IL304939B2 - Eye treatment devices and methods - Google Patents

Description

RS 304939/4 DEVICES AND METHODS FOR OCULAR THERAPY FIELD OF THE INVENTION The invention relates to ocular therapy, in general, and to devices and methods for treating dry eye diseases and/or related disorders, in particular.

BACKGROUND OF THE INVENTION Dry eye is defined as a disorder of the tear film due to insufficient tear production or excessive tear evaporation. The symptoms can manifest as mild discomfort, burning at varying intensity, foreign body sensation, dryness, and photophobia. In severe cases, the disease can progress to affect the corneal tissue and determine ulcers, infiltrates, and visual disturbances. The aging process appears to significantly affect dry eye disease (DED). Aging and female gender are risk factors for dry eye disease. At any age, about twice as many women as men have dry eyes.

The aging-dependent changes in the ocular surface with DED are related to biological changes in the lacrimal glands (LGs) and meibomian glands (MGs). The lacrimal glands are paired exocrine glands, one for each eye, that secrete the aqueous layer of the tear film. In humans, they are situated in the upper lateral region of each orbit, in the lacrimal fossa of the orbit formed by the frontal bone. The lacrimal gland (LG) plays a vital role in maintaining ocular physiology, and changes related to aging directly affect eye diseases. The dysregulation of the immune system in aging leads to quantitative and qualitative changes in tear film chemical components such as antibodies, cytokines, proteins, and vitamins. The tear film contains between dozen to several hundred proteins and other chemical molecules such as: Electrolytes (sodium, potassium, chloride, RS 304939/4 bicarbonate, magnesium, and calcium), Proteins (lysozyme, lactoferrin, lipocalin, IgA, EGF, and other growth factor, etc.), Lipids, Mucins and vitamins.

The aged lacrimal gland affects the initial chemical composition of the tear film therefore affects the functionality of the eye and the eyelid. One aspect of the aged lacrimal gland is a gradual decline of the immune system. Research has shown that there is an increase in autoimmunity, with a reciprocal pathway between low levels of inflammation and aging mechanisms. The aging of the lacrimal gland is related to functional changes, reduced innervation, and decreased secretory activities. Lymphocytic infiltration, destruction, and atrophy of glandular parenchyma, ductal dilatation, and secretion of inflammatory mediators modify the volume and composition of tears. Meibomian glands (also called tarsal glands, palpebral glands, and tarsoconjunctival glands) are sebaceous glands along the rims of the eyelid inside the tarsal plate. They produce meibum, an oily substance that prevents evaporation of the eye's tear film.

In the TFOS DEWS II Report , dry eye disease is divided into two types: tear deficient; and evaporative. In most cases, tear deficiencies are a result of lacrimal gland malfunctioning. The evaporative dry eye is associated with meibomian gland dysfunction.

(J.P. Craig, K.K. Nichols, E.K. Akpek, B. Caffery, H.S. Dua, C. Joo, MD, Z. Liu, J.D.

Nelson, J.J. Nichols, K. Tsubota, F. Stapleton, TFOS DEWS II Definition and Classification Report, The Ocular Surface Volume 15, Issue 3, July 2017, Pages 276-283, https://doi.org/10.1016/j.jtos.2017.05.008) Dartt states that the activation of the lacrimal gland is also controlled by the activation of sensory nerves in the corneal and conjunctival epithelia (D.A. Dartt, Neural Regulation of Lacrimal Gland Secretory Processes: Relevance in Dry Eye Diseases, Prog Retin Eye Res. 2009 May; 28(3): 155–177. doi:10.1016/j.preteyeres.2009.04.003). Quoting Dartt "The first segment of the lacrimal RS 304939/4 gland functional unit that regulates lacrimal gland secretion is the activation of sensory nerves in the corneal and conjunctival epithelia. The ocular surface epithelia are richly endowed with sensory nerve endings that respond to changes in the environment causing a rapid secretion of lacrimal gland fluid to wash away and chemically neutralize foreign substances that have entered the tear film. Stimulation of corneal sensory nerves causes fluid secretions and vasodilation in the lacrimal gland. Lacrimal gland fluid secretion is dependent upon vasodilation with increased blood flow augmenting secretion and decreasing blood flow inhibiting stimulated secretion." Dartt states that the mechanism responsible for the coupling between lacrimal gland vasodilation and fluid secretion is unknown.

The conventional therapy suggested by the US National Eye Institute for treating DED includes: over-the-counter eye drops (artificial tears) or moisturizing gels and anti-inflammatory topical formulations; prescription medicines such as cyclosporine (Restasis) or lifitegrast (Xiidra); and lifestyle changes such as avoiding smoke, wind, and air conditioning. A traditional homemade remedy is to apply warm compresses to the eyes.

In accordance with Butcher et. al (BUTCHER EO, COONIN A. The physical properties of human sebum. J Invest Dermatol. 1949 Apr;12(4):249-54. PMID: 18120703.), human sebum viscosity vs. temperature can be linear and approximate. At 37°C, the viscosity is about 600 millipoises, and at 27°C, the viscosity is about 1,000 millipoises. As meibum may be approximate as sebum, we may conclude that even slight heating of the meibum by contacting the eyelid skin may lead to a substantial decrease of the meibum viscosity, therefore, may lead to improved flow of meibum within the meibomian gland and therefore relief the symptoms of dry eyes and meibomian gland dysfunction (MGD). Heating of the eyelid skin of the epithelium layer may be done by direct contact as previously presented RS 304939/4 by Alcon Systane® iLux2®. In another case, a combination of heat and pressure is aimed to obtain similar results as demonstrated by JNJ Lipiflow. Using the Lipiflow, the eyelid is heated to about 40°C; therefore, the meibum temperature is elevated, resulting in a change in meibum viscosity. MGD is thus relieved by making the meibum more flowable. The combination of lower meibum viscosity with an external pressure applied by the device provides meibum that may flow easily; hence the flow of meibum is restored.

Many patent publications suggest devices based on this traditional remedy, one of which is US Patent Application Publication No. 20180344512 which describes dry eye treatment apparatus which comprises a patch or strip affixed to the skin of the upper and/or lower eyelids to deliver heat or other forms of energy to the one or more meibomian glands contained within the underlying skin of the eyelid of a subject. Additional devices are disclosed in CN102846423, JP5137956, US20200146881 and US20210052216.

Another dry eye treatment strategy known in the art proposes electrical nerve stimulation of the lacrimal gland through electrodes which are implanted in the eye. Such implants are described in EP 3349848, WO2017072575, US20180116872, WO20201984 and WO2021086924. This is an invasive method which does not suit everyone.

US2021138232 describes transcutaneous nerve stimulation such as facial nerve stimulation for artificially eliciting eye blink, such as with humans with acute facial paralysis (Bell's palsy or Dry Eye syndrome). US20150100001 discloses therapeutic ultrasound device for treating an eye condition.

JP 4242195 discloses an optical treatment appliance which accelerates the secretion of tears by stimulating the lacrimal gland. The appliance is equipped with a probe which irradiates light from its tip when in contact with the vicinity of the lacrimal gland on RS 304939/4 the upper part of the eyelid. The probe is equipped with a touch sensor and the treatment is performed without irradiating the eyeball.

Eyelid illumination with an infrared (IR) light for imaging meibomian glands for meibomian gland analysis is disclosed in US20140330129 and KR 101776226.

KR1020210027842 discloses an ophthalmic wearable treatment device comprising: a part wearable on a user's head, a light irradiation part and irradiating light having a wavelength absorbable into the user's eyelid tissue. The treatment light irradiated by the light irradiation unit is absorbed by the eyelid tissue and converted into thermal energy to treat dry eye syndrome, thereby dissolving lipid residues or wastes formed in the secretion path to secure a discharge path. The treatment light has a wavelength band having excellent absorption characteristics by lipids (900 nm to 950 nm, or 1140 nm to 1260 nm). The device includes a detection unit for detecting real-time position information of the eyelid so that the treatment can be performed in response to situation in which a patient moves the eyelid.

Thus, prior art for treating dry eye syndrome suggests one of the following: • pharmaceutical compositions required to be administered to the eye very often during the day and usually in long term use lose effectiveness; • medical implants; • medical devices that treat the eyelid or the skin in vicinity of the lacrimal glands and/or meibomian glands by transferring light energy which transforms into heat energy in order to artificially stimulate the glands to secret tears or sebum. The treatment is provided mainly wherein the eyeball is covered and requires a direct contact of the probe with the skin.

It is therefore an object of the present invention to suggest alternative options for treating DED. The invention integrates innovatively several mechanisms in a single RS 304939/4 device which may be operated on a patient for stimulating the lacrimal gland and/or meibomian gland of the patient. The invention also aims at activating the lacrimal reflex in order to re-balance the gland function and restore, at least partially, the initial chemical composition of the tears necessary for the regular function of both the lacrimal and meibomian glands.

SUMMARY OF THE PRESENT INVENTION The present disclosure generally relates to ocular therapy and more particularly relates to methods and apparatus for treating dry eye diseases (DED) and other dry eye related disorders or syndromes. Embodiments of the present invention integrate visible and IR light mechanisms in a single device operated by a healthcare professional on a patient for stimulating the lacrimal gland and/or meibomian gland of the patient. The proposed device is a handheld device with an optional gripping handle. The invention can be considered a contribution over previous inventions with regards to improved performance.

The improved performance is related to the infrared energy mechanism which enhances the effect of the proposed medical device.

In accordance with some embodiments of the disclosed invention, there is thus provided a handheld device for stimulating the lacrimal gland and potentially or optionally the meibomian gland of an eye of a patient. According to these embodiments, there is provided a handheld device for treating Dry Eye Disease (DED) and other dry eye related disorders or syndromes including at least one light source constructed to emit on a retina of an eye of a patient, light stimulation pulses in the visible region of the spectrum and at least one energy source constructed to emit light in the infrared region. According to some embodiments, the at least one light source is constructed to emit visible light on the retina.

RS 304939/4 According to at least one other embodiment, the at least one energy source is constructed to emit light in the direction of the eye and periorbital region including the eyelids. According to some embodiments, when the handheld device is in operation mode, a light intensity gradient between the light stimulation pulses emitted by the at least one light source and the light around the eye is maintained at least 0.5 lumens. According to at least one other embodiment, the light around the eye is maintained at least 0.5 lumens by movement of any one or both of the following: a) at least one light source; and b) at least one energy source.

According to some embodiments, the emission of visible and infrared light in the direction of the eye activates a brain reflex and thereby induce tear production. By exposing the retina to light stimulation pulses in the visible region and in the infrared region, the device activates a brain reflex. Furthermore, the device may in addition to the brain reflex activate a lacrimal reflex and a pupillary light reflex and optionally one or more reflexes selected from: blink reflex; corneal reflex and menace reflex. Activation of these reflexes induces tear production and secretion, and thereby results in the outpouring of tears.

Therefore, according to embodiments of the invention, the device activates in addition to the brain reflex, a lacrimal reflex and a pupillary light reflex and optionally one or more reflexes selected from: blink reflex; corneal reflex and menace reflex.

According to some embodiments of the invention, at least one light source emits light on the retina and thereby activates the lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex, blink reflex; corneal reflex and menace reflex, and thereby induce tear production. According to some embodiments, the device includes at least one light source that emits visible light on the retina. The at least one light source RS 304939/4 generates light pulses in a random or non-random sequences and thereby activates the lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex, blink reflex; corneal reflex and menace reflex, and thereby induce tear production.

According to alternative embodiments of the invention, the device includes at least one light source that generates light stimulation pulses in a manner of a change in light intensity in a random or non-random sequences. These light stimulation pulses are emitted on the retina and thus activate the lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex, blink reflex; corneal reflex and menace reflex, and thereby induce tear production. Yet in accordance with some embodiments of the invention, when the device is in operation mode, a light intensity gradient between the light pulses emitted by the at least one light source and the light around the eye is maintained at least 0.5 lumens.

According to some embodiments of the invention the device includes at least one energy source that emits light in the infrared region on the eyelids and/or the periocular and/or periorbital areas of the patient. According to some embodiments of the invention the at least one energy source generates light pulses in a manner of a change in light intensity in a random or non-random sequences by a movement of the IR light generator and the IR dispersing element and thereby activates the lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex, blink reflex; corneal reflex and menace reflex, and thereby induce tear production.

Alternative embodiments of the invention include a handheld device for stimulating the lacrimal gland of an eye of a patient by emitting visible and IR light on the retina of the patient. The device includes a controller, an optical system connected to the controller and arranged in the viewing direction of the patient. The optical system includes RS 304939/4 at least one light source, and is configured for providing visible light stimulation pulses to an eye of the patient by the at least one light source. In addition, the device includes a power supply unit for supplying power to the controller and/or optical system and at least one energy source emitting light in the infrared region on the retina and optionally on the eyelids and/or the periocular and/or periorbital areas of the patient. The at least one energy source is electrically connected to the controller and to the power supply unit. The visible and IR light stimulation pulses activate a brain reflex and a lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex; blink reflex; corneal reflex; and menace reflex. When the device is in operation mode, a light intensity gradient between the light pulses emitted by the at least one light source and the light around the eye is maintained at least 0.5 lumens. The activation of the visible and IR light stimulation pulses induces tear production.

Some embodiments of the invention further stimulate the meibomian gland.

Other embodiments of the invention include an optical system with only one light source.

Alternative embodiments include at least one energy source that emits infrared light on the eyelids and/or the periocular and/or periorbital areas of the patient. According to some additional embodiments, the device further includes an IR dispersing element coupled to the at least one energy source. Other embodiments include at least one energy source that generates light pulses in a manner of a change in light intensity in a random or non-random sequences. Further, the infrared light pulses may be controlled by a movement of the IR light generator and/or the IR dispersing element. In one or more embodiments of the invention, the infrared light pulses are controlled by a movement of only the IR dispersing element. Optionally, the IR dispersing element contacts the skin randomly and may create RS 304939/4 some minor thermal lesions or slight burns on the skin, and thereby activates the lacrimal reflex to induce tear production.

Yet, in one or more embodiments of the invention, there is thus provided a handheld device for stimulating the lacrimal gland of an eye of a patient by emitting visible and IR light on the retina of the patient. The device includes a controller coupled to a power supply unit. The device further includes an optical system connected to the controller and arranged in the viewing direction of the patient, wherein the optical system includes at least one light source configured for providing visible light stimulation pulses to an eye of said patient by the at least one light source. The device also includes at least one energy source emitting light in the infrared region on the retina of the patient. The least one energy source is electrically connected to the controller and to the power supply unit. The visible and IR light stimulation pulses activate a brain reflex and a lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex; blink reflex; corneal reflex; and menace reflex. When the device is in operation mode, a light intensity gradient between the light pulses emitted by the at least one light source and the light around the eye is maintained at least 0.5 lumens. As a result, the activation of the visible and IR light stimulation pulses induces tear production. In some embodiments of the invention, the optical system is coupled to an independent power supply. In some other embodiments of the invention, the at least one energy source emits light in the infrared region also on the eyelids and/or the periocular and/or periorbital areas of the patient.

The present invention, in some embodiments relates to methods for stimulating dry eyes. In some embodiments of the invention, a method for stimulating the lacrimal gland of an eye of a patient is provided. The method comprises the following steps: RS 304939/4 applying a device for stimulating the lacrimal gland of an eye of a patient in the vicinity of a facial region of an eye of a patient; emitting light in the visible region of the spectrum and in the infrared region of the spectrum on the retina; exposing the retina to light stimulation pulses in the visible region and to light in the infrared region, and thereby activating a brain reflex, wherein such activation induces tear production.

Additional embodiments of the method further activate a lacrimal reflex and a pupillary light reflex and optionally one or more reflexes selected from: blink reflex; corneal reflex and menace reflex.

BRIEF DESCRIPTION OF THE DRAWINGS Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. Other devices, methods, features, and advantages of the present invention will be apparent to one skilled in the art upon examination of the following detailed description. Component parts shown in the drawings are not necessarily to scale, and may be exaggerated to better illustrate the important features of the present invention.

Fig. 1 is a side schematic view of a handheld device for treating Dry Eye Disease (DED) and other dry eye related disorders or syndromes, generally referenced 100, constructed and operative in accordance with a preferred embodiment of the disclosed invention.

RS 304939/4 Fig. 2 schematic illustration of a cross-section view of the eye showing the organs and the view angles during treatment.

Fig. 3 illustrates schematically the mode of operation of an embodiment of a device according to the invention, with the eye of the patient.

Fig. 4 illustrate the light system pulse characteristics of an exemplary optical system that may be used in conjunction with the device of the invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS The following disclosure provides different embodiments or examples. Specific examples of components and arrangements are illustrated in the drawings and described below to simplify the present disclosure and for ease of understanding. These are, of course, merely examples and are not intended to be limiting. Thus, the invention is not limited to the specifically described products and methods and may be adapted to various applications without departing from the overall scope of the invention. In addition, the present disclosure may repeat reference numerals and/or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed.

Definitions: The term "patient" and its derivatives will be used herein to indicate any person or animal benefiting from lacrimal gland and optionally meibomian gland stimulation.

The term "healthcare professional" and its derivatives will be used herein to indicate any trained person in the medical profession, for example, a doctor or nurse or an RS 304939/4 individual licensed, registered, certified or trained to work with the device such as a family member that can provide the treatment to the patient at home.

The term "eye" will be used herein to indicate one eye of a patient or both eyes of a patient.

As used herein the term "stimulation pulses" and its derivatives includes light pulses, sound pulses, vibration pulses, eyelash disturbance, air flow or any combination thereof that activates one or more reflexes selected from: eye nerve brain reflex, blink, corneal, menace, lacrimal or pupillary light reflexes.

As used herein the term "stimulating the lacrimal gland and/or meibomian gland" refers to stimulation of the lacrimal gland only, stimulation of both lacrimal and meibomian glands and stimulation of only the meibomian gland when it is activated in connection with stimulation of the lacrimal gland. Preferable meaning is stimulating the lacrimal gland and optionally the meibomian gland. Each of these terms will be used herein to indicate stimulating one gland of each eye of a patient or stimulating both glands of both eyes of a patient.

As used herein the term "periorbital" is defined as the tissues surrounding or lining the orbit of the eye including but not limited to: brow, eyebrow, eyelashes, eyelid and lacrimal punctum. The meaning of this term also includes all adjacent skin areas that upon receiving IR stimulation pulses may trigger stimulation of the glands and secretion of tears such as parts of the nose and nostrils. See also USA NIH National Human Genome Research Institute (https://elementsofmorphology.nih.gov/anatomy-periorbital.shtml).

As used herein the term "photon energy" is defined as electromagnetic radiation (EMR). Types of EMR include radio waves, microwaves, infrared, (visible) light, ultraviolet, X-rays, and gamma rays. A preferrable photon energy for the present RS 304939/4 invention is infrared. The meaning of the term "Infrared light" in the description is a light in a wavelength of 1 millimeter (300 GHz) to a nominal red edge of the visible spectrum, around 700 nanometers (430 THz).

The applicant has previously filed patent applications disclosing devices and methods for treating DED: Israeli Patent Application Nos. 290389 and 294455, U.S. Patent Application Ser. No. 18/159,978, and PCT/IL2023/050124, not yet published. These patent applications relate to devices and methods using light pulses in the visible spectrum. The current invention relates to devices and methods that integrate visible light and infrared light (IR) mechanisms.

The disclosure below presents embodiments of a novel device designed to stimulate tear production by operating two mechanisms: one that emits visible light stimulation pulses towards the eye without direct physical contact with the eye itself, and the other that is an infrared mechanism which transfers IR energy to the cornea, retina, and potentially to the skin around the eye, including the periorbital and eyelid regions. The disclosed embodiments of the device provide handheld devices for treating dry eye disease (DED) and other dry eye related disorders or syndromes. All embodiments of the device comprise at least one light source emitting light in the visible spectrum and at least one energy source emitting photon energy in the infrared region. The device emits visible and infrared light stimulation pulses towards the eye and may in addition to a brain reflex activate a lacrimal reflex to induce tear production. In some embodiments of the device, the device emits visible and infrared light stimulation pulses towards the eye and retina to activate a brain reflex and a lacrimal reflex and optionally one or more reflexes selected from: pupillary light reflex; blink reflex; corneal reflex and menace reflex, such activation induces tear secretion.

RS 304939/4 The spinal reflex arc is one of the most important neural circuits in the body, it runs through the spinal cord and controls reflexes. The spinal reflex arc doesn’t involve the brain. In the present application, the definition of a brain reflex is a non-spinal-arc reflex (or reflex arc). Specifically, a brain reflex is a non-spinal-arc reflex (reflex arc) in which the signal passes to the brain.

A brain reflex is induced through the emission of a combination of visible and infrared light on the retina, rather than the spinal arc reflex that is triggered in the action of blinking. The device may change tear chemical composition and may induce severe meibum secretion by re-activating the aged lacrimal gland. The combination of both energy sources in the disclosed technology results in an enhanced response of the neural system in the midbrain. The change in the intensity (light intensity gradient) of the visible light in combination with the infrared light emitted on the retina stimulates specifically the lacrimal reflex which triggers the neural system to the midbrain of the patient.

A reflex is an automatic action of the body in response to a stimulus. The anatomical pathway of a reflex consists of an afferent (or sensory) nerve, usually one or more interneurons within the central nervous system, and an efferent (motor, secretory, or secreto-motor) nerve. The pupillary light reflex is a well-known reflex. If a light is flashed near one eye, the pupils of both eyes contract. Light is the stimulus; impulses reach the brain via the optic nerve; and the response is conveyed to the pupillary musculature by autonomic nerves that supply the eye. The pupillary light reflex is a response to light that is modulated by visual awareness. The pupillary light reflex controls the amount of light entering into the eye therefore in light pulses the importance of activating this reflex is laying on the fact that although blinking reflex is activated by the light, the pupillary light reflex is important to prevent any potential damage to the eye retina when the device is activated.

RS 304939/4 Another reflex involving the eye is the lacrimal reflex (Trigeminal Blink Reflex). When something irritates the conjunctiva or cornea of the eye, the lacrimal reflex causes nerve impulses to pass along the fifth cranial nerve (trigeminal) and reach the midbrain. The efferent limb of this reflex arc is autonomic and mainly parasympathetic.

These nerve fibers stimulate the lacrimal glands of the orbit, causing the outpouring of tears.

The eye blink reflex is elicited by an external stimulus such as a loud noise or a flash of a light or by predefined scenes or a tap on the forehead or by "irritating" the eyelash directly or indirectly.

The menace response is a blink reflex that occurs in response to the rapid approach of an object. The menace reflex comprises blinking of the eyelids, in order to protect the eyes from potential damage. Potential damage may be either actual i.e., potential movement of an element towards the eye, or virtual. When the human brain interprets a visual effect as a potential real threat to the eye, it responds in the same way even when there is no real threat. For example, a series of frames creating video for example a punch toward the system user, or car chase in which car seems going out of the device toward the user face may result the menace reflex although no actual contact between the virtual object and the eye are created.

The corneal reflex causes both eyes to blink in response to tactile stimulation of the cornea. As the cornea is the first substance irritants or foreign objects will touch when they come in contact with the eye. Contact with the cornea initiates the corneal reflex and tear production. The reflex activates when a sensory stimulus contacts either free nerve endings or mechanoreceptors within the epithelium of the cornea. When activated, any one of the-above mentioned reflexes or a combination thereof stimulates the lacrimal gland and/or meibomian gland to output tears. Moreover, any combination of the blink, corneal, RS 304939/4 menace and lacrimal reflexes invokes a stronger blinking compared to a voluntary blink alone. Such a strong response may ease the dry eye symptoms of both the lacrimal and the meibomian glands. To sum the above, the pulses emitted from the device of the present invention trigger neural signals through two separate anatomic pathways: 1. Optic tract fibers that terminate at the pretectal nucleus in the midbrain. 2. Autonomic and mainly parasympathetic neural pathways.

Furthermore, activation of sensory nerves in the corneal and conjunctival epithelia and stimulation of corneal sensory nerves cause fluid secretions and vasodilation in the lacrimal gland. The stimulation of corneal sensory nerves stimulates the lacrimal gland by a trigeminal-parasympathetic reflex. Visible light stimulation pulses emitted towards the open or closed eye activate a sequence of eye blinks. In turn these eye blinks re-activate the lacrimal gland and optionally the meibomian gland leading to tear generation and self-restoration of the tear mechanism. In particular, use of the device of the invention is advantageous in cases where blinking reflex is weak due to environmental reasons, such as long exposure to computer screens at work. During the operation of the device, the eye may be open or closed, depends on the intensity of the visible light pulse emitted from the at least one light source, and the physical condition of the eye. The activation of these reflexes can be simultaneous or one after the other.

A visible light stimulation therapy which combines specific patterns and stimuli combinations can also be utilized for certain eye disorders. The retina contains molecules that undergo a chemical change upon absorbing light. For example, Retinol can be converted to retinal, and retinal is a chemical necessary for rhodopsin which enables night vision. As light enters the eye, the molecules may undergo an isomerization, or a change in their molecular arrangement. The new molecular form may not fit as well into the protein, and so RS 304939/4 a series of geometry changes in the protein begins. (Chemistry LibreTexts. 2016. Chemistry of vision. [online] Available at: Biological_Chemistry)/Photoreceptors/Chemistry_of_Vision>). The device of the invention activates the fifth cranial nerve (trigeminal) and reach the midbrain to create an excessive tear production by the lacrimal gland and to change the composition of the tear film proteins hence affecting the biochemical processes in the eye and the eyelid. Among proteins within the tear film, growth factors, other proteins and vitamins such as vitamin A are playing a crucial role in controlling the process of dry eyes.

One embodiment of the device for use in the treatment of eye conditions comprises: a power source coupled to an optical system which includes at least one light source emitting light stimulation pulses in the visible region of the spectrum. In this embodiment the power source is also coupled to an infrared mechanism with at least one energy source (IR light generator) emitting infrared light in the infrared region. In an alternative embodiment, each of the at least one light source and the at least one infrared mechanism are coupled to their own power supply (as shown in Fig. 1). In addition, the device includes a controller coupled to the at least one light source and to the at least one energy source (IR light generator). The controller is configured to operate each of the sources independently according to the required treatment. In addition, the controller is able to regulate the light intensity (visible and IR) by setting a fixed light intensity by pulse width modulation (PWM) or by other means of voltage or current regulation such as simple switching (on/off as a sequence of time in a predefined algorithm), analog to digital setting by a microcontroller. Alternatively, the controller may regulate the light intensity so that the light source can work continuously or in flashing mode and thus emit light pulses in a RS 304939/4 manner of a change in light intensity in a random or non-random sequences. Some alternatives will be detailed hereinafter in connection with Fig. 4. Some alternative embodiments of the device include a controller constructed to actuate additional stimulation pulses in combination with the light stimuli described above, according to a specific predetermined treatment.

At least one light source stimulates the lacrimal gland and optionally the meibomian gland of an eye of a patient by emitting light on the retina in a sequence resulting a change in the light intensity on the retina. The at least one energy source emits photon energy from the infrared light source on the retina and on the periorbital areas of the patient and activates a brain reflex. In some embodiments, the infrared light activates both lacrimal and brain reflex. Alternatively, the infrared light activates both lacrimal and brain reflex and in conjunction with the visible light further activate one or more reflexes selected from: pupillary light reflex; blink reflex; corneal reflex and menace reflex. The at least one energy source is an IR light generator (as shown in Fig. 1) which is coupled to IR dispersing element. The IR dispersing element may slightly contact the skin around the eye , including the periorbital and eyelid regions. The IR dispersing element is coated with or formed from any heat-conductive material. The heat conductive material may have high, medium, low or extremely low thermal conductivity. The external design of IR dispersing element is constructed such that it achieves two objectives: spreading the IR energy to a relatively large surface in an even manner and reducing the contact area between the conductive material to the tissue, in case of short thermal contact with the skin during operation. The at least one energy source (IR light generator) is also coupled to a motion (driving) system for advancing the IR light generator towards the periorbital region. Conveying the IR light generator closer to the periorbital region achieves two objectives: exposing the retina to the IR energy and at RS 304939/4 least partially blocking the emission of the visible light from the eye. Furthermore, the motion of the IR energy source provides light gradient between steady-state light and a light stimulation pulse which is useful for activating the lacrimal reflex. In addition, by advancing the IR energy source (which is coupled to the IR energy spreading element), the retina is exposed to the IR energy or at least exposed to a change in the IR energy gradient, as well.

To clarify, any above reference to the IR energy source should be regarded as referring to at least one of IR energy sources included in the device, or to an element of one IR energy source, depending on the specific embodiment of the invention. For instance, in some embodiments, the IR energy source that travels forward may be only one element of multiple sources included in the device. In such case, only this one element will advance forward, for example, rather than the complete IR mechanism itself that includes all IR energy sources.

Reference is now made to Fig. 1 which is a side schematic view of a handheld device for treating Dry Eye Disease (DED) and other dry eye related disorders or syndromes, generally referenced 100, constructed and operative in accordance with a preferred embodiment of the disclosed invention. Handheld device 100 includes a gripping handle 102 which in Fig. 1 is located at the rear part of the device. The gripping handle may also be formed as a half-ball, a circular knob, or in any other shape. Device 100 also includes a distal section 104, which is located at the front section of the device. As seen in Fig. 1, an imaginary line 106 separates the two portions (102; 104) simply to better illustrate the device.

Gripping handle 102 is designed to provide for the healthcare professional an easy-to-hold and operate tool, and may also include a screen or a display, touch pad, buttons and any other operating aids. Alternative designs of handheld device 100 are constructed RS 304939/4 for use in a home environment by a non-expert user (i.e., a patient at home cared for by a family member or a nurse). Such embodiments further include a specific mechanism that prevents applying excessive pressure on the eye, beyond a pre-defined pressure. This specific mechanism is constructed into distal section 104, the part of the device that may touch the eyelids and/or the periocular and/or periorbital areas of the patient. In some embodiments, when the pressure on the sclera exceeds a defined permissible value, such as mmHg, the device releases a warning signal to alert the user not to apply additional pressure on the eye. The mechanism is based on a pressure gauge, strain gauge, or spring located between the transparent part (or its guides) and the handle. If the spring is compressed above a pre-determined threshold, it activates a switch that triggers a warning signal. The warning signal can be a light and/or sound indication . Alternatively, other possible configurations of the device may be designed for self-use, these may have additional features that provide further protection to the end user.

Referring back to Fig. 1, the angle (not shown) between the gripping handle and imaginary line 106 may vary between 0 to 180 degrees to allow optimal positioning of the tip of part 104 (aperture 108) on the periorbital region. Gripping handle 102 also includes an actuator 120 which is operated by button 122. In Fig. 1, button 122 is a press button.

However, it should be noted that, the button may be operated by any other technique or gesture or positioned in any other part of the device, as well. Distal section 104 includes at the end, an aperture 108 which is designed to allow close contact with the patient's periocular and/or periorbital areas. Distal section 104 is at least partially transparent to allow the passage of light in the visible range and in the infrared range through the shell. In other words, distal section 104 may be completely transparent or transparent in part. For example, some embodiments of the invention may have a distal section which is only transparent at 1.8.24 RS 304939/4 the front, i.e., at the section around the aperture. Other embodiments of the invention may have a transparent window that allows passage of both visible and infrared light. As long as the transparent part is capable of delivering visible light to the eye of the patient and photon energy, such as infrared, to the patient's eye and retina and optionally to the eyelids, periocular and/or periorbital locations, the extent of the transparent portion is sufficient for the invention.

The objective of the system is to generate visible light and IR energy pulses and emit these light pulses on the retina. Therefore, distal section 104 is also designed for conveying stimulation pulses, such as visible light pulses, towards the direction of the patient's eye. A light pulse (including visible light and light in the IR range) is defined as a gradient between the steady-state light and the intermediate light intensity. The difference in light gradient between steady-state light and a stimulation pulse varies between 1 to 5 lumens. The ratio between visible light and the effective IR emission that can be sensed by the skin and eye nociceptors shall vary between 50:1 to 1:50 (visible to IR). The visible light source intensity may vary between 0.1 to 500 lumens. The number of visible light sources included in the device may vary between 1 and up to 15. The number of IR light generators in the device may vary between 1 and 4. The requirement that the light intensity gradient between the light source and the environment shall be at least 0.5 lumens may be achieved by adjusting the current or voltage of the light sources (visible and/or IR). For example, light intensity of the visible light source can be regulated by modifying the electrical current or voltage supplied to the light source. Alternative embodiments of the invention may include specific current or voltage regulators coupled with or included in the visible light source or IR light generator. 1.8.24 RS 304939/4 Device 100 also includes optical system 110 that comprises visible light source item 112, which may be a LED. Visible light source 112 is positioned inside the device at a location that ensures emission of light in the direction of the eye of the patient. When distal section 104 is placed on or near the patient's periorbital region, light source 112 is activated, then at least a portion of the light emitted by light source 112 enters the retina and the eye of the patient. It should be stated that, the position of visible light source item 112 is not limited to the position shown in Fig. 1, but can be anywhere else inside or outside the device as long as the location ensures emission of light in the direction of the eye of the patient.

For example, in an alternative embodiment of the invention that includes more than one visible light source item, these are located in different positions along the inner frame of the device. As shown in Fig. 1, device 100 includes two optical systems 110. Each of the optical systems is connected to either a single power supply 128 or to a single power supply 1 that supply the appropriate power to the visible light source. Both optical system 110 and power supply 128 are connected to and operated by controller 118. Other embodiments of the invention include an optical system with only one light source. Alternative embodiments of the invention include an optical system with at least two light sources. Additional details in respect of the optical system and light source 112 will be provided herein after.

As stated above, the present invention integrates visible and IR light mechanisms in a single device. The IR mechanism includes IR light generator 116 which is coupled to a dispersing element 126, a controller 118, a driving system 124, and an internal power supply 130. Alternatively, instead of using internal power supply 130, the IR mechanism may be powered by an external power supply. IR light generator 116 may have a ceramic heating element, nichrome element, LED, quartz, or any similarly electrical- powered thermal IR generator. IR light generator 116 is connected to controller 118 and RS 304939/4 through which to an actuator 120 which is electrically powered via power supply 130. Upon switching on button 122, actuator 120 operates controller 118 that activates optical system 110 and IR light generator 116 according to the desired treatment program. Controller 1 controls the spatial motion (movement) of IR light generator 116 and speed of the travel of IR light generator 116 relative to visible light source 112 and the skin around the eye.

Controller 118 is also electrically connected to driving system 124 which conveys IR light generator 116 from position A to B. Furthermore, IR light generator 116 is positioned in such a way that during its travel from position A to B (Figs. 2-3), it may be able to partially screen light or even prevent light from reaching the patient's eye from light source 112. The patient's field of vision may be blocked to varying degrees, ranging from 5 to 100%.

Controller 118 also controls the emission intensity of dispersing element 126 (i.e., temperature or IR radiation emission). IR dispersing element 126 may also limit the amount of IR energy emitted to the eye and to the retina. The emitted IR energy levels should be below the threshold level that might damage the eye or the retina. In order to accomplish this goal, IR dispersing element 126 exploits spatial dispersion of the surplus IR radiation.

Dispersing element 126 may have a cylindrical, pyramids or other shapes that creates at least one apex and not more than 150 apexes in different dimensions. Optionally, controller 118 also adjusts the spatial position of IR light generator 116 and speed the travel of IR light generator 116 relative to the intensity of the visible light source. The controller also controls the IR emission (IR light generator 116) by an open loop (current or voltage regulation) or alternatively by using a temperature sensor (not shown) positioned in the IR light generator 116 for a close loop temperature control to achieve the anticipated IR energy emission. Alternatively, the temperature sensor may be positioned on dispersing element 126. The temperature of the IR light generator 116 may be set either by the user or present RS 304939/4 by the system designer. The emission of light from IR light generator 116 is dictated by the measured temperature, therefore, the intensity of emission may be set as a function of the severity of dry eye. Controller 118 also regulates the light intensity of the visible light and, optionally, selects the most appropriate emission program for the light source according to the required treatment. The light emission program may be for example, a sequence of pulses that varies between 0.1 to 10 second pulses with an interval of 0.2 to 20 seconds. The ratio between visible light and the effective IR emission that can be sensed by the skin and eye nociceptors shall vary between 50:1 to 1:50 (visible to IR).

Driving system 124 is represented in Fig. 1 as a solenoid or any type of an electric motor. However, driving system 124 may also be chosen from any one of the following: electric motors such as AC, DC, Stepper or Brush-less motors, or electromechanical actuators such as voice coil, solenoid, piezo electric actuators. IR light generator 116 is rigidly clasped to driving system 124. By forwarding IR light generator 1 towards the eye, driving system 124 controls the amount of thermal energy reaching the eye and periorbital tissue and reduces the amount of visible light A sensor 114 may be attached to IR light generator 116 or to dispersing element 126. Sensor 114 is configured to provide controller 118 indications for the position and speed of IR light generator 116. In some embodiments, sensor 114 may be integrated within any one of IR light generator 116 or dispersing element 126. As stated above, dispersing element 126 is connected to IR light generator 116. Dispersing element 126 spreads the photonic energy all over its surface and towards the treated tissue. For example, infrared energy is transferred to the treated tissue and warms it. Dispersing element 126 may be manufactured from biocompatible materials that are used in medical devices and are not toxic or harmful to the body. Some of the materials that can be used are: thionium, titanium RS 304939/4 alloy, tantalum, tungsten. Furthermore, the specific material and structural design for dispersing element 126 should be selected according to the particular use of the device. The required result and the nature of the treatment will determine which material and which structure of dispersing element 126 are required for the working temperature of this element.

The geometric planning is done according to the principles of Fig. 2 that will be explained hereinafter. The temperature of dispersing element 126 varies between room temperature to 550°C.

Driving system 124 moves IR dispersing element 126 forward to the treatment position and backwards to the retracted position. The movement of dispersing element 126 may be accompanied by a movement of IR light generator 116 towards distal end 104 and aperture 108. However, in some embodiments of the device of the invention, dispersing element 126 moves toward the distal end 104 without IR light generator 116.

When IR light generator 116 is in its retracted position, it is substantially nested in the gripping handle 102. The travel of the IR light generator 116 back and forth enables setting of the distance from the retracted position to the tissue. In the retracted position, when device 100 is placed over the skin, such that aperture 108 is close to the treated tissue, neither the eye nor the skin is exposed to any substantial IR radiation as expressed by heat sensation.

When IR light generator 116 reaches the end of travel, heat spreading element 126 may create tiny thermal lesions or slight burns on the skin depending on the curvature of the tissue. In addition, during the travel of the IR light generator, some of the visible light generated by the visible light source is blocked, resulting in a decrease of photonic energy passing through the cornea via the vitreous humor and to the retina.

The IR light generator's total pulse (movement) may vary between 0.1 to seconds resulting in a light pulse intensity change of similar duration; however, to mitigate RS 304939/4 any severe damage to the skin tissue, the contact duration of the IR spreading element is limited to 1-50 milliseconds. The movement of the IR light generator shall reduce the light intensity retina exposure by at least 2% to achieve a light intensity gradient between steady state conditions when the device is located on the skin, and the light intensity when the IR light generator is forwarded towards the skin. The visible light gradient shall be calculated as the maximum visible light intensity gradient during the whole movement of the IR light generator. The light intensity reaching the cornea is calculated as the total visible and IR light intensity reaching the cornea that concentrates the light via the lens. The retinal light intensity exposure also depends on the reflection of the visible light by the IR light generator, including the IR light generator enclosure.

In one or more embodiments of the device of the invention, driving system 1 also moves optical system 110 with visible light source 112 along a travel path to achieve a light intensity gradient of at least 2% between steady-state light and a light stimulation pulse. Furthermore, a light intensity gradient between the light pulses emitted by the at least one light source and the light around the eye is maintained at least 0.5 lumens. The movement of visible light source 112 may be a spatial motion i.e., in the direction of aperture 108 or in the opposite direction to the rear part of the device. Another option to achieve the same effect may be conducted by connecting visible light source 112 and IR light generator 116 to driving system 124 to advance the visible light source in parallel to the motion of IR light generator 116 and/or IR dispersing element 126. Alternatively, visible light source 1 may be advanced forward or backward by driving system 124 while IR light generator 1 and IR dispersing element 126 are stationary. In another embodiment, visible light source 112 may be conveyed by driving system 124 while IR light generator 116 and IR dispersing element 126 travel along the same path with visible light source 112. In yet another RS 304939/4 embodiment of the invention, visible light source 112 may move independently without relation to the motion of IR light generator 116 and the dispersing element 126. In yet another embodiment, the movement of visible light source 112 may be opposite to the motion of the IR light generator 116 and/or dispersing element 126.

A sample of IR light generator may be a metal wire element made of nichrome, a ceramic heating element made of, for example, a nickel embedded inside a ceramic material such as silicon nitride or alumina, short wavelength IR led. The geometric planning is done according to the principles of Fig. 2, which means that the movement of the IR light source changes the intensity of the photonic energy of the two light sources in the visible field and in the infrared field.

Referring now to Fig. 2, which is a schematic illustration of a cross-section view of the eye showing the relevant organs and the view angles during treatment, aspects of the operation of the device will be further explained. During the operation of the device, IR light generator 116 is traveling between at least two positions: first (A) and second (B). At the first position (A), a direct line of sight 200 between the patient's eye 250 to light source 2 is enabled. Light source 212 emits light towards the eye whereas at the same time, IR light generator 116 is located at a distance from the eye (retracted position). Angle 210 represents the amount of visible light emitted to eye 250. At the end of the travel, IR light generator 116 reaches the second position (B), where it conceals partially or completely the light pulses generated by light source 212. Angle 220 represents the reduced amount of visible light that now may enter to the eye. In other words, at the end of travel, a larger portion of the visible light is blocked (up to 100%), resulting in decrease of the visible light passing through the cornea 230. In some alternative embodiments of the invention, at the first RS 304939/4 position (A), the visible light generated by light source 212 may be slightly blocked (up to 95%).

When IR light generator 116 reaches position (B) at the end of travel, heat spreading element 126 may then transfer thermal energy to the skin. The motion of IR light generator 116 provides light gradient between steady-state light and a light stimulation pulse. The light gradient is useful for activating the lacrimal reflex. In addition, by advancing IR light generator 116 towards the retina, the retina is exposed to the IR energy or at least exposed to a change in the IR energy (gradient), as well. Upon operation of the device, IR light generator 116 changes positions and travels back and forth from the first position to the second position.

Referring now also to Fig. 3 which illustrates schematically the mode of operation of an embodiment of a device according to the invention, it can be seen that the visible light intensity block may be expressed by the field of view angles 302 and 304.

Point 300 is the location from which the energy is directed towards eye 308. When the IR light generator is at the nested position (position A, also shown in Fig. 2), angle 3 represents the intensity of the visible light emitted directly towards eye 308. Angle 3 represents the amount of photon energy emitted from IR light generator 116. At the end of travel, as IR light generator 116 is located at position B, the visible light generated by the light source 112 (or 212 in Fig. 2) may be slightly blocked or substantially blocked (up to 100%), according to the required treatment. The skin around the eye 306 is now exposed to the thermal energy.

In an alternative embodiment of the present invention driving system 124 is replaced by a shield element which may be a disc or any mechanical element. This shield element completely or partially blocks the thermal energy emitted from IR light generator RS 304939/4 in the direction of the eye and periorbital region. This shield element will move from a nested (retracted) position to a fully extended position in order to achieve a similar result as exemplified above in connection with the mechanism of the driving system.

As stated above, light source 112 may be connected to a power supply unit which can be an internal power pack (for example, batteries rechargeable or disposable).

Alternatively, light source 112 may be coupled to an external power source. Light source 112 may comprise, for example, a series of LEDs, a light bulb, electroluminescent display (ELD), LCD display, OLED display or any combination thereof. Light source 112 may be configured to emit light pulses, light frames or short video scenarios or scripts for activation of an eye to induce blink reflex and/or pupillary light reflex and/or lacrimal reflex. A combination of different types of reflexes may further contribute to activate the lacrimal gland and optionally the meibomian gland. When light is emitted directly to the retina and the light gradient between the projected light and the light level of the surrounding area is maintained at 0.5 lumens, the pupil reflex (pupillary light reflex) is activated. The system may include at least one light source that emit light. In some embodiments, the device includes between 1-15 light sources. However, the number of light sources may vary and depends on different parameters of the device and the light source characteristics.

Then, when light source 112 emits light, the light is directed to the eye retina of the patient. This light stimulation pulse activates one or more of the above-mentioned reflexes, and thus the eye blinks due to a rapid exposure of the eye retina to a light in the visible range. Each light source can be activated alone or simultaneously with at least another light source. The sequence of light pulses is random and unexpected. It may be in different patterns, from different angles and directions. Light pulses may be programmed to activate blinking on each eye separately in response to blink reflex, corneal reflex, menace RS 304939/4 reflex, lacrimal reflex and/or pupillary light reflex, although activation of the said reflexes in one eye may result the activation of the reflexes in both eyes simultaneously. Light source 112 may emit light stimulation pulses in non-random sequences for a predetermined time and then alternate these with stimulation pulses in random sequences.

The optical system 110 further includes a power supply unit 128 (shown in Fig. 1) so that it can be self-energized. The power supply may be a battery, a radiated power source or a solar panel. Alternatively, optical system 110 may be powered by the controller or by the same power supply unit that provides power to the controller . Yet, in other alternative embodiments optical system 110 and power supply unit 128 may be electrically connected to controller 118 and to power supply 130, as well. In the embodiment shown in Fig. 1, a power supply unit 130 is integrated with controller 118. However, it should be noted that, the power supply unit may be integrated with or arranged within the optical system, as well and then supply power to both controller and optical system 110. In other embodiments, the device may be constructed to connect an external power supply unit or even plug to domestic power via a wire/adapter.

The light panel of optical system 110 may have at least one light source for emitting light to any eye of the user. However, some embodiments of the invention may include two or more light emitting sources, as necessary for the specific design. The light pulses are emitted at a random sequence. In some embodiments, the light source provides light stimulation pulses in a random pattern and sequence in order to prevent the development of endurance of the eye. In other words, the light source generates light stimulation pulses in a random pattern that surprises the patient. In one or more embodiments, the optical system further comprises lens, adjustable lens and/or lens adjusting mechanism that can be adjusted horizontally, vertically, or a combination thereof RS 304939/4 to fit a specific face structure. In alternative embodiments, the at least one light source provides non-random light stimulation pulses.

The light source is limited to the visible spectrum (wavelength 350-750nm). The maximal light intensity depends on the light source, pulse sequence and other factors as describe by Boyuan Yana et. al., "Maintaining ocular safety with light exposure, focusing on devices for optogenetic stimulation", Vision Res. 2016 April; 121: 57–71. doi:10.1016/j.visres.2016.01.006. In addition, the American National Standards Institute (ANSI) Z136.1-2000 Standard provides details on the amount of energy for ophthalmic device. For example, some embodiments of the device of the invention may emit light at an intensity between 5 lumens to 2500 lumens, measured at a distance of 1cm from the light source. It should be noted that the device may include a pulse light source in a close chamber for various sizes of the device. The light source pulse maintains the requirement that the light intensity gradient between the light source and the environment shall be at least 0. lumens.

Furthermore, the controller may be programmed to operate the optical system in a predetermined sequence according to a required treatment. The controller may be further provided with a user-friendly app that enables a user to select the most suitable treatment for the eye condition of the patient. Such app can be a computer program or software application designed to run on a mobile device such as a phone, tablet, or smart watch. Optionally, the controller includes an algorithm that is programmed to allow the optical system to generate a sequence of pulses at period varies between 0.1 msec (millisecond) to 10 minutes. The number of pulses per session shall vary between 1 to 1,0 pulses. Treatment regimen shall include between 1 to 20 treatment sessions every 1 to 1 days.

RS 304939/4 An embodiment of the device may include a feedback element such as a camera (not shown). The camera is provided for allowing close loop control on the activation of the different eye reflexes and to enable modifying the light pulses characteristics such as light intensity, pulse duration, pulse sequence according to the requirements of the user. The camera may also provide the option to better monitor and control the sound and vibration characteristics used for inducing the menace reflex solely or in parallel to the light pulse sequences. Furthermore, in another embodiment of the invention, the camera is interconnected with the light source and the control unit for evaluating the tear breakup time (TBUT) by measuring the time elapse from blinking until tear film breaks. The measurements can be presented in seconds or by any other indicative form. The system may be used before the treatment, during treatment and/or after the treatment for evaluation. The evaluation may provide indication of the progress made by the user. An alternative embodiment of the device may include a feedback element such as a camera or photo sensor that can for example evaluated the blinking effect as a function of the reflex activation mechanism (light, sound, irritation, etc.) and can modify the activation sequence, intensity, period, frequency and light and/or sound combined with "irritation algorithm for example changing the VR scenario (i.e., from car race to snow collapse).

In some embodiments, the device may contain one, two or up to 10 cameras allowing recording the correlation between the reflex’s activation methods, i.e., light, sound, vibration, eye lashes irritation as later described and the eye pupil, blinking and lacrimal reflex. The reflex reaction shall be analyzed using deep learning algorithms aiming to analyze the eye blinking characteristics. The deep learning algorithm allows determine the blinking characteristics such as: blinking speed, pupil dimensions in correlation with the different reflexes’ activation. In addition, the data may be integrated into AI algorithm to RS 304939/4 allow teaching the system to adjust the different pulses sequences to fit a specific user based on his unique behavior following the reflex activation element as described herein.

Handheld device 100 can optionally be used with an external control unit, such as a personal computer, laptop, tablet, cell phone and any other microprocessor-controlled unit that is capable of controlling the optical system and the IR mechanism. Yet in additional embodiments of the invention the controller includes two elements one is external and the other is installed inside the device. In these embodiments, both elements are wireless interconnected.

Controller 118 is programmed to activate optical system 110 to generate stimulation pulses in order to control the blinking, and/or pupil, and/or lacrimal reflex of the patient eyes without any contact between the light emitted from light source 112. Controller 118 may be programmed to activate optical system 110 to generate a sequence of light pulses at a frequency of 10 pulse per seconds up to 1 pulse every 5 minutes, in the visible range.

Pulse duration may vary between 0. 1 millisecond to 20 seconds, in order to initiate the photo-lacrimal reflex. While the retina is stimulated by an excess of light, it produces a lacrimal secretion through the afferent optic and efferent lacrimal pathways. It should be noted that optical system 110 is not connected to the eye, eyelid or to the face.

Light source 112 may emit light in all the visible range. Furthermore, Light source 112 may emit a single color i.e., white, blue, green, red or any combination of the RGB (red, green, blue), or any color defined by Panton color scheme light composition. The light source 112 refresh time for generating a new pulse of light vary between 1 millisecond to 2 minutes. Certain embodiments of the device may include arrays of light emitting elements that can project light towards the eye of the patient according to a predesigned pattern.

RS 304939/4 Figure 4 illustrates the light system pulse characteristics of an exemplary optical system that may be used in conjunction with the device of the invention. Light intensity 4 as a function of time may have different pulse shapes. For example, a step function with pulse duration 402 and intensity (a), which can vary between 1 millisecond to 5000 seconds and time interval between pulses (b) that can vary between 1 millisecond to 5000 seconds.

The duration of the second pulse 403 can be similar to the first pulse or as shown a bit longer. The number of pulses per session can vary between 1 to 5000. An alternative pulse shape is trapezoid or trapezoid-like shape where the light intensity vs. time take 406 is in the form of PL=f(t). The function can be linear, logarithmic, exponential, polynomic of up to 10th order. The total pulse duration 404 (d) may vary between 1 millisecond to 50 seconds and time interval between pulses 405 may vary between 1 millisecond to 50 seconds. Similarly, the duration of the high intensity of the pulse illustrated as (c) may vary between 1 millisecond to 5000 seconds. The number of pulses per session can vary between 1 to 5000. An additional alternative is illustrated at the lower graph, in which the pulse shape is a Sawtooth wave or Sawtooth wave like shape 407 where the light intensity vs. time takes 408 is in the form of PL=f(t). The function can be linear, logarithmic, exponential, polynomic of up to 10th order. The total pulse duration 408 may vary between 1 millisecond to 5000 seconds and time interval between pulses 409 may vary between 1 millisecond to 5000 seconds. The number of pulses per session may vary between 1 to 5000. In some embodiments, the light source provides light stimulation pulses in a random pattern in order to prevent the development of endurance. For example, a combination of different pulse shapes and durations selected from a predetermined data set for a specific disorder and age.

The light source generates light stimulation pulses in an unpredictable pattern that surprises RS 304939/4 the patient. In one or more embodiments, the optical system further comprises lens, adjustable lens and/or lens adjusting mechanism.

The disclosed technique also provides a method for use in the treatment of eye conditions. The method applies stimulation pulses of two different mechanisms and may alternate between at least two states: emitting stimulation pulses of light in the visible region of the spectrum on the retina, and emitting infrared light in the infrared region on the eyelids and/or the periocular and/or periorbital areas of the patient. Alternatively, the method may use these two mechanisms at the same time, continuously or randomly or non-randomly in order to achieve stimulation of a lacrimal gland of an eye of a patient.

The present invention, in some embodiments relates to methods for treating Dry Eye Disease (DED) and other dry eye related disorders or syndromes by stimulating a brain reflex. The method includes the procedures of applying a device for stimulating the lacrimal gland of an eye of a patient in the vicinity of a facial region of an eye of a patient. The method also includes the procedure of emitting light in the visible region of the spectrum and in the infrared region of the spectrum on the retina. The method also includes the procedure of exposing the retina to light stimulation pulses in the visible region and in the infrared region, and thereby activating a brain reflex. Such activation induces tear production.

In some embodiments of the invention, a device may be applied in the vicinity of a facial region of an eye of a patient, for stimulating the lacrimal gland and optionally the meibomian gland of an eye of the patient. The health professional or doctor selects the treatment plan for a specific patient. The treatment plan enables selection of preferably: the number of pulses, range of wavelength band and time intervals between the stimulation pulses. According to some embodiments the method includes applying a device for RS 304939/4 stimulating the lacrimal gland and optionally the meibomian gland of an eye of a patient in the vicinity of a facial region of an eye of a patient. When the device is in operation mode, it emits light on the retina. The emitted light is in the visible region of the spectrum, and in the infrared region. By exposing the retina to light stimulation pulses in the visible region and in the infrared region, the device activates a brain reflex. Optionally, in addition to the brain reflex the device may also activate a lacrimal reflex and a pupillary light reflex. The device may also activate one or more reflexes selected from: blink reflex; corneal reflex and menace reflex, such activation induces tear production.

In other embodiments of the invention the method further includes a procedure of controlling the infrared light via a movement of the at least one energy source.

Alternatively, in one other embodiment the procedure of controlling the infrared light is conducted by actuating a shield element to partially or completely block the thermal energy emitted in the direction of the eye and periorbital region. The emitted light may also result in changes in the tear chemical composition and severe meibum secretion. The device comprises: a controller; an optical system connected to the controller and arranged in the viewing direction of the patient. The optical system includes at least one light source, and is configured for providing light stimulation pulses to the eye of the patient. In addition, the device includes IR mechanism which is electrically connected to the controller. The IR mechanism includes IR light generator coupled to a dispersing element and to, a driving system, and an internal power supply. A power supply unit for supplying power to the controller and/or the optical system may also be provided.

The method further includes the steps of generating visible and IR light pulses by at least one light source and at least one IR light generator; emitting the pulses towards the eye of the patient; activating a brain reflex; activating in addition to the brain reflex a RS 304939/4 lacrimal reflex and a pupillary light reflex and optionally one or more reflexes selected from: blink reflex; corneal reflex and menace reflex. Wherein when the device is in operation mode, a light intensity gradient between the visible light pulses and IR light emitted by the at least one light or IR sources and the light around the eye is maintained at least 0.5 lumens.

Yet, alternative embodiments of the invention relate to methods for stimulating the lacrimal gland and optionally meibomian gland of an eye of a patient. The method comprises applying light stimulation pulses in the vicinity of a facial region of an eye of a patient by emitting light on the retina; activating a brain reflex, a lacrimal reflex and a pupillary light reflex of the patient, and optionally one or more reflexes selected from: blink reflex; corneal reflex and menace reflex, and wherein such activation induces tear secretion, and thereby resulting in the outpouring of tears.

Although embodiments of the present invention integrate visible and IR light mechanisms in a single device operated by a healthcare professional (including any person who was qualified to use the system for example home use applications) on a patient for stimulating the lacrimal gland and/or meibomian gland of the patient, other possible configurations of the present invention may be designed for self-use.

It will be appreciated by persons skilled in the art that the disclosed invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the disclosed invention is defined only by the claims, which follow.

Claims (18)

RS 304939/4 -39- CLAIMS

1. A handheld device for treating Dry Eye Disease (DED) and other dry eye related disorders or syndromes comprising at least one light source constructed to emit on a retina of an eye of a patient, light stimulation pulses in the visible region of the spectrum and at least one energy source constructed to emit infrared light towards the eye and periorbital and/or periocular regions, including the patient's eyelids, wherein when said handheld device is in operation mode a light intensity gradient between said light stimulation pulses emitted by said at least one light source and available light in a surrounding area around said eye is maintained at least 0.5 lumens.

2. The device according to claim 1, wherein said light intensity gradient between the light stimulation pulses emitted by said at least one light source and said available light in the surrounding area around said eye is maintained at least 0.5 lumens by movement of any one or both of the following: a) said at least one light source; and b) said at least one energy source.

3. The handheld device according to any one of the preceding claims, wherein said at least one light source that emits visible light on the retina, generates light stimulation pulses in a random or non-random sequences. RS 304939/4 -40-

4. The handheld device according to any one of the preceding claims, wherein said at least one light source that emits visible light on the retina, generates light stimulation pulses in a manner of a change in light intensity in a random or non-random sequences.

5. The handheld device according to any one of the preceding claims, wherein said at least one energy source emits infrared light on said eyelids and/or said periorbital and/or periocular regions of said patient.

6. A handheld device for stimulating a lacrimal gland of an eye of a patient by emitting visible and IR light on a retina of said eye of the patient, said device comprising: a controller; an optical system connected to said controller and arranged in a viewing direction of the patient, said optical system includes at least one light source, and is configured for providing visible light stimulation pulses to said eye of said patient by said at least one light source; a power supply unit for supplying power to said controller and to said optical system; and at least one energy source emitting infrared light towards the retina and optionally on the patient's eyelids and/or periocular and/or periorbital areas of said patient; said at least one energy source is electrically connected to said controller and to said power supply unit; wherein when said device is in operation mode, a light intensity gradient between the light pulses emitted by said at least one light source and available light in a surrounding area around the eye is maintained at least 0.5 lumens. RS 304939/4 -41-

7. The handheld device according to any one of the preceding claims, further comprising an IR dispersing element coupled to said at least one energy source.

8. The handheld device according to any one of the preceding claims, wherein said at least one energy source that emits infrared light generates light pulses in a manner of a change in light intensity in a random or non-random sequences.

9. The handheld device according to any one of the preceding claims, wherein said infrared light pulses are controlled by a movement of said IR light generator and said IR dispersing element.

10. The handheld device according to any one of the preceding claims, wherein said infrared light pulses are controlled by a movement of only said IR dispersing element.

11. The handheld device according to any one of the preceding claims, wherein said visible light stimulation pulses are controlled by a movement of said at least one light source.

12. The handheld device according to claim 6, wherein a light intensity gradient between the light pulses emitted by said at least one light source and available light in a surrounding area around the eye is maintained at least 0.5 lumens by movement of any one or both of the following: a) said at least one light source; and b) said at least one energy source. RS 304939/4 -42-

13. The handheld device according to any one of the preceding claims, wherein said IR dispersing element contacts said patient's skin randomly to create some minor thermal lesions or slight burns on the skin, and thereby activates a lacrimal reflex to induce tear production.

14. A handheld device for stimulating a lacrimal gland of an eye of a patient by emitting visible and IR light on the retina of the patient, said device comprising: a controller coupled to a power supply unit; an optical system connected to said controller and arranged in a viewing direction of the patient, wherein said optical system includes at least one light source configured for providing visible light stimulation pulses to an eye of said patient by said at least one light source; and at least one energy source emitting infrared light on the retina of the patient; said at least one energy source is electrically connected to said controller and to said power supply unit; wherein when said device is in operation mode, a light intensity gradient between the light pulses emitted by said at least one light source and available light in a surrounding area around the eye is maintained at least 0.5 lumens.

15. The handheld device to any one of the preceding claims, wherein said optical system is coupled to an independent power supply. RS 304939/4 -43-

16. The handheld device to any one of the preceding claims, wherein said at least one energy source emits infrared light also on said patient's eyelids and/or periocular and/or periorbital areas of the patient.

17. The handheld device according to any one of the preceding claims, wherein said device also stimulates said patient's meibomian gland.

18. The handheld device according to claim 14, wherein a light intensity gradient between the light pulses emitted by said at least one light source and available light in a surrounding area around the eye is maintained at least 0.5 lumens by movement of any one or both of the following: a) said at least one light source; and b) said at least one energy source.