rays emitted from the emission surface have total radiated power, and the light rays have total luminous flux within a 20 mm cross-sectional circle that is concentrated at the emission surface, and this is 75% or less of the total radiated power. In at least some embodiments, the light rays emitted from the emission surface have total radiated power, and the light rays have total luminous flux within a 26 mm cross-sectional circle that is concentrated at the emission surface, and this is 50% or less of the total radiated power.

[0233] In at least some embodiments, the beam intensity profile has a half-Gaussian profile, while in at least some embodiments, the beam intensity profile has a "crown" profile. In at least some embodiments, the ray is substantially free of high-flux regions in the beam intensity profile, or free of "hot spots" where the localized flux averaged over 3 mm × 3 mm is more than 10% higher than the average flux. In at least some embodiments, the device generates a ray substantially free of hot spots, thereby avoiding large temperature gradients, which could otherwise cause discomfort to the subject.

[0234] Beam spread In at least some embodiments, the beam spread from the emission surface is significantly smaller than the scattering angle of light within the irradiated tissue, which is typically a few degrees. In at least some embodiments, the ray has an aperture angle greater than zero and less than 35 degrees.

[0235] Total treatment time The total treatment time can be controlled by a programmable controller. The real-time clock and timer of the programmable controller can be used to control the timing of a particular treatment regimen to enable scheduled treatments (e.g., daily, twice a day, or every other day). In at least some embodiments, the treatment proceeds continuously in periods of 10 seconds to 2 hours, 1 to 20 minutes, or 1 to 5 minutes. For example, in at least some embodiments, the total treatment time is 2 minutes. In at least some embodiments, light energy is delivered for at least one total treatment period of at least 5 minutes per eye, or for at least one total treatment period of at least 10 minutes for both eyes.

[0236] The minimum treatment time in at least some embodiments is limited by the biological reaction time (which is on the order of microseconds). The maximum treatment time in at least some embodiments may be limited by heating and the actual treatment time (e.g., completing treatment within approximately 24 hours of injury). The light energy may be pulsed during the treatment period, or the light energy may be applied continuously during the treatment period. If the light is pulsed, the pulses may be 2 milliseconds in length and may occur at a frequency of 100 Hz or at least 10 nanoseconds in length, and at a frequency up to 100 kHz, although shorter or longer pulse widths and lower or higher frequencies may be used. For example, the light may be pulsed at frequencies of 1 Hz to 100 Hz, 100 Hz to 1 kHz, 1 kHz to 100 kHz, less than 1 Hz, or greater than 100 kHz.

[0237] In at least some embodiments, treatment may be completed after one treatment period, while in other embodiments, treatment may be repeated for multiple treatment periods. The time between treatment periods may be at least 5 minutes, 24 hours, at least 1-2 days, or at least 1 week. Treatment may be repeated multiple times per day or multiple times per week. The length of treatment time and the frequency of treatment periods may depend on several factors, including the functional recovery of the subject, the results of image analysis of the injury, disease, or condition being treated, the use of pulsed or continuous light, the amount of light irradiation, the number of light sources used, and the order or pattern of treatment. In at least some embodiments, timing parameters may be adjusted in response to feedback signals from sensors or other devices (e.g., magnetic resonance imaging apparatus) that monitor the subject.

[0238] The penetration of the human eye In at least some embodiments, 3-5 J / cm 2 Low levels of red light or NIR fluence are beneficial in vivo, but 50-100 J / cm² is beneficial. 2 High doses of radiation, such as those mentioned above, may lose their beneficial effects.

[0239] The descriptions and illustrations provided herein are intended to inform those skilled in the art of the disclosure, its principles, and its practical applications. Those skilled in the art can apply the disclosure in numerous forms to suit their specific usage requirements. Accordingly, the specific embodiments of the disclosure described herein are not intended to be exhaustive or limiting.

[0240] While this disclosure is discussed in relation to specific embodiments and examples, it should be understood that this disclosure extends beyond the particularly disclosed embodiments to other alternative embodiments, or to this disclosure and obvious modifications and their equivalents. Some embodiments are described with reference to the accompanying drawings. However, it should be understood that the drawings are not drawn to scale. Distances, angles, etc., are merely illustrative and do not necessarily have an exact relationship to the actual dimensions and layout of the shown apparatus. Components can be added, removed, or rearranged. Furthermore, those skilled in the art will understand that any of the above methods can be carried out using suitable apparatus. Moreover, this disclosure, which describes specific structures, aspects, methods, properties, features, qualities, attributes, elements, etc., related to various embodiments, can be used in all other embodiments described herein. Furthermore, processing steps can be added, removed, or rearranged. A wide variety of designs and methods are possible.

[0241] For the purposes of this disclosure, specific aspects, advantages, and new features of the disclosure are described herein. It should be understood that not all such advantages may necessarily be achieved by any particular embodiment of the disclosure. Thus, a person skilled in the art will recognize that the disclosure may be implemented or performed in a manner that achieves one or more advantages taught herein without necessarily obtaining other advantages, for example, as taught or suggested herein.

[0242] Multi-wavelength phototherapy system and method As described in further detail herein, as part of this disclosure, the tuned and targeted delivery of light having two or more specific and different wavelengths (or frequency ranges) to cells can also be advantageously used to (a) improve intracellular mitochondrial function via increased cytochrome c oxidase ("CCO") activity, (b) restore intracellular mitochondrial membrane potential ("MMP"), and (c) upregulate intracellular ATP synthesis. Moreover, such enhanced intracellular activity can be further utilized to promote local cellular responses, including, for example, cellular responses that are absent or present at insufficient levels in damaged and / or diseased tissue compared to the corresponding normal undamaged and / or healthy tissue.

[0243] Accordingly, in certain embodiments, the Disclosure provides multi-wavelength phototherapy systems and methods for promoting a desired cellular response, the methods comprising the tuned and targeted delivery of two or more doses of light to cells. Thus, a first dose having a first wavelength or range of wavelengths can stimulate a first intracellular activity, and a second dose having a second wavelength or range of wavelengths can stimulate a second intracellular activity. The tuned and targeted delivery of the first and second doses of light promotes the desired cellular response.

[0244] In a related embodiment, the Disclosure provides a multiwavelength phototherapy system and method for the treatment of damaged and / or diseased tissue, the method comprising the tuned and targeted delivery of two or more doses of light to damaged and / or diseased tissue. Thus, a first dose of light having a first wavelength or range of wavelengths can stimulate a first intracellular activity, and a second dose of light having a second wavelength or range of wavelengths can stimulate a second intracellular activity. The tuned and targeted delivery of the first and second doses of light can promote a desired cellular response within the damaged and / or diseased tissue, thereby promoting the healing of the damaged tissue and / or reversing or slowing the progression of disease in the diseased tissue.

[0245] In certain embodiments of these embodiments, the Disclosure illustrates multiwavelength phototherapy systems and methods for the treatment of damaged and / or diseased tissue, the methods comprising the tuned and targeted delivery of two or more doses of light to damaged and / or diseased ocular tissue within the eye. Thus, a first dose of light having a first wavelength or range of wavelengths can stimulate a first intracellular activity within the damaged and / or diseased ocular tissue, and a second dose of light having a second wavelength or range of wavelengths can stimulate a second intracellular activity within the damaged and / or diseased ocular tissue. The tuned and targeted delivery of the first and second doses of light can promote a desired cellular response within the damaged and / or diseased ocular tissue, thereby promoting the healing of the damaged tissue and / or reversing or slowing the progression of disease in the diseased ocular tissue.

[0246] Figure 24 shows one embodiment of multiwavelength phototherapy and methods for improving or restoring the function of target cells or tissues, wherein the activation of two or more photosensitive factors is promoted by the regulated and targeted delivery of two or more different wavelengths of light to cells or tissues, thereby improving or restoring the function of the target cells. In these systems and methods, a first light source is positioned for targeted delivery of a first wavelength of light to target cells (2402), a second light source is positioned for targeted delivery of a second wavelength of light to target cells (2404), a first photosensitive factor of the target cells is activated by the first wavelength of light (2406), and a second photosensitive factor of the target cells is activated by the second wavelength of light (2408).

[0247] Figure 25 shows one embodiment of a multi-wavelength phototherapy system and method for providing a method to stimulate cytochrome c oxidase (CCO) activity in cells. It involves the regulated and targeted delivery of two or more photodose doses to cells having two or more photosensitive factors associated with and required for CCO activity. A first dose has a first wavelength that can activate a first photosensitive factor of CCO, and a second dose has a second wavelength that can activate a second photosensitive factor of CCO, thereby stimulating CCO activity. These systems and methods position a first light source for targeted delivery of a first wavelength of light to target cells that produce cytochrome c oxidase (2502), a second light source for targeted delivery of a second wavelength of light to target cells that produce cytochrome c oxidase (2504), activating a first cytochrome c oxidase-related photosensitivity factor in the target cells with the first wavelength of light (2506), and activating a second cytochrome c oxidase-related photosensitivity factor in the target cells with the second wavelength of light (2508).

[0248] Figure 26 shows one embodiment of a multiwavelength phototherapy apparatus, system, and method for treating a patient suffering from a disorder or disease associated with one or more lost or reduced cellular functions, by tuned and targeted delivery of two or more different wavelengths of light to one or more cells of the patient, in order to restore lost or reduced cellular functions and thereby treat the disorder or disease. By these systems and methods, a first light source is positioned for targeted delivery of a first wavelength of light to target cells associated with the disorder or disease in the patient suffering from the disorder or disease (2602), a second light source is positioned for targeted delivery of a second wavelength of light to target cells associated with the disorder or disease in the patient suffering from the disorder or disease (2604), activating a first photosensitive factor of the target cells associated with the disorder or disease with the first wavelength of light (2606), and activating a second photosensitive factor associated with the disorder or disease with the second wavelength of light (2608).

[0249] Figure 27 shows one embodiment of a multiwavelength phototherapy system and method for treating patients suffering from ocular disorders or diseases associated with the loss or reduced function of one or more ocular cells. The system and method includes the tuned and targeted delivery of two or more different wavelengths of light to the patient's eye in order to restore or enhance the function of the lost or reduced ocular cells, thereby treating the disorder or disease. By these systems and methods, a first light source is positioned for targeted delivery of a first wavelength of light to target cells associated with the eye disorder or disease in a patient suffering from an eye disorder or disease (2702), a second light source is positioned for targeted delivery of a second wavelength of light to target cells associated with the eye disorder or disease in a patient suffering from an eye disorder or disease (2704), activating a first photosensitive factor in target cells associated with the eye disorder or disease with the first wavelength of light (2706), and activating a second photosensitive factor associated with the eye disorder or disease with the second wavelength of light (2708).

[0250] Multiwavelength phototherapy systems and methods for the treatment of damaged and / or diseased ocular tissue are illustrated herein by multiwavelength phototherapy systems and methods for the treatment of ocular disorders and / or ocular diseases. The treatments restore and / or exacerbate one or more symptoms of ocular disorders and / or diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber's disease, ocular injury and / or uveitis resulting from surgical procedures.

[0251] In certain embodiments of these embodiments, light can be delivered through closed eyelids, and most of the light can be expected to scatter over a relatively large area of ​​the retina, or it can be carried out with eyes open. With eyes open, most of the therapeutic light can be delivered to the retina through the lens and pupil of the eye with minimal scattering. This can be carried out, for example, by incorporating a spatial light modulator (SLM) that precisely forms and controls the exposed area on the retina. The SLM may be an LCOS panel, a scanning mirror, a deformable mirror array, or other modulator.

[0252] Various parameters of the light emitted from the light source can be conveniently selected to control, suppress, prevent, minimize, or reduce the damage and / or discomfort to the patient that may result from photo-induced heating of the target tissue (e.g., skin or eye tissue), and to provide therapeutic benefits. These various parameters can be selected by those skilled in the art and combined within the range of values ​​disclosed herein to obtain a suitable state for the treatment of tissue damage or disease according to the system and method.

[0253] The ray parameters include, but are not limited to, (1) the wavelengths of two or more light sources, (2) the dose or power density of two or more light sources, (3) the temporal pulse width and shape, duty cycle, repetition rate, and dose per pulse for each of the two or more light sources, and (4) the total treatment time for each of the two or more light sources. Next, these parameters used in the multi-wavelength systems and methods disclosed herein, as well as guidance in the selection of these parameters, will be described.

[0254] In certain embodiments, light in the visible to near-infrared wavelength range can be delivered to target cells or tissues (e.g., patient skin or eye tissue). The light can be substantially monochromatic (i.e., having a single wavelength or a narrow frequency band of wavelengths), and the desired cellular response can be obtained using two or more selected wavelengths of light.

[0255] For example, a single light source may have wavelengths ranging from approximately 550 nm to 1064 nm, or from approximately 590 nm to 980 nm. Multiple wavelengths of light can be used, with the first wavelength of light being delivered simultaneously with the second wavelength of light, or the first wavelength of light being delivered independently and continuously from the second wavelength of light.

[0256] In certain embodiments of the phototherapy system and method, the light has a wavelength distribution exhibiting a peak wavelength, and its wavelength distribution has a line width of less than ±10 nm from the peak wavelength at 90% energy and a line width of less than ±4 nm from the peak wavelength. In related embodiments, each wavelength of light is independently selected from 590 nm ± 10%, 670 nm ± 10%, 810 nm ± 10%, and 1064 nm ± 10%, respectively, with a spectral line width of less than 4 nm and a total width at 90% energy. In further embodiments, each wavelength of light is independently selected from a wavelength distribution that peaks at the peak wavelength, and it has a line width of less than ±40 nm from the peak wavelength at 50% energy. In yet another embodiment, each wavelength of light is independently selected from 590 nm ± 10%, 670 nm ± 10%, 810 nm ± 10%, and 1064 nm ± 10%, respectively, with a spectral line width of less than 40 nm and a total width at 50% energy.

[0257] To ensure that the amount of light delivered to the treated cells or tissue is maximized, each pre-selected wavelength of light can be chosen so as to be the transmission peak or near the transmission peak (or near the absorption minimum) with respect to the intervening tissue. For example, the first wavelength can correspond to the peak of the tissue's transmission spectrum at approximately 820 nm (NIR), and the second wavelength can correspond to the peak of the tissue's transmission spectrum at approximately 670 nm (red visible light).

[0258] The phototherapy system and method can be carried out using a light source having one or more continuously emitting GaAlAs laser diodes, each having a wavelength as described herein. Alternatively, the method can be carried out using a light source having one or more LEDs, each providing non-coherent light having a wavelength as described herein.

[0259] Two or more wavelengths of light can be selected to stimulate or activate one or more photoreceptors within target cells or tissues. While not constrained by theory or specific mechanisms of action, it is believed that the delivery of light to one or more CCO photoreceptors increases, for example, ATP production in target cells or tissues, thereby controlling, inhibiting, preventing, minimizing, or reducing apoptosis in damaged tissues, and thus producing beneficial therapeutic effects as detailed herein. Wavelengths may be selected to activate one or more photoreceptors to control, inhibit, or stimulate different biological responses in the target tissue.

[0260] Some photoreceptors (e.g., water or hemoglobin) are ubiquitous and absorb light to such an extent that the light energy cannot reach the tissue. For example, water is known to absorb light above approximately 1300 nm. Therefore, light of such wavelengths cannot effectively penetrate target tissue due to its water content. However, water transmits, or almost transmits, light with wavelengths of approximately 300 nm to approximately 1300 nm. Similarly, hemoglobin, which absorbs light from approximately 300 nm to approximately 670 nm, transmits light above approximately 670 nm to a moderate degree. Based on these well-known factors that limit the effective delivery of light, the "IR window" can be defined with respect to the transmittance of light delivered to target tissue. Within this IR window, certain wavelengths of light can be transmitted with little restriction by light-absorbing molecules (e.g., water and hemoglobin).

[0261] In certain embodiments of this phototherapy system and method, the light source is approximately 0.005 mW / cm² across the cross-section of the ray. 2 ~about 10W / cm 2 , about 0.01mW / cm 2 ~about 5W / cm 2 , about 0.01mW / cm 2 ~about 1W / cm 2 , about 1mW / cm 2 ~about 500mW / cm 2 , or approximately 500 mW / cm² 2 ~about 1W / cm 2It can be used to emit a ray with a time-averaged irradiation dose or power density at the emission surface of the light source (for example, on a tissue surface such as the retinal surface).

[0262] In other embodiments of this phototherapy system and method, the light source can be used to emit a ray having a time-averaged dose or power density that can typically be reduced by 1 / e from the value used when the light source is applied directly to the retina through a closed eyelid. For example, the time-averaged dose to the target tissue (e.g., to a depth of about 2 cm below the eyelid) may be about 0.001 mW / cm² at the tissue level, depending on the desired therapeutic application. 2 ~about 1W / cm 2 , or at the organizational level, at least about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mW / cm² 2 It could be any of the above.

[0263] In pulsed light, the time-averaged dose can be averaged over a longer period compared to the temporal pulse width of the pulse (for example, averaged over a very short period, or over one second, or several seconds). In continuous wave (CW) light with time-variable dose, the time-averaged dose may be the average of instantaneous doses averaged over a period longer than the characteristic period of the light's variation.

[0264] In certain embodiments of this phototherapy system and method, the duty cycle is approximately 0.001 mW / cm². 2 ~about 1W / cm 2 , about 0.01mW / cm 2 ~about 500mW / cm 2 , about 10mW / cm 2 ~about 100mW / cm 2 Or approximately 25 mW / cm² 2 ~Approx. 125mW / cm 2 The peak irradiation dose to the target tissue can be approximately 1% to 80% or approximately 10% to 30%. For example, at a 20% duty cycle, the target tissue is irradiated at approximately 50 mW / cm². 2A pulsed dosimetry with a peak irradiation dose of approximately 0.001 μJ / cm² can be used. In certain embodiments, the pulsed light is approximately 0.001 μJ / cm². 2 ~About 150J / cm 2 , about 0.01μJ / cm 2 ~about 5J / cm 2 , about 0.1μJ / cm 2 ~About 1J / cm 2 , about 0.01μJ / cm 2 ~Approx. 100mJ / cm 2 , about 100mJ / cm 2 ~About 1J / cm 2 The light source emits an energy or fluence per pulse (e.g., peak irradiation dose multiplied by the temporal pulse width) on its emission surface.

[0265] The cross-sectional area of ​​a ray (e.g., multimode ray) can be measured using an approximation of the ray intensity distribution. For example, the measured value of the ray intensity distribution can be expressed as a Gaussian (1 / e 2 The ray intensity distribution can be approximated by the measured value or by the "crown" distribution, and the selected outer edge of the ray intensity distribution can be used to define the boundary of the ray area.

[0266] The irradiation of the emitting surface can be selected to provide a desired dose of light to the target tissue. The dose of light is variably controllable, and as a result, the emitted light energy can be adjusted to provide a selected dose of light to the target tissue. The light emitted from the emitting surface may be continuous with a total radiated power of approximately 4 watts to approximately 6 watts. For example, the radiated power of the light may be 5 watts ± 20% (CW).

[0267] The peak power of pulsed light can range from approximately 10 watts to approximately 30 watts (e.g., approximately 20 watts). Multiplying the peak power of pulsed light by the duty cycle of the pulsed light results in an average radiated power of approximately 4 watts to approximately 6 watts (e.g., approximately 5 watts).

[0268] The amount of light emitted can be selected to provide a predetermined dose to the target tissue (for example, at the depth of the pigmented epithelial layer of the retina). The selection of an appropriate amount of light emitted from the emitting surface to obtain the desired dose to the target tissue generally takes into account light scattering caused by non-target intervening tissues. Further information regarding light scattering by tissues is provided in U.S. Patent No. 7,303,578 and Tuchin, SPIE Press 3-11 (2000), both of which are incorporated herein by reference in their entirety.

[0269] Phototherapy for the treatment of eye conditions (e.g., glaucoma, AMD, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber's disease, ophthalmic surgery, and uveitis) is based to some extent on the findings disclosed herein that the irradiation dose or power density applied to the target tissue (i.e., power per unit area or number of photons per unit area per unit time) and the energy density of the light energy (i.e., power per unit area or number of photons per unit area) practically influence the effectiveness of a given phototherapy. These factors are particularly relevant when designing phototherapy to preserve the effectiveness of surviving but endangered cells within a “danger zone” in the area surrounding the site of major damage.

[0270] It has been further discovered and presented herein as part of this disclosure that, with respect to a given wavelength of light energy, the amount of light delivered to a target tissue and / or energy density—as opposed to the total power or total energy delivered to the tissue—determines the relative therapeutic effect of a given phototherapy.

[0271] While not bound by theory or specific mechanisms of operation, it is believed that light energy delivered within a specific range of luminescence and energy density provides a photobiomodulatory effect on the intracellular environment, resulting in the restoration of normal mitochondrial function to previously dysfunctional or underfunctioning mitochondria in compromised cells. Such photobiomodulatory effects may include, for example, one or more interactions with one or more photoreceptors within the target tissue, which may facilitate ATP production and / or suppress, prevent, minimize or reduce apoptosis in diseased or senescent cells, increase blood flow in ischemic tissue, or modulate the release of NO, ROS, or other intracellular mediators to modify gene and protein expression in compromised cells. The roles of irradiation dose and exposure time are discussed, for example, in Hans et al., Lasers in Surgery and Medicine 12:528-537 (1992), which is incorporated herein by reference in its entirety.

[0272] Delivering a cellular protective dose of light energy can also include selecting a surface dose of light energy to a tissue surface (e.g., the surface of the eyelid or cornea), where the surface dose corresponds to a predetermined dose in a target area of ​​the tissue (e.g., the cornea or retina of the eye). As will be described in more detail herein, light propagating through tissue is both radiated and absorbed by that tissue. The calculation of the dose applied to a target area (eyelid or corneal surface) can therefore take into account the attenuation of light energy, since it propagates through one or more intervening non-target tissues, to ensure that a predetermined and desired dose is delivered to a selected area of ​​the target tissue (e.g., ocular tissue). Factors influencing the degree of attenuation of light spreading from the skin to the tissue include, for example, skin thickness, the age and / or sex of the subject, and the location of the target area of ​​the tissue, particularly the depth of the area related to the skin surface, and in the case of the eye, the corneal surface.

[0273] Factors influencing the selection of the irradiation dose for delivery to a target area of ​​a given tissue include the light applied, consideration of photo-induced heating of the tissue, and the condition and area of ​​the patient's damaged and / or diseased tissue. The irradiation dose or power density of light energy delivered to the target area of ​​the eye in question is influenced and consequently adjusted when the desired phototherapy regimen is delivered with one or more additional therapeutic agents (e.g., one or more neuroprotective agents) to achieve the desired biological effect. It will be understood that the selection of light parameters (e.g., wavelength and irradiation dose) is influenced by the specific therapeutic agent selected.

[0274] The systems and methods of this disclosure further explore various temporal profiles of pulsed light, which can be conveniently used to enhance the therapeutic efficacy of a given phototherapy regimen. The temporal profile consists of multiple pulses (P1, P2...P1). i ) and each pulse exhibits a temporal pulse width, during which the instantaneous intensity or dose I(t) of the pulse is substantially non-zero. For example, in a pulsed light ray, pulse P1 has a temporal pulse width (also known as pulse ON time) from time t=0 to time t=T1, and pulse P2 has a temporal pulse width from time t=T2 to time t=T3. and pulse P i is time t = T i ~time t=T i+1 The pulses have a temporal pulse width. The pulses are spaced apart from each other by a certain period, during which the instantaneous intensity or dose of light is substantially zero. For example, pulse P1 is spaced apart from pulse P2 by a time t = T2 - T1 (also known as the pulse OFF time). The pulse ON and pulse OFF times may be substantially equal to each other or may be different from each other.

[0275] As used herein, the term "duty cycle" generally refers to the pulse ON time divided by the sum of the pulse ON time and pulse OFF time. Therefore, a pulsed ray has a duty cycle of less than 1. Both the duty cycle and the temporal pulse width specify the repetition rate of a given pulsed ray.

[0276] A pulse may have a temporal pulse shape that describes the instantaneous intensity or dose of pulse I(t) as a function of time. For example, the temporal pulse shape of a pulsed ray may be irregular and not substantially identical across different pulses, or it may be substantially identical across different pulses. For example, a pulse may have a square temporal pulse shape and have a substantially constant instantaneous dose over the pulse ON time. The peak doses of pulses may be different from each other or substantially equal to each other. Various other temporal pulse shapes (e.g., triangular and trapezoidal) are also considered for use in the systems and methods of this disclosure.

[0277] Rise and fall times can be expressed in relation to a specific fraction of the pulse's peak dose (e.g., rise / fall times for 50% of the pulse's peak dose). In this specification, pulse P i The term "peak dose" refers to the maximum instantaneous dose I(t) within the temporal pulse width of the pulse. The instantaneous dose may vary or remain substantially constant within the temporal pulse width of the pulse.

[0278] The pulsed dose and duty cycle can be selected to provide a predetermined time-averaged dose. In specific applications of this system and method, where the time-averaged dose is equal to the dose of continuous-wave (CW) light, the pulsed and CW light have equivalent photons and / or fluxes. For example, 5 mW / cm². 2 A pulsed light beam with a pulsed irradiation dose and a duty cycle of 20% has a pulsed irradiation dose of 1 mW / cm². 2 This provides the same number of photons as a CW ray with the same irradiation dose. However, in contrast to CW rays, the parameters of the pulsed ray can be selected to deliver photons in a manner that obtains intracellular and / or therapeutic effects that cannot be obtained by CW rays.

[0279] One or more of the temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and / or pulse dose of the pulsed light beam can be independently selected so as not to heat any portion of the tissue to temperatures above approximately 60°C, 55°C, 50°C, or 45°C.

[0280] One or more temporal pulse widths, temporal pulse shapes, duty cycles, repetition rates, and pulse doses of the pulsed light beam can be independently selected so as not to heat any portion of the tissue to a temperature greater than approximately 30°C above its baseline temperature, or greater than approximately 20°C above its baseline temperature, or greater than approximately 10°C above its baseline temperature.

[0281] One or more temporal pulse widths, temporal pulse shapes, duty cycles, repetition rates, and pulse doses of the pulsed light beam can be independently selected so that no part of the tissue is heated to a temperature of about 5°C above its baseline temperature, or about 3°C ​​above its baseline temperature, or about 1°C above its baseline temperature, which, as used herein, generally means the temperature of the target tissue before irradiation with the light beam. A pulsed light beam that can be appropriately used in the systems and methods disclosed herein may have an average radiant power of about 1 watt to about 10 watts, or about 4 watts to about 6 watts.

[0282] Based on the precise phototherapy regimen considered, pulsed irradiation can provide one or more performance enhancements to cellular function and / or therapeutic efficacy. Pulsed irradiation, for example, can provide a higher peak dose in a shorter time, thereby applying more power to deliver to the target tissue, while allowing thermal relaxation of interstitial tissues and blood between pulses, thereby reducing the degree to which interstitial tissues are heated. The time scale for thermal relaxation is typically in the range of 2 to 3 milliseconds. For example, the thermal relaxation time constant of human skin (e.g., the time it takes to cool tissue from high temperature to half the temperature between high temperature and baseline) is approximately 3 to 10 milliseconds, while the thermal relaxation time constant of human hair follicles is approximately 40 to 100 milliseconds. Therefore, previous applications of pulsed light to the body for hair removal have optimized temporal pulse widths greater than 40 milliseconds with time between pulses of several hundred milliseconds.

[0283] While pulsed light within this timescale conveniently reduces heating of intercellular and blood tissues, it does not exhibit optimal efficacy compared to other timescales. Target tissues (e.g., eyes or ocular tissue) may be irradiated with pulsed light having parameters optimized not to reduce the effects of heat, but instead to stimulate, excite, induce, and / or support one or more intercellular or intracellular biological processes that enhance the persistence, regeneration, or recovery of cellular performance within the target cells. Thus, the selected temporal profile can result in a temperature of the irradiated tissue that is higher than that resulting from other temporal profiles, which offer further improved therapeutic efficacy compared to temporal profiles that maintain the target tissue temperature at or near baseline.

[0284] In other embodiments of the system and method, the pulsed parameters may be selected to favor the dynamics of biological processes rather than optimizing thermal relaxation of tissue. For example, pulsed light may be selected to have a temporal profile (e.g., peak dose per pulse, temporal pulse width, and pulse duty cycle) that modulates the membrane potential, thereby enhancing, restoring, and / or promoting the survival or function of one or more irradiated cells (e.g., cells associated with ocular damage, injury, and / or disease). In some embodiments of the system and method, pulsed light may have a temporal profile that supports one or more intercellular or intracellular biological processes related to the survival or regeneration of cells or tissues (e.g., retinal cells or tissues), but is not optimized to obtain thermal relaxation of the irradiated cells or tissues. In such embodiments, cells and / or tissues survive longer after irradiation compared to unirradiated cells and / or tissues of the same kind. For example, the light may have a protective effect and / or produce a method of regeneration of the target cells or tissues.

[0285] The temporal profile (e.g., peak dose, temporal pulse width, and duty cycle) can be selected to maintain the irradiated cells or portion of the tissue below a predetermined temperature while favoring the dynamics of the biological process. This predetermined temperature can be higher than the optimized temperature achievable with other temporal profiles (e.g., other values ​​of peak dose, temporal pulse width, and duty cycle), which limits or minimizes the temperature rise of adjacent cells and / or surrounding tissue due to irradiation.

[0286] 10W / cm 2 The temporal profile with a peak irradiation dose and a 20% duty cycle is 2 W / cm². 2 It has a time-averaged irradiation dose of 2 W / cm². Such pulsed light has a pulsed dose of 2 W / cm². 2A pulsed beam provides the same number of photons to the irradiated surface as a continuous wave (CW) beam with the same irradiation dose. However, due to the "dark time" between pulses, the pulsed beam can produce a lower temperature increase than the CW beam, while still providing the same number of photons to the irradiated surface.

[0287] To minimize the temperature rise at the irradiated site of tissue, the temporal pulse width and duty cycle can be selected so that most of the heat generated per pulse dissipates before the next pulse reaches the irradiated site. Instead of optimizing the temporal parameters of the ray in this way to minimize the temperature increase of the target tissue, the temporal parameters can be selected to effectively correspond to and / or be well aligned with the timing of biomolecular processes that are involved in photon absorption and thereby increase therapeutic efficacy. Instead of having a temporal pulse width on the order of hundreds of microseconds, a temporal pulse width of (e.g., milliseconds, tens of milliseconds, hundreds of milliseconds) is used, which does not optimize the thermal relaxation of the irradiated tissue. Since such pulse widths significantly exceed the thermal relaxation timescale, the resulting temperature rise is greater than that of smaller pulse widths, but due to heat dissipation between pulses, the time between pulses is less than the temperature increase resulting from irradiation with CW light.

[0288] The various effects of in vitro irradiation of cells using pulsed light have been documented in the literature. In vitro cell adhesion has been shown that non-coherent pulsed irradiation at a wavelength of 820 nm (pulse repetition frequency of 10 Hz, pulse width of 20 ms, dark period of 80 ms between pulses, and duty factor of 20%) promotes cell matrix bonding. Karu et al., Lasers in Surgery and Medicine 29:274~281 (2001), this entire work is incorporated herein by reference. It was hypothesized that the regulation of monovalent ion bundles across the plasma membrane and the release of arachidonic acid were related to the cellular signaling pathway activated by irradiation at 820 nm.

[0289] Photo-induced changes in the membrane conductance of abdominal photoreceptor cells were found to be dependent on pulse parameters, suggesting that two or more processes are involved in photo-induced membrane function. Lisman et al., J. Gen. Physiology 58:544~561 (1971), this entire work is incorporated herein by reference. Laser-activated electron injection into oxidized cytochrome c oxidase resulted in the establishment of reaction sequences of the proton pump mechanism, with some of its thermodynamic properties exhibiting time constants on the order of milliseconds. Belevich et al., Proc. Nat'l Acad. Sci. USA 104:2685~2690 (2007) and Belevich et al., Nature 440:829~832 (2006), this entire work is incorporated herein by reference. In vivo studies of nerve activation based on pulsed infrared radiation have proposed a photothermal effect from transient tissue temperature changes, which can result in direct or indirect activation of transmembrane ion channels that trigger the propagation of action potentials. Wells et al., Proc. SPIE 6084:60840X (2006), this entire work is incorporated herein by reference.

[0290] The temporal profile of a pulsed beam may include peak dose, temporal pulse width, temporal pulse shape, duty cycle, and pulse repetition rate. In these embodiments of the systems and methods disclosed herein, in at least some embodiments in which the pulsed beam penetrates a region of tissue (e.g., eye tissue), at least one of the peak dose, temporal pulse width, temporal pulse shape, duty cycle, and / or pulse repetition rate is about 0.01 mW / cm² across the cross-sectional region of the beam. 2 ~about 1W / cm 2 During that time, approximately 10 mW / cm² 2 ~about 10W / cm 2 During that time, approximately 100 mW / cm² 2 ~About 1000mW / cm 2 During that time, approximately 500 mW / cm² 2 ~about 1W / cm 2 Between or approximately 650 mW / cm² 2 ~about 750mW / cm2 The emission surface of the light source between pulses may be selected to impart a time-averaged dose (averaged over time, including multiple pulses). For example, in certain embodiments of these systems and methods, the time-averaged dose to tissue (e.g., retinal tissue) may be 0.01 mW / cm². 2 It's incredible.

[0291] The temporal pulse shape can generally be rectangular, generally triangular, or any one of a broad range of shapes. The pulse may have a rise time of less than 1% of the pulse ON time (e.g., 10% to 90% of the peak irradiation dose) or a fall time of less than 1% of the pulse ON time (e.g., 90% to 10% of the peak irradiation dose).

[0292] The pulse can have a temporal pulse width (e.g., pulse ON time) of approximately 0.001 milliseconds to approximately 150 seconds, approximately 0.1 milliseconds to approximately 150 seconds, approximately 0.01 milliseconds to approximately 10 seconds, or approximately 0.1 milliseconds to approximately 1 second, approximately 0.5 milliseconds to approximately 100 milliseconds, approximately 2 milliseconds to approximately 20 milliseconds, or approximately 1 millisecond to approximately 10 milliseconds. For example, the pulse width may be approximately 0.5, 1, 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 milliseconds.

[0293] The time between pulses (e.g., pulse OFF time) can be approximately 0.01 milliseconds to approximately 150 seconds, or approximately 0.1 milliseconds to approximately 100 milliseconds, or approximately 4 milliseconds to approximately 1 second, or approximately 8 milliseconds to approximately 500 milliseconds, or approximately 8 milliseconds to approximately 80 milliseconds, or approximately 10 milliseconds to approximately 200 milliseconds. For example, the time between pulses can be approximately 4, 8, 10, 20, 50, 100, 200, 500, 700, or 1000 milliseconds.

[0294] The pulse duty cycle may be about 1% to about 80%, or preferably about 10% to about 30%. For example, the pulse duty cycle may be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0295] The peak irradiation dose and pulse energy density per pulse across the light cross-section at the light source's emission surface are approximately 0.01 mW / cm². 2 ~about 1W / cm 2 , about 10mW / cm 2 ~about 10W / cm 2 , about 100mW / cm 2 ~About 1000mW / cm 2 , about 500mW / cm 2 ~about 1W / cm 2 , about 650mW / cm 2 ~about 750mW / cm 2 , about 20mW / cm 2 ~about 20W / cm 2 , about 200mW / cm 2 ~about 2000mW / cm 2 , about 1W / cm 2 ~about 2W / cm 2 , about 1300mW / cm 2 ~Approx. 1500mW / cm 2 , about 1W / cm 2 ~Approx. 1000W / cm 2 , about 10W / cm 2 ~about 100W / cm 2 , about 50W / cm 2 ~about 100W / cm 2 , or approximately 65W / cm² 2 ~about 75W / cm 2 It could be within the range of.

[0296] Pulse energy density, or energy density, can be calculated as time-averaged power density divided by pulse repetition rate or frequency. For example, the minimum pulse energy density occurs at the minimum average power density and the fastest pulse repetition rate, where pulse repetition rate is the duty cycle divided by the temporal pulse width. The maximum pulse energy density occurs at the maximum average power density and the slowest pulse repetition rate. For example, a time-averaged power density of 0.01 mW / cm². 2 At a frequency of 100 kHz, the pulse energy density is 0.1 μJ / cm². 2 The time-averaged power density is 10 W / cm². 2At a frequency of 1 Hz, the pulse energy density is 10 J / cm². 2 As another example, a time-averaged power density of 10 mW / cm² is given. 2 At a frequency of 10 kHz, the pulse energy density is 1 μJ / cm². 2 As yet another example, a time-averaged power density of 700 mW / cm². 2 At a frequency of 100 Hz, the pulse energy density is 7 mJ / cm². 2 That is the case.

[0297] The multi-wavelength phototherapy systems and methods of this disclosure further provide preferred total treatment times for obtaining enhanced cellular function and / or improved therapeutic efficacy. Treatment regimens can be carried out, for example, continuously, from about 10 seconds to about 2 hours, or from about 1 minute to about 20 minutes, or from about 1 minute to about 5 minutes. For example, the total treatment time may be about 2 minutes.

[0298] In the relevant embodiments, light energy may be delivered for at least one total treatment period of at least about 5 minutes, or for at least one total treatment period of at least 10 minutes. The minimum treatment time may be limited by the biological response time (which is on the order of microseconds). The maximum treatment time may be limited by the heating and / or substantial treatment time (e.g., completing treatment within about 24 hours of injury).

[0299] Light energy can be pulsed during the treatment period, or it can be applied continuously during the treatment period. When light energy is pulsed, the pulses can be 2 milliseconds in length, can be generated at a frequency of 100 Hz or at least about 10 nanoseconds in length, and can be generated at a frequency up to about 100 kHz, but shorter or longer pulse widths and / or lower or higher frequencies can be used. For example, light can be pulsed at frequencies of about 1 Hz to about 100 Hz, about 100 Hz to about 1 kHz, about 1 kHz to about 100 kHz, less than about 1 Hz, or above about 100 kHz.

[0300] Treatment can be completed after one treatment period, or treatment can be repeated for multiple treatment periods. The time between treatment periods can range from about 5 minutes to at least 24 hours, at least about 1-2 days, or at least about 1 week. Treatment can be repeated multiple times per day and / or multiple times per week. The length of treatment time and the frequency of treatment periods can depend on several factors, including the recovery of cells, tissues, and / or the patient's function; the results of imaging analysis of damaged and / or impaired tissue; the disease or condition being treated; the use of pulsed or continuous light; the amount of light exposure; the number of light sources used; and / or the order or pattern of treatment.

[0301] The total treatment time can be controlled by a programmable controller. The programmable controller's real-time clock and timer can be used to control the timing of a specific treatment regimen to enable scheduled treatments (e.g., daily, twice daily, or every other day). Timing parameters can be monitored and adjusted in response to feedback signals from sensors or other devices (e.g., magnetic resonance imaging apparatus).

[0302] The multiwavelength phototherapy systems and methods of this disclosure use one or more light sources to obtain the delivery of two or more doses of light. Each dose has a different wavelength or frequency range. Suitable light sources include, for example, wearable and / or implantable devices for facility-centered use described in U.S. Provisional Patent Application No. 62 / 048,182 (appointment number LUMI-01-0101USPl; “DEVICES AND METHODS FOR NON-INVASIVE MULTI-WAVELENGTH LOW LEVEL LIGHT THERAPY FOR OCULAR TREATMENTS”) and No. 62 / 048,187 (appointment number LUMI-01-0201USP1, “WEARABLE DEVICES AND METHODS FOR MULTI-WAVELENGTH LOW LEVEL LIGHT THERAPY FOR OCULAR TREATMENTS”), each incorporated herein by reference. Other suitable light sources for use in the multiwavelength phototherapy systems and methods disclosed herein include Warp10® (Quantum Devices, Inc.; Barneveld, WI) and GentleWaves® (Light Bioscience LLC; Virginia Beach, VA) instruments. Such light sources can be configured to deliver two or more therapeutically effective doses of low-level light having two or more different wavelengths or combinations of wavelength ranges to a target tissue (e.g., ocular tissue).

[0303] Such a device, which delivers low levels of multiple wavelengths of light to damaged or diseased tissue independently in a targeted manner, can be used in combination with sensors and / or other imaging techniques to establish optimal spatial and tissue parameters of the eye and provide effective treatment to the target tissue.

[0304] The light source can be used in combination with one or more non-optical energy sources, such as a magnetic energy source, a high-frequency energy source, a DC electric field source, an ultrasonic energy source, a microwave energy source, a mechanical energy source, or an electromagnetic energy source, in the systems and methods of this disclosure.

[0305] For example, phototherapy provides instruments with therapeutic, diagnostic, tracking, and / or enhanced targeting capabilities for use in combination with OCT, PET, MRI, femtosensors, etc., to optimize phototherapy. The light source includes lenses, diffusers, waveguides, and / or other optical elements or components.

[0306] One or more light-emitting diodes (LEDs) and / or one or more laser diodes can be used as light sources. The laser diodes may be gallium-aluminum-arsenide (GaAlAs) laser diodes, aluminum-gallium-indium phosphide (AlGaInP) laser diodes, diode-excited solid-state (DPSS) lasers, and / or vertical-cavity surface-emitting laser (VCSEL) diodes. In such applications of the system and method using multiple light sources, the light sources can be coupled to one or more optical fibers. Other light sources that generate or emit light can also be used, with suitable wavelengths and irradiances and / or combinations of multiple types of light sources.

[0307] The amount of light irradiated can be selected to provide a predetermined dose to the target tissue (e.g., eye tissue). The target tissue (e.g., eye tissue) may be affected by a disease or damaged by trauma confirmed using standard medical imaging techniques. The target tissue (e.g., eye tissue) may also be a part of tissue known to be affected by a particular disease or disorder. For example, the target tissue may be a part of the eye known to control a certain function and / or process.

[0308] To obtain the desired irradiation dose at the level of target tissue (e.g., eye tissue), the selection of an appropriate irradiation dose of light emitted from the emitting surface may include the wavelength of light selected based on the nature of the cells and / or tissues to be treated; the type of disease, injury, and / or disorder to be treated; the patient's clinical condition; and the distance between the light source and the area of ​​target cells and / or tissues to be treated.

[0309] In some embodiments, where there are multiple light sources, certain light sources emit light with a higher or lower intensity compared to others. Therefore, the output of the light sources can be adjusted as needed depending on the thickness of other intervening tissues (such as eyelids or cornea) between the light source's emission surface and the target eye tissue.

[0310] PBM therapy (670nm) is involved in altering gene expression patterns in multiple genes associated with cellular metabolism (Masha, 2012). Energy metabolism and oxidative phosphorylation are observed in the regulation of multiple genes associated with electron chain transport, thereby restoring cellular metabolic capacity and stimulating increased ATP production. This stimulates other pleiotropic expression processes, all of which lead to long-term improvement and / or normalization of cellular function. It is established that phototherapy can affect NFκB, inflammatory pathways, and key cellular regulators of gene expression. While it is not yet clear that the combined benefits of photons from one or more wavelengths allow for the targeting and modulation of gene expression in specific pathways, this disclosure currently teaches the use of gene expression mapping in multiwavelength phototherapy to confirm its suitability for photobiomodulation applications. It differs from the light used in other applications.

[0311] In another embodiment, the use of phototherapy in combination with gene therapy offers a unique approach that can stimulate, enhance, or control the regulation and expression of novel genes embedded in the nucleus by viral vectors or other gene therapy techniques. This differs from using light-activated gene products, but utilizes selected wavelengths to naturally stimulate cellular gene expression profiles for a newly implanted gene therapy approach. In a further embodiment, the use of gene therapy is thought to facilitate the regeneration of retinal tissue or to facilitate the provision of gene therapy for mitochondrial eye disorders (such as Leber hereditary optic neuropathy or AMD). In such cases, gene therapy combined with PBMs that stimulate the expression of specific mitochondrial electron transport proteins may be intended as a better or optimized therapeutic combination approach.

[0312] Separately, RNA and protein expression patterns are utilized by cells to effectively modulate numerous pathways and subsequent cellular activity. The use of multiple wavelengths of light offers a unique approach to indirectly modulate and improve RNA and protein expression, thereby restoring cellular function in damaged or diseased tissue. While it is not obvious that the individual benefits of photons from one or more wavelengths can modulate protein expression in specific pathways, this disclosure here teaches the use of protein expression mapping in phototherapy combinations to confirm features suitable for photobiomodulation applications. It differs from the light used in other applications. AMD is considered a chronic inflammatory disease, and protein attachments further exacerbate the inflammatory state and disease progression. Therefore, the use of multi-wavelength PBMs may deliver unique combination therapies, as individual wavelengths do not provide such therapies. In RPE cell experiments, the use of 590 nm light has been shown to suppress VEGF expression, and therefore the use of 590 nm PBMs is useful in one aspect of the treatment of the exudative AMD subtype. VEGF antibody therapy (Lucentis®) is the currently approved drug therapy for exudative AMD. Separately, the use of 810nm PBM was shown to improve mitochondrial function, reduce inflammatory markers, and prevent β-amyloid precipitation in mice with age-related Alzheimer's disease (De Taboada et al, 2011), and it is applicable to other aspects of the disease. Furthermore, the use of 670nm PBM was shown to reduce inflammatory markers such as complement C3 expression and precipitation in AMD mouse models, but without affecting β-amyloid precipitation. Both lipofusion and β-amyloid precipitation were associated with the pathogenesis of diseased eyes in AMD patients.The multi-wavelength PBM combination can be used individually, or with anti-VEGF MoaB (Lucentis®, Avastin®), anti-amyloid agents (e.g., β-secretase inhibitors), anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs), anti-complement agents (e.g., Properidin, C3, MASP-2, C5 inhibitors), antioxidants or vitamins (e.g., AREDS supplements (Lipotriad Visionary®, Viteyes2®, ICaps®, and PreserVision®, containing similar components in different ratios or with additional components)), or visual cycle disruptors (e.g., isomerase inhibitors (ACU-4429)). These examples provide unique PBM therapeutic combinations, which can be represented by one or more wavelengths by the device, or by drugs, or by two or more wavelengths of light alone.

[0313] In another embodiment, targeted use of phototherapy to improve mitochondrial function through increased CCO activity, MMP recovery, and regulation of ATP synthesis can be best achieved using multiple light wavelengths to generate a localized cellular response suitable for the injury or disease.

[0314] The local cellular state of trauma and disease can differ in different tissue or organ regions and is under dynamic local regulation. For example, multiwavelength phototherapy of local CCO activity can lead to the release of inhibitory NO from O2 binding sites. NO is a potent vasodilator and signal transducer that can modulate local blood flow to target tissue. Therefore, the methods disclosed herein can be used to reverse local ischemia or restricted blood flow in damaged or diseased tissue.

[0315] The multiwavelength phototherapy systems and methods disclosed herein provide for targeting different tissues (e.g., the retina and associated surrounding tissue types) with phototherapy. As an example, these multiwavelength phototherapy systems and methods may be suitable for treating separate focal optic nerve ischemia seen in non-arteritic ischemic optic neuropathy (NAION), or for targeting anatomical islands of cellular deposition that may be foci in inflammation, ischemia, or disease in atrophic AMD.

[0316] In early-stage AMD, separate cellular precipitates of lipofusions can be confirmed in the retina by standard imaging techniques (OCT, fluorescence imaging). In such cases, the present system and method can be used to target multiwavelength phototherapy using one or more imaging techniques (e.g., OCT or fluorescence) to slow disease progression, stop or reverse protein (e.g., lipofusion or β-amyloid) deposition, and / or reduce, slow, or stop disease progression. These embodiments of the targeted phototherapy systems and methods disclosed herein provide disease-modifying approaches to chronic eye diseases.

[0317] Therefore, this multi-wavelength phototherapy system and method can be used alone to deliver a therapeutically effective dose of light, or it can be used in combination with OCT or other imaging devices (e.g., PET, MRI, ultrasound, Doppler, fluorescence, femtosensor, etc.) to identify specific areas of interest, thereby facilitating the targeting of cell or tissue boundaries in combination with the wavelength of light, and thereby optimizing or personalizing patient treatment.

[0318] Imaging techniques (e.g., femtosensors) can be used in combination with this multi-wavelength phototherapy system and method to monitor O2 levels in the local retina, identify AMD patients with local hypoxia, improve treatment, and monitor elevated O2 levels to restore mitochondrial retinal function. It will be understood that the selection of wavelength, dose, and other therapeutic parameters may vary depending on the underlying disease or condition. Tuned targeting of multiple wavelengths of light can enable individualized treatment of patients, restore cellular performance, and slow or halt disease propagation. Thus, certain embodiments of this system and method can be performed alone or in combination with one or more diagnostic devices and / or instruments that combine with phototherapy and diagnostic methods.

[0319] In further embodiments of the system and method, a desired phototherapy regimen includes selecting suitable wavelength and dose parameters to obtain the desired therapeutic effect. It will be understood that different wavelengths of light exhibit tissue-specific absorption properties, which affect the depth of light transmission and therefore the suitable dose required to obtain therapeutic efficacy.

[0320] By using additional instrument functions such as cameras or other sensors in this system and method, patient-specific characteristics, including orbital features (e.g., depth, size, skin color, and distance), can be captured, allowing for the individual or predefined combination of irradiation doses for each set wavelength to optimize treatment parameters. Sensors can also be used to assist in selecting irradiation doses based on eyelid opening and closing, thereby taking into account changes in tissue color and thickness.

[0321] In certain systems and methods, including systems and methods for the treatment of chronic disorders or diseases (e.g., chronic neurological or ocular conditions), patients may need to receive phototherapy irradiation repeatedly and frequently (e.g., daily). Therefore, minimally invasive phototherapy systems and methods may be used. For example, in systems and methods for the treatment of intraocular pressure in glaucoma patients, daily or periodic monitoring and phototherapy treatment may be performed at regular intervals. In another example, patients with optic nerve damage may have limited ability to initiate treatment, or it may be physically impossible to perform treatment. In such cases, minimally invasive phototherapy systems and methods may utilize implantable devices (e.g., LEDs).

[0322] In some cases, specific parameters of the delivered light can be used to prevent scattering and / or heating by intervening tissue between the light source and the target tissue to which the light is delivered. Such parameters that may vary include the wavelength and / or intensity of the delivered light. In such cases, the light may be, for example, about 100 μW / cm² at the target tissue site. 2 ~about 10W / cm 2 Light can be delivered at low but effective doses. For example, the temporal profile of the delivered light (temporal pulse width, temporal pulse shape, duty cycle, and / or pulse frequency), as well as the duration of light delivery, can be limited from several hundred microseconds to several minutes, thereby achieving an effective energy density at the target tissue site being treated.

[0323] The target region of the target tissue (e.g., the optic nerve and surrounding ocular tissue) may include the damaged area, which is referred to herein as the “danger zone.” The target region of the target tissue may further include a portion of the tissue outside the danger zone (e.g., ocular tissue). The biomedical mechanisms and responses involved in phototherapy are described in Karu, Proc. SPIE 4159:1~17 (2000) and Hamblin et al., Proc. SPIE 6140:614001 (2006), each of which is incorporated herein by reference in its entirety.

[0324] The multiwavelength phototherapy systems and methods disclosed herein may be used for the treatment of physical trauma (e.g., injuries resulting from cataract or lens surgery); for the treatment of inflammation or degeneration of target tissue; to provide cytoprotective effects to delay or prevent irreversible degeneration and loss of target tissue (e.g., ocular tissue) after major destructive events; to enhance target tissue function to prevent or delay the progression of loss of target tissue function and / or restore previously lost target tissue function; and to promote the proliferation, migration, and translocation of endogenous protozoan retinal stem cells for use in the treatment of diseases.

[0325] In the case of ocular tissue, the term “function of the eye” usually refers to both visual acuity and contrast sensitivity. Diseases or conditions that affect the function of the eye include, but are not limited to, disease processes or physical injuries or injuries (e.g., glaucoma, age-related macular degeneration, glaucoma, stroke, diabetic retinopathy, retinitis pigmentosa, CRS, NAION, Leber disease, ophthalmic surgery, uveitis, cerebral ischemia including focal optic nerve ischemia, and physical trauma (e.g., cerebral ischemia including focal optic nerve ischemia and physical trauma including major destructive events such as contusions or compressive injuries to ocular tissue, or any acute injury or invasiveness that results in degeneration of the eye).

[0326] As used herein, the terms “therapeutic regimen” and “treatment regimen” mean protocols and associated procedures used to provide therapeutic treatment, comprising one or more periods during which light is irradiated onto one or more target areas of the eye. As used herein, the terms “target,” “target area,” and “target region” mean a specific area, region, location, structure, population, or projection (e.g., within the retina or optic nerve) of the eye to which light is irradiated in connection with the treatment of a particular eye condition, disease, disorder, or injury. In certain embodiments, the irradiated area of ​​the eye includes the entire eye. In other embodiments, the irradiated area of ​​the eye may include target areas of the eye (e.g., retinal region, macula, or cornea).

[0327] This multi-wavelength phototherapy system and method can be advantageously used to promote the proliferation, migration, and translocation of endogenous progenitor retinal stem cells for retinal or ocular diseases. Stem cells have both the ability to autogenerate and to generate postmittal cells. The retinal pigment epithelium (RPE) is a monolayer of cells that underlies and supports the neural retina. It begins as plastic tissue and, in some species, generates the lens and retina, but differentiates early in growth and usually remains nonproliferative throughout life. A subpopulation of adult RPE cells can be activated in vitro into autogenerating cells, retinal pigment epithelial stem cells (RPESCs) that lose the RPE marker, and can proliferate extensively and redifferentiate within a stable, cobblestone-like RPE monolayer. RPESCs are pluripotent and can generate neural and mesenchymal offspring under certain conditions. It may be used in replacement therapy and disease modeling.

[0328] Following retinal stem cell transplantation for the treatment of retinal or eye diseases (e.g., retinal degenerative diseases), current multi-wavelength phototherapy systems and methods can be more conveniently used to advance proliferation, migration, and regenerative cell characteristics. Historically, however, treatment plans have been hampered by the limited ability of retinal stem cells to migrate and integrate into the host retina.

[0329] This multi-wavelength phototherapy system and method can also be advantageously used in vitro for preparing cell lysates and membrane-enriched and soluble cell fragments from mesenchymal stem cells and / or ectoderm stem cells.

[0330] In certain embodiments, the Disclosure provides multiwavelength phototherapy systems and methods that further include the administration and / or delivery of one or more small molecule drugs, biomolecules, or other suitable devices to a human patient to optimize and personalize a given phototherapy regimen for a target tissue (e.g., ocular tissue). In other embodiments, the multiwavelength phototherapy systems and methods of the Disclosure may further include the diagnosis and / or monitoring of damage and / or disease of the target tissue.

[0331] The multiwavelength phototherapy systems and methods of this disclosure may be suitable for the treatment of AMD, a chronic inflammatory disease characterized by the formation of protein precipitates that propagate the inflammatory state and promote disease progression. In certain embodiments, such multiwavelength phototherapy systems and methods for the treatment of AMD may include the delivery of a combination of light irradiations, for example, a 590 nm dose to inhibit VEGF expression; an 810 nm dose to enhance mitochondrial function, reduce inflammatory markers, and suppress β-amyloid precipitation; and a 670 nm dose to reduce the production and precipitation of inflammatory markers (e.g., complement C3) and lipofuscin.

[0332] These multi-wavelength phototherapy systems and methods can be used in further combinations: one or more anti-VEGF antibodies (e.g., Lucentis®, Avastin®); one or more anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs); one or more anti-amyloid agents (e.g., β-secretase inhibitors); one or more anti-complement agents (e.g., Properidin, C3, MASP-2, C5 inhibitors); one or more antioxidants or vitamins (e.g., AREDS adjuvants (e.g., Lipotriad Visonary®, Viteyes 2®, ICaps®, and PreserVision®)); one or more visual cycle disruptors (e.g., isomerase inhibitors (ACU-4429));

[0333] This disclosure is intended for use in combination with compositions and methods applicable to cell-centered or regenerative therapies for retinal diseases and disorders. In particular, this disclosure provides multiwavelength phototherapy systems and methods, which include use in combination with the administration of one or more compositions or devices, or with one or more methods for the regeneration or repair of retinal tissue using stem cells (e.g., very small emryonic-like stem cells (VSELs), mesenchymal stem cells, ectodermal stem cells, etc.). One aspect of this disclosure is a method for treating retinal disorders with phototherapy systems and methods after administering an ectodermal stem cell population to the patient's retinal tissue in the patient in need, and after intravenous administration of a mesenchymal stem cell population to the patient. The ectodermal stem cells may be derived from fetal neural tissue.

[0334] Another aspect of the disclosure relates to obtaining a mesenchymal stem cell population from a source selected from at least one of umbilical cord blood, adult bone marrow, and placenta. In yet another aspect of the disclosure, the retinal disorder is one or more macular degeneration, retinitis pigmentosa, diabetic retinopathy, glaucoma, or corneal marginal epithelial cell deficiency.

[0335] In certain embodiments, cells may be in vitro induced and differentiated into cells or epithelial hematopoietic cells before administration and pre-conditioned for phototherapy. In other embodiments, cells are administered together with at least one other agent (e.g., an eye treatment agent, or other beneficial adjuvants (e.g., anti-inflammatory agents, anti-apoptotic agents, antioxidants, or growth factors)). In these embodiments, phototherapy may be performed simultaneously with, before, or after postpartum cell administration. Phototherapy systems and methods can be used to promote stem cell regeneration, to support beneficial adjuvant therapeutic agents, or both.

[0336] While various embodiments are disclosed herein, other embodiments will also be apparent to those skilled in the art. The various embodiments disclosed herein are illustrative and not intended to limit, and the actual scope and spirit of the invention are shown in the following claims. [Examples]

[0337] (Example 1) Photobiomodulation therapy for atrophic age-related macular degeneration This example demonstrates that photobiomodulation (PBM) can be conveniently used as a method to improve vision and contrast sensitivity in patients with atrophic age-related macular degeneration (AMD).

[0338] The study presented in this embodiment was planned as a prospective IRB-approved trial applying low-power near-infrared (NIR), far-red, and yellow wavelength light in a sequential treatment to the eyes of patients with atrophic AMD. Patients with atrophic AMD aged 50 years or older with a maximum corrected visual acuity (BCVA) in the range of 20 / 20 to 20 / 200 were included in this study. The primary endpoints included (i) visual acuity, (ii) contrast sensitivity, and (iii) stable fixation. Subjects with a history of exudative AMD, a history of epilepsy, cognitive impairment, other retinal diseases, previous retinal surgery, significant intermediate transparent media opacity, or pupillary contraindications were excluded from the study.

[0339] The absence of new angiogenesis was confirmed prior to registration through Ocular Coherence Tomography (OCT) and Intravenous Fluorescein Angiography (IVFA) examinations, and was confirmed by a retinal specialist.

[0340] All subjects' visual acuity was recorded in logMAR units on a 4-meter ETDRS chart (Precision Vision, USA), contrast sensitivity was recorded as log contrast sensitivity at 1.5 and 3 cycles per degree (Stereo Vision Optec 6500, USA), and fixation stability was assessed using a Nidek MP1 microperimeter (Nidek Technologies, Padova, Italy). Accurate assessment of fixation stability was possible from the raw data by calculating the hyperbolic elliptic area (BCEA), as described in Tarita et al., Retina 28:125~133 (2008). The calculation considered two standard deviation measurements for each recorded eye movement, based on the major and minor axes of the elliptic area corresponding to the fixation micromovement. Results were expressed in square degrees.

[0341] Measurements were taken (i) before treatment; (2) immediately after the treatment protocol; (3) 6 weeks after the treatment protocol; (4) 4 months after the treatment protocol; (5) 6 months after the treatment protocol; and (6) 12 months after the treatment protocol.

[0342] The treatment involves the use of low-level phototherapy (PBM) in the yellow, far-red, and near-infrared (IR) ranges, using low-energy delivery with Warp10 (Quantum Devices) and Gentlewaves (Light Bioscience) devices, which are commercially available and approved by the FDA and Health Canada for use under other conditions. The treatment parameters followed with the Warp10 delivery system were 50–80 mW / cm². 2 At 670nm±15nm, 4-7.68 J / cm² over 88±8 seconds. 2 The treatment parameters followed with the Gentlewaves delivery system were 4 mW / cm². 2 At 590nm±8nm and 0.6mW / cm² 2 At 790nm±60nm, 0.1J / cm² 2The treatment was pulsed at 2.5 Hz during delivery (on 250 ms, off 150 ms). All subjects were treated using two devices consecutively during each treatment visit for a total of 18 treatments over a 6-week period (3 times per week for 6 weeks).

[0343] Data analysis was based on descriptive statistics, including frequency distribution, measure of central tendency (mean), and variance (standard deviation). Statistical comparisons of mean values ​​between populations were performed using t-tests and repeated measures analysis of variance (ANOVA). Differences were considered statistically significant with a p-value < 0.05. The study was conducted in accordance with the guidelines of the Declaration of Helsinki. The study protocol was approved by the Independent Research Ethics Committee (IRB Services, Aurora, Canada). Informed consent was obtained from all participants.

[0344] Over a 12-month period, 18 AMD trial eyes (6 males and 12 females) (ages 61-90 years (mean 74.3 years / SD 7.7)) were enrolled and treated.

[0345] Repeated-measures ANOVA for contrast sensitivity (3 cycles / degree) yielded F(4.68) = 11.44 with p-value < 0.0001, and repeated-measures ANOVA for contrast sensitivity (1.5 cycles / degree) yielded F(4.68) = 4.39 with p-value < 0.0032. The mean ETDRS BCVA of the AMD group was measured at 0.25 log Mar units before treatment and at 0.13 log Mar units (p< 0.0001) at 12 months after treatment. Repeated-measures ANOVA yielded F(4.68) = 18.86 with p-value < 0.0001.

[0346] The photobiomodulation treatment regimen disclosed in this embodiment regenerated, activated, and improved the function of impaired retinal cells at the periphery of geographic atrophy, resulting in immediate improvement of visual acuity within six months or less.

[0347] Contrast sensitivity was statistically significantly improved by the photobiomodulation treatment regimen described herein. This improvement in contrast sensitivity lasted for 12 months (Figures 16-17).

[0348] ETDRS visual acuity improved statistically significantly immediately after treatment, and although a slight decrease in the ETDRS logMAR score was evident after 4 months (Figure 18), this improvement in clinical status persisted at a statistically significant level until 12 months.

[0349] Photobiomodulation was extremely well-suited. No discomfort was reported, and individual treatments were easily performed in less than 5 minutes per eye. No significant adverse events were observed during the studies described in this example.

[0350] (Example 2) Photobiomodulation (PBM) method for reducing central retinal thickness in atrophic age-related macular degeneration (AMD) This example demonstrates that photobiomodulation (PBM) can be conveniently used with optical coherence tomography (OCT) measurements as a method for reducing central retinal thickness in patients with atrophic age-related macular degeneration (AMD).

[0351] In separate, non-randomized cases, eight patients with atrophic age-related macular degeneration (atrophic AMD) were treated with multiwavelength phototherapy for three weeks. Clinical endpoints of CS and VA were performed as in Example 1. In addition, changes in retinal thickness were determined from continuous spectral optical coherence tomography (SD-OCT) scans before and after treatment. An overall decrease in central retinal thickness was observed in atrophic AMD patients immediately after treatment with multiwavelength phototherapy according to the systems and methods disclosed herein. Overall, these data support the clinical and anatomical therapeutic efficacy of these multiwavelength photobiomodulation treatment systems and methods and confirm their applicability for the non-invasive treatment of atrophic AMD. The results are shown in Table 1.

[0352] Patients with atrophic AMD receiving PBM treatment (based on retinal examination, fundus photography, OCT evaluation, and IVFA (in some cases) determining the absence of neovascular lesions) are evaluated with SD-OCT on the SPECTRALIS SD-OCT system (Heidelberg Engineering, Carlsbad, CA) before and after treatment. This system combines high-speed image acquisition and noise reduction with custom TruTrack technology, enabling accurate long-term tracking by actively tracking the eye during imaging. The results are accurate and reproducible alignment of OCT and fundus images, superior image detail and clarity, and point-to-point anatomical correlation between fundus and OCT scans, allowing for more confident assessment of small changes. By integrating SD-OCT with confocal laser scanning ophthalmography (cSLO), the Heidelberg SPECTRALIS platform enables scanning placement for accurate follow-up.

[0353] Volume retinal scans were obtained before treatment, immediately after the treatment process, and at the following intervals after treatment. The same data acquisition method used in the study described in Example 1 was utilized, with visual acuity determined using an ETDRS chart (Precision Vision, USA) recorded as a letter score at a distance of 4 meters, and contrast sensitivity recorded and determined as log contrast sensitivity at 3 cycles per degree (Stereo Vision Optec 6500, USA). In addition, a continuous study using Heidelberg Spectralis SD-OCT was used in this patient group to clarify changes in retinal thickness.

[0354] Patients received treatment three times a week for three weeks over a total of nine sessions, receiving the same total PBM dose as in the trial described in Example 1, but with shorter treatment times to facilitate patient compliance. Sessions included the use of yellow and red to near-infrared (NIR) PBMs with low-energy delivery using Warp10 (Quantum Devices) and Gentlewaves (Light Bioscience) instruments. Treatment parameters followed with the Warp10 delivery system were 50–80 mW / cm².2 At 670nm±15nm, 4-7.68 J / cm² over 88±8 seconds. 2 The treatment parameters followed with the Gentlewaves delivery system were 4 mW / cm². 2 At 590nm±8nm, 0.6mW / cm² 2 At 790nm ± 60nm for 35 seconds, 0.1 J / cm² 2 The treatment was pulsed at 2.5 Hz during delivery (on 250 ms, off 150 ms). These three wavelengths were pre-selected to stimulate the CuA and CuB moieties of mitochondrial cytochrome c oxidase (CCO) activity to suppress the level of VEGF protein production. All AMD patients were treated using two devices consecutively during each treatment visit, and then the same session was repeated.

[0355] The following is a summary of each patient, obtained from SD-OCT analysis.

[0356] Subject 1 was a 55-year-old white woman who immediately showed a 24-micrometer reduction in central retinal thickness after treatment, which further decreased to 27 micrometers after 3 months. Subject 1 chose to undergo a further 3-week treatment period. After 4 months, the reduction in retinal thickness was 19 micrometers. Subject 1's initial letter score was 39, which increased to 47 immediately after treatment, 46 after 3 months, and to 42 after two treatment periods.

[0357] Subject 2 was a 52-year-old white male whose letter score increased from 52 to 57 immediately after treatment, and whose contrast sensitivity increased from log1.76 to log2.06. Image difference scans showed changes in retinal thickness in the post-treatment scan compared to the pre-treatment reference scan. The central minimum decreased by 20 micrometers. In this individual region, immediately after treatment, the retinal thickness at the highest point of Patient 2's central druze decreased by 18 micrometers.

[0358] Subject 3 was a 68-year-old white woman who showed a 14-micrometer reduction in foveal thickness after the treatment protocol. Her letter score increased from 55 to 58, and her contrast sensitivity increased from log1.60 to log1.90.

[0359] Subject 4 was an 85-year-old white woman whose letter score was 51 before treatment, increased to 55 after treatment, and increased to 53 one year after the end of treatment. Her logCS score increased from 1.60 to 1.76. An OCT scan at one year showed a decrease of 18 micrometers. At the one-year stage, she chose to receive a further treatment period, and three months after treatment, her central retinal thickness had decreased to 25 micrometers from the reference scan. Six months after the second treatment, her retinal thickness continued to decrease by 19 micrometers. One year after the second treatment, her retinal thickness showed a decrease of 18 micrometers. Three months after the second treatment period (17 months from baseline), it showed a decrease of 25 micrometers. The differential thickness map showed a decrease in central retinal thickness from baseline over the subsequent two treatment periods of 20 months.

[0360] A follow-up OCT scan of Subject 4 one year later showed an 18-micrometer reduction in retinal thickness due to improvements in CS and VA. A follow-up OCT scan of Subject 4 three months after the second treatment period (i.e., 17 months from baseline) showed a 25-micrometer reduction in retinal thickness.

[0361] Subject 5 was an 80-year-old white male whose letter score increased from 48 before treatment to 53 immediately after treatment, and whose logCS increased significantly from 1.00 to 1.90. Scans of two sections (sections 12 and 13) of Subject 5 after treatment showed reductions of 45 micrometers and 22 micrometers, respectively.

[0362] Subject 6 was a 67-year-old white male whose initial letter score increased from 31 to 36 after treatment, and whose retinal thickness decreased by 19 micrometers. His contrast sensitivity increased from log1.00 to log1.18.

[0363] Subject 7 was an 86-year-old white woman who received treatment for both eyes. Subject 7's initial letter score was 51, which increased to 54 after treatment, 54 at 3 months, and 57 at 6 months. Her LogCS score was initially 1.6, increased to 1.9 after treatment, 1.76 at 3 months, and 1.6 at 6 months. Her initial letter score was 41, increased to 43, and remained at 43 at all subsequent visits. Her LogCS score started at 1.46, increased to 1.46 after treatment, 1.60 at 3 months, and 1.46 at 6 months.

[0364] The results shown in Figures 16-19 and summarized in Table 1 for Examples 1 and 2 demonstrate anatomical changes in central retinal thickness, particularly a reduction in central retinal thickness immediately above the most diseased retina, and no reduction in retinal thickness in normal areas. This suggests that the treatment specifically reduces retinal thickness on the diseased retina. The anatomical evidence from the resolution of the SD-OCT scan, and the reliable scanning of the same retinal location in continuous measurements, suggest that there is no influence from the placebo effect and represent an important objective endpoint that can be used in future clinical trials.

[0365] [Table 1]

[0366] The seven subjects participating in this case study showed improvements in visual acuity and contrast sensitivity, which were consistent with the improvements observed in the atrophic AMD clinical pilot study described in Example 1. The anatomical evidence presented herein, obtained from high-resolution SD-OCT scans ensuring that the same retinal location was scanned in sequential measurements, represents important objective endpoints and is not considered to be affected by the placebo effect and can be used in future clinical trials. Such objective changes in retinal tissue after PBM treatment, as well as their correlation with improvements in subjective parameters (i.e., ETDRS, VA, and CS), support the use of PBM for the non-invasive, low-risk treatment of atrophic AMD patients.

[0367] PBM has recently been shown to produce a significant reduction in focal retinal thickness in non-central diabetic macular edema. Tang et al., Br J Ophthalmol, published online 28Mar14 doi:10.1136 / bjophthalmol-2013-304477. The apparatus used in the study described by Tang et al. is the same as the apparatus used in the case presented in Example 2. However, this study in AMD patients used pulses of yellow and infrared wavelength light, designed to reduce the expression of vascular endothelial growth factor and thereby reduce the conversion of atrophic AMD to exudative AMD. Kiire et al.,Retina Today(Jan / Feb 2011)(sub-threshold micropulse laser therapy for retinal disorders;Barnstable et al.,Prog Ret Eye Res.23(5):561~577(2004);Glaser et al.,Ophthalmology 94:780~784(1987);Miller et al. al.,Invest.Ophthalmol.Vis.Sci.27:1644~1652(1986);and Ogata et al.,Am.J.Ophthalmol.132(3):427~429(2001).

[0368] (Example 3) Further treatment of atrophic age-related macular degeneration in patient data collection (TOPRA II) The study presented in Example 3 was designed for patient data collection, involving the application of low-power near-infrared (NIR), far-red, and yellow wavelengths in sequential treatment to the eyes of patients with atrophic AMD. The TORPA II trial investigated the use of photobiomodulation (PBM) as a treatment for visual acuity outcomes and for retinal anatomical changes in subjects with atrophic AMD. This trial included subjects who met the inclusion and exclusion criteria and who had received off-label PBM treatment after the conclusions of the previously published TORPA trial.

[0369] This study included patients with atrophic AMD aged 50 years or older with a maximum corrected visual acuity (BCVA) in the range of 20 / 20 to 20 / 200. The primary endpoints included (1) visual acuity and (2) contrast sensitivity. Subjects with a history of exudative AMD, a history of epilepsy, cognitive impairment, other retinal diseases, previous retinal surgery, significant intermediate transparent media opacity, or pupillary contraindications were excluded from the study.

[0370] The absence of confirmed neovascularization was confirmed by ocular coherence tomography (OCT) and intravenous fluorescein angiography (IVFA) examinations prior to enrollment and confirmed by a retinal specialist. Visual acuity was determined for all subjects by recording logMAR units on a 4-meter ETDRS chart (Precision Vision, USA), and contrast sensitivity was determined by recording log contrast sensitivity at 1.5, 3, and 6 cycles per degree (Stereo Vision Optec 6500, USA). Measurements were taken (i) before treatment; (2) immediately after 3 weeks post-treatment protocol; (3) 3 months post-treatment protocol; (4) 6 months post-treatment protocol; and (5) 12 months post-treatment protocol. At these points, patients were participating in the treatment, and a partial list of data was presented.

[0371] The treatment involves the use of low-energy delivery using Warp10 (Quantum Devices) and Gentlewaves (Light Bioscience) devices, with PBMs in the yellow, far-red, and near-infrared (NIR) ranges. These devices are commercially available and approved by the FDA and Health Canada for use under other conditions. The treatment parameters followed with the Warp10 delivery system were 50–80 mW / cm². 2 At 670nm±15nm, 4-7.68 J / cm² over 88±8 seconds. 2 The treatment parameters followed with the Gentlewaves delivery system were 4 mW / cm². 2 At 590nm±8nm and 0.6mW / cm², 2 At 790nm±60nm, for 35 seconds, 0.1J / cm². 2The treatment was pulsed at 2.5 Hz during delivery (on 250 milliseconds, off 150 milliseconds).

[0372] The purpose of data collection for this patient was to demonstrate safety and efficacy while maintaining the same total PBM dose, and to reduce the overall number of treatments. All subjects were treated using two devices consecutively at each treatment visit for a total of nine treatments over a three-week period (three times per week). In the three-week treatment group, patients received the same PBM dose, while in the six-week treatment group, each session was doubled.

[0373] Descriptive statistics for all endpoints in each treatment include the number of subjects, mean, standard deviation, median, minimum and maximum values ​​for continuous variables, and frequency and percentage for categorical variables. Differences were considered statistically significant with a p-value < 0.05. Primary analysis.

[0374] PBM effect on VA: The primary analysis will examine the difference in mean changes from BL (pre-treatment) to 3 weeks after VA treatment in subjects who received PBM treatment. The analysis will use a linear mixed-effects model. Exploratory analyses will examine the same endpoints from 3 months onward, depending on the sample size.

[0375] Secondary analysis of the CS effect of PBM: The first secondary analysis tests the difference in mean change from BL (pre-treatment) to 3 weeks after contrast sensitivity treatment in subjects who received PBM treatment. The analysis uses a linear mixed-effects model. Exploratory analyses examine the same endpoints from 3 months onward, depending on the sample size.

[0376] The impact of fundus autofluorescence (FAF) on retinal imaging and optical coherence tomography (OCT) of PBM: OCT scans were compared to reproducible scans in the exact anatomical region of a reference scan, and subjects were scanned at the base line to confirm atrophic AMD pathology. With repeated FAF, OCT scans were performed post-treatment and at follow-up visits (e.g., 3, 6, and 12 months). OCT analysis was exploratory. Descriptive statistics were obtained for pre- and post-treatment FAF and OCT scans. In FAF and OCT image analysis, a focus leader confirmed anatomical parameters and compared anatomical changes before and after PBM. OCT analysis examined changes from baseline to 3 weeks post-treatment. Analysis used a linear mixed-effects model. Exploratory analysis examined the same endpoints from 3 months onward, depending on sample size. Drusen volume, mean central 1 mm drusen thickness, and geographic atrophic lesion area were the main endpoints here. CRT and retinal volume were also assessed. The analysis was conducted to compare the efficacy of subgroups based on the AREDS category and the presence or absence of reticular pseudodrusen (RPD). Complete photoreceptor status before and after treatment was compared using Fisher's exact test. Variables that do not distribute normally can be analyzed using power conversion or rank values.

[0377] Approximately 41 atrophic AMD test eyes were included in this analysis. All patients received 3 weeks of treatment. Preliminary data, three times per week for the 3-week period, are shown in VA (Figures 20 and 21).

[0378] [Table 2]

[0379] The photobiomodulation therapy regimen disclosed in this embodiment regenerated, activated, and improved the function of impaired retinal cells at the periphery of geographic atrophy, resulting in immediate improvement of visual acuity (Figures 20 and 21) and contrast sensitivity (not shown). The clinical efficacy remained statistically significant at 3-month intervals for both clinical endpoints.

[0380] Visual acuity improved statistically significantly immediately after 3 weeks of treatment, and this clinical improvement was similar to that of the extended 6-week treatment in the TORPA trial (Figures 16-18). Both treatments provided the same dose of three wavelengths but were optimized to reduce the total number of treatment sessions. Further analysis will determine the frequency of repeated treatments to maintain maximum benefit.

[0381] The data presented in this example demonstrate that the PBM system and method disclosed herein are well tolerable. More specifically, no discomfort was reported, individual procedures were easily performed in less than 5 minutes per eye, and no significant adverse events were observed during the experiments described in this example.

[0382] Even more surprising is that PBM treatment resulted in a significant reduction in central drusen volume, a characteristic of the disease. By analyzing optical coherence tomography (OCT) retinal scans of 19 patients and 33 eyes, the reduction was evident immediately after 3 weeks of treatment and maintained for a period of 3 months post-treatment (Table 3 and Figure 22). This is the first time that treatment has demonstrated clinical and anatomical effects on central drusen volume. The beneficial reduction in the pathology of atrophic AMD disease without any focal cell damage did not affect the retinal photoreceptor layer, indicating the safety of PBM treatment at the anatomical level. Visual acuity (VA), contrast sensitivity, and central drusen data obtained from the TORPA II study of this disclosure are summarized in Figure 23.

[0383] [Table 3]

[0384] (Example 4) Corpse testing Each wavelength has different tissue scattering and light transmission properties, thus ensuring effective delivery of known light intensities to ocular tissue. The optical properties of intervening tissues at the desired wavelengths were obtained from the tests of this disclosure, in which light transmittance was measured in the eyes of a pair of human cadavers. The design of the experiments performed during the cadaver tests and the data obtained from the cadaver studies established the retinal fluence rates resulting from the application of light of specific wavelengths and powers to the ocular region. The results disclosed herein were used to determine the expected retinal fluence rates of the clinical trial (TORPA) disclosed in Example 3 and, accordingly, to establish safety limits for future therapeutic devices.

[0385] Intraocular power was measured using an isotropic fiber probe from a Medlight (SD200) and connected to a silicon-based power detector from an Ophir (PD300). The detector was connected to an Ophir meter (Nova II). The overall instrument output was measured using a wide-area thermal power meter from an Ophir (L50) 300A, which was connected to the same meter. Spectral measurements were performed using an Ocean Optics spectrometer (USB2000) and saved to a laptop. The measurement locations shown in Figure 28 and the general procedure for testing each eye are outlined in Table 4.

[0386] [Table 4]

[0387] Measurements were taken using both eyes for each cadaver. Six (12 eyes) were used in the primary test.

[0388] Table 5 shows the subject data for each test specimen in the main study, along with any applicable observations. Skin color was qualitatively assessed per Fitzpatrick skin type classification scale.

[0389] [Table 5]

[0390] The device output P3 for each light source was transcribed from the data acquisition sheet into the electronic database. Raw measurement data was also transcribed from the acquisition format. While this raw data does not represent the exact fluence level, it represents the power delivered from the probe to the Ophir PD300 detector, as shown on the meter. These represent the actual fluence rate (mW / cm²). 2 To convert this to ), the probe acquisition efficiency, the detector's spectral sensitivity, and the illumination's isotropy must be taken into account and multiplied by a calibration coefficient. The calibration coefficient is determined for each light source in the test and is shown in Table 4.

[0391] [Table 6]

[0392] As shown in Table 6, the probe calibration value differed depending on whether the probe was wet or dry. Therefore, the correct value to use depended on the probe's position during the particular measurement. In measurements made on the eyelid, the probe was mostly surrounded by air, so the "dry" calibration value was used. When measurements were made in the anterior and posterior chambers of the eye, the probe was immersed in fluid, so the "wet" calibration value was used for these readings. If the probe was mostly in contact with a wet wipe at its position, the "wet" value was used for measurements on the closed cornea. In measurements on the open cornea, if the probe was in partial contact with a wet surface during the reading, the average of the dry and wet calibration values ​​was used.

[0393] These calibration values ​​were applied to the raw recorded data, which was then normalized to a typical value of 1W power output from each power supply. The mean and standard error of each measurement are shown in Table 5. These data are visually represented in Figure 29, where the mean fluence rate and standard error are plotted as a function of the eye-open measurement location.

[0394] [Table 7]

[0395] The uncertainty of each measurement is a linear function of the uncertainty of the calibration value. These were calculated for each light source, with an additional ±3% added to account for the uncertainty of the meter used to measure the total device power. The resulting total uncertainty was ±7.3% for yellow, ±14.3% for red, and ±6.9% for IR. The uncertainty of the probe position during measurement was ±2 mm for the eyelid, cornea, and anterior chamber, and ±5 mm for the posterior chamber. The mean fluence rate and standard error are shown as a function of the closed-eye measurement position in Table 6 and visually illustrated in Figure 30, and the mean fluence rate and standard error are plotted as a function of the closed-eye measurement position. The spectra collected at each position were included in Matlab and normalized for comparison.

[0396] [Table 8]

[0397] The peak wavelength was measured for each curve. Table 9 shows the minimum, maximum, mean, and standard deviation of the peaks for each light source.

[0398] [Table 9]

[0399] Some variations in the measured spectra occurred during the test, most particularly with the red light source. This deviation is independent of the measurement location and is highly dependent on the LED power output during spectral display. Since the output spectrum depends on the LED temperature, it is understandable and expected that the power increases as the temperature increases. Comparing the measured spectra of all light sources with their published specifications shows that all peak wavelength ranges are within the specified range.

[0400] With the eyes open and closed, the measured fluence rates shown in Figures 29 and 30 are predicted, with the highest transmission for infrared light, followed by red and yellow. This is consistent with published transmission data on human tissue.

[0401] While the results presented herein are normalized to a 1W instrument power, the fluence rate of the eyelid is significantly higher at yellower wavelengths than at the other two wavelengths, before transmission through any tissue. This deviation is understandable if we consider the probe to be isotropic and to collect both light emitted from the instrument as well as light reflected backward from the eyelid and surrounding tissue. For yellow light sources that reflect at a higher percentage than red or IR, the deviation then shows a spectral dependence on the diffuse reflectance of the tissue. This is generally consistent with previous measurements of the diffuse reflectance of human skin. (Murphy et al., J.Biomed.Opt.10:064020 (2005) and Lim et al., J.Biomed.Opt.16:011012 (2011)). Further factors in determining the fluence value on the corneal surface may include the selection of calibration values ​​at that location. While "dry" values ​​are used for the eyelid, "mean" values ​​for the open cornea, and "wet" values ​​for the closed cornea, the degree of "dryness" or "wetness" of the latter probe can introduce deviations. This may result in greater uncertainty in the calculated fluence rate at this location.

[0402] The optical emission limits for ophthalmic devices are defined by IEC 15004-2 (International Organization for Standardization. Ophthalmic optical devices - Essential requirements and test methods - Part 2: Protection from optical hazards. ISO 15004-2:1~37(2007)). The emission limits for Group 1 devices, which are set to prevent emission hazards, are shown in Table 10.

[0403] [Table 10]

[0404] Using the calculations described above, the specified limits, and the measured instrument spectra, the maximum emission limits for each light source in the retina and cornea can be calculated. The results are shown in Table 11. These values ​​assume that the instrument operates in continuous wave (CW) mode and that only a single light source is activated for a given time.

[0405] [Table 11]

[0406] Dividing the values ​​in Table 11 by the normalized fluence rates in Tables 5 and 6 gives the maximum output of the instrument, so that it can be classified as Group 1 according to IEC 15004-2. Strictly speaking, the values ​​from Tables 7 and 8 used in this calculation are the maximum values ​​(mean + SEM). The results are shown in Table 12. These values ​​provide a direct comparison to commercially available instruments to establish a safety class for therapeutic interventions.

[0407] [Table 12]

[0408] The tests presented in this embodiment provide a reliable understanding of light scattering and penetration in human cadaver eyes, further establishing the safety and efficacy of PBM in human medical conditions. When developing therapeutic applications using phototherapy, the eye, a unique optical organ, requires special consideration of its light absorption and tissue diffusion properties. Cadavers are not living tissues, and their anatomical and tissue characteristics are susceptible to the influence of tissue scattering and absorption measurements, allowing for estimates of human light exposure in clinical situations. Further tests were conducted to demonstrate the importance of establishing individual wavelength-dependent dose curves that represent actual tissue scattering and absorption at a given wavelength.

[0409] The test results presented herein show measurable light at all levels of the eye with an increase in absorption as light penetrates deeper into the eye. Absorption is wavelength-dependent, and the results obtained are consistent with and confirm other tests that focus on light scattering and absorption in human tissue. The NIR wavelengths of light penetrate most directly into eye tissue with less loss in deeper regions, including the anterior and posterior chambers. Yellow < far infrared < NIR is the established order of tissue penetration, corroborating other multi-wavelength tissue tests. Murphy et al., J. Biomed. Opt. 10:064020 (2005) and Lim et al., J. Biomed. Opt. 16:011012 (2011). These studies are important to enable optimization of clinical exposure levels for targeting the retina or other regions of the eye.

[0410] The TORPA test shown in Example 3 (see also Merry et al., Association for Research in Vision and Ophthalmology 53:2049 (2012)) utilized two commercially available instruments, the Quantum WARP 10 and Gentlewaves. The wavelengths and exposure levels shown in Table 13 were tested over a series of six weeks and repeated.

[0411]

Table 13

[0412] Based on the TORPA test parameters and the results obtained in the cadaver tests of the present disclosure, the retinal fluence rates shown in Table 14 can be measured for the TORPA test.

[0413]

Table 14

[0414] The three wavelengths target different cell types and thus have individual dose-response curves, but this study provides relevance to tissue exposure, which translates into beneficial clinical outcomes as shown in the TORPA study. Under ocular safety standards set by industry guidelines (i.e., IEC 15004), all fluences are good. However, there are distinct and surprising differences in the fluence levels of the three wavelengths that make this multi-wavelength approach effective for atrophic AMD.

[0415] In contrast to the coherent light produced by lasers, the light emitted by Lumithera LED devices is non-coherent, and no optical gain occurs within the diode. Therefore, safety standards have evolved to treat LEDs as equivalent to lamps that emit non-coherent light. Applicable standards include those stated by the International Commission on Non-Ionizing Radiation Protection (ICNIRP), the American Conference of Governmental Industrial Hygienists (ACGIH), and numerous other independent researchers focusing on non-coherent light sources. Exposure limits (EL) and limit values ​​(TLV) for LEDs have been established.

[0416] Cadaver testing of the three LED light sources within the Lumithera device confirmed that the delivered light doses of yellow, red, and NIR wavelengths were within established safety parameters, provided that the power emitted from each light source remained below the relevant values ​​shown in Table 14.

[0417] Overall, the data presented herein support the safety and therapeutic efficacy of the multiwavelength photobiomodulation system and methods, and further demonstrate objective improvement of retinal tissue after multiwavelength photobiomodulation treatment, which is associated with improved subjective parameters (ETDRS VA and CS). Thus, the data presented herein support the use of the multiwavelength phototherapy system and methods of this disclosure for the treatment of ocular disorders and diseases, and more specifically, macular degeneration in dry skin (atrophic AMD).

Claims

1. A wearable device for delivering photobiomodulation (PBM) to the retinal tissue of a patient's eye to stimulate the retinal tissue and / or reverse or slow down disease in the retinal tissue: A frame comprising an anterior piece configured to be positioned in front of the patient's eye, and at least one additional element attached to the anterior piece, wherein the frame is wearable by the patient; A first light source disposed within or on the at least one additional element and configured to generate a first ray consisting of PBM light having a first therapeutic PBM wavelength and irradiation dose; and The system includes a second light source disposed within or on the at least one additional element and configured to generate a second ray consisting of PBM light having a second therapeutic PBM wavelength and dose. Here, the second therapeutic PBM wavelength differs from the first therapeutic PBM wavelength by at least 25 nm, and At least a portion of the PBM light in the first and second rays is directed from each of the first and second light sources toward the front side piece of the frame, A diffuser is disposed within or on the frame and is configured to diffuse the PBM light in the first ray or the second ray, or in both the first and second rays, wherein the diffuser homogenizes the PBM light in the first and / or second rays, thereby reducing non-uniformity. A wearable device in which an optical element is disposed within or on the front side of the frame, wherein the optical element is configured to receive the first and second rays and redirect at least a portion of the first and second rays toward the retinal tissue of the patient's eye when the patient is wearing the frame.

2. After the PBM light in the first ray and / or the second ray has been diffused by the diffuser, the PBM light in the first ray or the second ray has an energy density profile that is substantially uniformly distributed within a range of emission angles. The wearable device according to claim 1.

3. The aforementioned at least one additional element comprises an earpiece, and the optical element comprises at least one reflector. Here, the first and second light sources are arranged on the earpiece and are configured to direct the first and second light rays toward at least one reflector. Furthermore, the at least one reflector is configured to receive the first and second rays and redirect at least a portion of the first and second rays toward the retinal tissue of the patient's eye. The wearable device according to claim 1.

4. The at least one reflector is located within a visual port defined on the inside of the front piece, and the at least one reflector is partially transparent. The wearable device according to claim 3.

5. At least one of the first ray and the second ray includes near-infrared (NIR) light. The wearable device according to claim 1.

6. The system further comprises a spatial light modulator disposed within or on the at least one additional element, which is configured to receive the PBM light in the first and / or second light rays, and which modulates the PBM light to generate a modulated ray. Here, the optical element is configured to receive the modulated light and redirect at least a portion of the modulated light toward the retinal tissue of the patient's eye when the patient is wearing the frame. A wearable device according to any one of claims 1 to 5.

7. The system further comprises a beam splitter disposed within or on the frame and configured to direct at least a portion of the first ray and / or the second ray toward the spatial light modulator, Here, the spatial light modulator is configured to direct the modulated light ray back and, through the beam splitter, to an optical element that redirects the modulated light ray toward the retinal tissue of the patient's eye. The wearable device according to claim 6.

8. Furthermore, the system includes a third light source disposed within or on the at least one additional element, and configured to generate a third ray consisting of PBM light having a third therapeutic PBM wavelength and irradiation dose. Here, the third therapeutic PBM wavelength differs from the first and second therapeutic PBM wavelengths by at least 25 nm. Furthermore, at least a portion of the PBM light in the third ray is directed from the third light source toward the front side piece of the frame, and when the patient wears the frame, the optical element is configured to receive the third ray and redirect at least a portion of the third ray toward the retinal tissue of the patient's eye. A wearable device according to any one of claims 1 to 5.

9. The system further comprises a spatial light modulator disposed within or on the at least one additional element, configured to receive the PBM light in the first, second, and / or third rays, and which modulates the PBM light to generate a modulated ray. Here, the optical element is configured to receive the modulated light and redirect at least a portion of the modulated light toward the retinal tissue of the patient's eye when the patient wears the frame. The wearable device according to claim 8.

10. The optical element is a prism or a waveguide. A wearable device according to any one of claims 1 to 5.

11. The system further includes an internal controller located within or on the frame, connected to the first and second light sources, and controlling the generation of the first and second light rays. Here, the built-in controller is connected in a communication manner to an external controller that can be used to program the built-in controller so that it can control the operation of the first and second light sources according to a predetermined treatment regimen. A wearable device according to any one of claims 1 to 5.

12. The predetermined treatment regimen includes a set of periods or activation times during which each of the first and second light sources is in an emitting state, and a set of periods or activation times during which each of the first and second light sources is in a non-emitting state. The wearable device according to claim 11.

13. The first and second rays are configured to deliver PBM light to the patient's eye at least twice, wherein the first ray in the first dose has at least the first therapeutic PBM wavelength predetermined to stimulate a first activity in the retinal tissue, and the second ray in the second dose has the second therapeutic PBM wavelength predetermined to stimulate a second activity in the retinal tissue, wherein the second activity generates a second biological response in the retinal tissue that is different from the first biological response in the retinal tissue generated by the first activity. A wearable device according to any one of claims 1 to 5.

14. The amount of PBM light irradiated onto the retinal tissue by each of the first and second rays is set to facilitate treatment and / or reverse or slow the progression of disease in the retinal tissue. A wearable device according to any one of claims 1 to 5.

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