Formulations, devices and methods for relieving symptoms of ocular surface discomfort

Abstract

Disclosed herein are cold slurry formulations, devices, and methods for relieving symptoms of ocular surface discomfort. Disclosed are cold slurry formulations comprising ice, a freezing temperature lowering agent, and optionally a lipid. Disclosed are devices and methods for preventing a target ocular surface from contacting a cold slurry formulation used to maintain the target ocular surface at a temperature desired to relieve symptoms of ocular surface discomfort. Disclosed are self-contained devices configured to receive a cold slurry formulation for maintaining the target ocular surface at a temperature desired to relieve symptoms of ocular surface discomfort. Disclosed are devices and methods for protecting a subject's cornea and / or eyelid from freezing a cold slurry formulation applied or injected directly or indirectly to the target ocular surface. Disclosed are kits comprising multiple syringes for administering multiple doses of cold slurry to the target ocular surface.

Description

[Technical Field]

[0001] Technical Field This application claims priority under 35 USC § 119(c) to U.S. Serial No. 63 / 443,082, filed February 3, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates generally to devices, systems and methods for creating and administering biomaterials such as cold slurries. More specifically, the present invention relates to devices, systems and methods for treating ocular surface discomfort by reducing the temperature of a subject's eye surface to a temperature low enough for a time sufficient to cause ocular hypoesthesia or loss of ocular sensation in a safe and effective manner. [Background technology]

[0003] background The cornea of ​​the eye is a transparent, avascular tissue measuring approximately 11–12 mm horizontally and 9–11 mm vertically. Sridhar, MS, Anatomy of cornea and ocular surface. Indian Journal of Ophthalmology, 66(2), 190–194 (February 2018). It is the outermost surface of the eye and lies in front of the pupil and iris to refract entering light.

[0004] Innervation of the cornea begins in the brainstem, where a large sensory root branches from the pons and attaches to the trigeminal nucleus caudalis, located in the lateral part of the medulla. From there, the trigeminal nerve divides into three divisions, one of which is the ophthalmic division. This root further divides into three branches, one of which is the elongated pair called the nasociliary nerve. This purely sensory nerve travels along the upper part of the orbital cavity and contributes smaller branches to the cornea. Two divisions from this nerve are called the short ciliary nerve and the long ciliary nerve. The short ciliary nerve passes through a sensory root to the ciliary ganglion, then exits the nucleus, penetrates the sclera, and enters the extrachoroidal space, where it can travel to the cornea. Belmonte, C., Tervo, TT, & Gallar, J. (2011). CHAPTER 16 - Sensory Innervation of the Eye. Adler's Physiology of the Eye (Eleventh Edition, pp. 363-384). Elsevier Inc.

[0005] The extrachoroidal space is located between the sclera, the outermost layer of the eyeball, and the choroid, a highly vascularized layer responsible for providing nutrients to the ocular structures. Approximately 8–10 short ciliary nerves pierce the sclera, but once inside the extrachoroidal space, these nerves branch into approximately 15–20 segments. The long ciliary nerves have over 50 branches that penetrate the sclera and divide again inside the extrachoroidal space. At the limbus, the junction between the sclera and cornea, the nerves lose their myelin sheaths and continue as free nerve endings. The nerves collect sensory signals from the cornea and send them back toward the brainstem. Belmonte, C., Tervo, TT, & Gallar, J. (2011). CHAPTER 16 - Sensory Innervation of the Eye. Adler's Physiology of the Eye (Eleventh Edition, pp. 363-384). Elsevier Inc. All details of corneal innervation are not entirely well understood and may vary somewhat from patient to patient. There may be some contribution from other nerve fibers or some normal anatomical variation in the pathway of innervation.

[0006] Free nerve endings are located under the corneal epithelium, the anterior layer that protects the corneal structure, and often contribute to painful eye sensations. When patients suffer from these symptoms, the condition is called dry eye syndrome (DES), also known as ocular surface disease (OSD). The causes of this condition are multifactorial. One important cause is the production of inadequate amounts of aqueous tears, which deprives the eye of hydration and lubrication. Other causes of ocular surface disease may include meibomian gland dysfunction or damage to the corneal epithelium.

[0007] These "dry eye-induced alterations to the properties of corneal afferent neurons and the central processing of corneal inputs may have significant consequences for both tear regulation and ocular pain." McMonnies, CW, The potential role of neuropathic mechanisms in dry eye syndromes, Journal of Optometry, 10, 5-13 (2017). Importantly, some patients continue to have ocular surface pain even after their ocular surface has returned to a clinically normal appearance. This situation presents a clinical challenge because the cause is thought to be somatosensory dysfunction of corneal innervation that persists long after the original insult that irritated the nerve.

[0008] Other causes of corneal discomfort may include postoperative pain after photorefractive keratomileusis, a procedure used to treat refractive errors that requires removal of the corneal epithelium before applying excimer laser ablation. Other surgical procedures, such as procedures that do not necessarily involve epithelial removal but in which the epithelium experiences mild to moderate dryness during the procedure, can also cause corneal discomfort. Patients may also experience ocular discomfort after ocular trauma (e.g., corneal abrasion) and laser in situ keratomileusis (LASIK) surgery. Other treatments, such as injections to treat macular degeneration and other treatments for different ocular structures, can also cause corneal discomfort.

[0009] There are three different types of nociceptors that innervate the cornea. 20% of corneal nociceptors are Aδ mechanoreceptors, which are responsible for fast-conducting, sharp, painful stimuli caused by aggression against the ocular surface. 70% of corneal nociceptors are polymodal, which are stimulated by corneal nerve injury and cause neuropathic pain and "reflex tearing." Levitt, AE, et al., "Chronic dry eye symptoms after LASIK: parallels and lessons learned from other persistent post-operative pain disorders," Molecular Pain, 11:21 (2015). The remaining 10% of corneal nociceptors are C-fiber cold receptors, which play a critical role in maintaining basal tear secretion. These receptors are highly sensitive to temperature changes within the corneal tissue, and LASIK surgery can affect C-fiber signaling by causing tear evaporation at the tear film surface, decreasing temperature by approximately 0.3°C per second. (Levitt et al., 2015).

[0010] Many mechanisms, such as dryness, previous surgery, eyelid gland dysfunction, or previous chemical irritation, can cause the clinical symptoms of OSD, which are marked by signs of ocular irritation and symptoms characterized by dryness, burning, or discomfort. Even after the initial injury has resolved, i.e., normal ocular lubrication is restored, patients may still report significant symptoms of ocular surface discomfort, suggesting a component of hypersensitivity or allodynia, even though their ocular surface shows only minimal signs of disease. Indeed, a literature reference cautions that "ocular surface condition alone is not sufficient to understand ocular dryness; corneal somatosensory function must be considered when evaluating patients with dry eye." Spierer O, Felix ER, McClellan AL, et al. Corneal mechanical thresholds negatively associate with dry eye and ocular pain symptoms. Invest Ophthalmol Vis Sci. 57:617-625 (2016). This situation presents a challenge to the treating physician - patients have residual pain and discomfort (corneal somatosensory dysfunction) along with a normal-appearing ocular surface. Additional lubrication and other treatments targeted to improve the ocular surface are no longer of any help to these patients, as might be expected.

[0011] Current treatments for ocular pain, such as those associated with dry eye syndrome / ocular surface disease, PRK or LASIK surgery, or corneal somatosensory dysfunction, are either of limited temporary value or associated with negative side effects. Dry eye syndrome is most commonly treated with warm compresses, over-the-counter artificial tears, or prescription eye drops that target increased tear production or reduce inflammation. Doctors may also recommend topical eye lubricants, which are hygiene products that remove debris from just below the eyelid. These methods work by softening meibum, an oily, lipid-rich secretion from the meibomian glands, to help spread tear production across the cornea. A limitation of these treatments is their short-term relief and the need for continuous application. While lubricants or artificial tears may soothe irritation, they do not actually address the cause of eye dryness and may also contribute to increased debris collecting under the eyelid. Shen Lee, B., et al., Managing dry eye disease and facilitating realistic patient expectations: A review and appraisal of current therapies, Clinical Ophthalmology, 14 119-126 (January 2020).

[0012] Topical NSAIDs and soft bandage contact lenses are the most common treatments for postoperative pain management after photorefractive keratomileusis and LASIK eye surgery. NSAID medications prevent the production of prostaglandins, hormone-like substances associated with inflammation following corneal tissue injury. Pathak, A.K., & Karacal, H., (2019). Pain reduction after photoablation. EyeWiki by the American Academy of Ophthalmology. Topical NSAIDs carry the risk of corneal damage, such as erosion, defects, delayed corneal epithelial healing, or corneal melting (which can result in vision loss). Using soft bandage contact lenses can stimulate epithelial cell regrowth and act as a delivery system for antibiotics or topical NSAIDs. However, bandage contact lenses can promote bacterial growth and are often ineffective at reducing pain. Shetty, R., et al., Pain management after photorefractive keratectomy, Journal of Cataract Refract Surgery, 45(7):972-976 (2019).

[0013] Acute ocular pain can also be treated with topical ophthalmic anesthetic drops, such as proparacaine hydrochloride and tetracaine hydrochloride. These aqueous solutions are given as short-term pain treatment, or to measure intraocular pressure, remove foreign bodies, relieve intracorneal sutures, or as preoperative anesthetics for eye surgery. Local anesthetics can block the corneal nerves from transmitting pain impulses for approximately 15 to 20 minutes per dose. While this short-term pain relief requires continuous application, chronic use can ultimately lead to corneal toxicity. Toxic effects on the cornea include damage to stromal keratocytes, cells that play a critical role in healing trauma to the cornea. If epithelial cells cannot migrate across the cornea, the epithelium eventually begins to slough, resulting in chronic failure of the corneal epithelium to heal.

[0014] However, maintaining some pain perception is important for the normal function of a healthy cornea. Neuropathic keratopathy, also known as neurotrophic keratitis, is a syndrome in which the ocular surface undergoes a progression from tear film abnormalities to epitheliopathy and ultimately to stromal lysis due to pathological deficits in corneal and conjunctival sensation. For true neuropathic keratopathy, the eye must have corneal and conjunctival sensory deficits due to pathological destruction of the trigeminal nerve, which can result from surgery intended to treat trigeminal neuralgia, acoustic neuroma surgery, or infections such as herpes zoster ophthalmicus or leprosy. Other forms of neuropathic keratopathy result from the misuse of local anesthesia. In a rabbit model, typical trophic changes in the corneal epithelium have been demonstrated after controlled thermal coagulation of the trigeminal ganglion in rabbits. This denervation was found to significantly affect the proliferative activity of the epithelium, resulting in a paucity of mitoses.

[0015] As explained above, the cornea is highly sensitive to pain or discomfort. There are many human clinical conditions that cause mild to severe corneal pain and discomfort, all of which could potentially be addressed by developing a safe and effective treatment for corneal pain. Current topical numbing drops only numb the cornea for a few minutes, and chronic use is associated with severe morbidity, such as corneal infection and melting. Furthermore, conventional approaches to treating ocular pain result in complete numbness of the eye, which can be very problematic in chronic settings due to the risk of developing neuropathic keratopathy. Furthermore, in chronically inflamed and painful eyes, corneal somatosensory dysfunction becomes a dominant feature of the pain syndrome. In summary, many patients experience debilitating ocular surface discomfort that may be associated with active corneal pathology or may persist long after the original injury without detectable progressive pathology. Clearly, there is a large unmet clinical need for the development of longer-acting, safer corneal anesthetic therapies that partially block corneal sensation and significantly reduce patient discomfort. Summary of the Invention

[0016] overview The following embodiments describe non-limiting permutations of combinations of the described inventive features. Other permutations of feature combinations are also contemplated and / or described throughout this disclosure. In particular, each of these numbered embodiments is contemplated as dependent on or related to all preceding or succeeding numbered embodiments, independent of the order listed.

[0017] In one aspect, the present disclosure provides a cold slurry formulation for relieving symptoms of ocular surface discomfort, the cold slurry formulation comprising: water; and a freezing point depressant, the cold slurry formulation being configured to be applied directly or indirectly to the target ocular surface to cause numbness of the target ocular surface, and ocular sensation in the eye being restored after application of the cold slurry to the target ocular surface. In some embodiments, the cold slurry formulation further comprises a lipid. In some embodiments, the formulation comprises a freezing point depressant, the freezing point depressant being at a concentration of about 10% to 40% (v / v). In some embodiments, the formulation comprises a lipid, the lipid being at a concentration of about 0.1% to 10%, 10% to 20%, 20% to 30%, or 30% to 45% (v / v). In further embodiments, the formulation comprises a freezing point depressant, the freezing point depressant being at a concentration of about 10% to 20%, 20% to 30%, or 30% to 40% (v / v). In some embodiments, the formulation includes a lipid, the lipid being at a concentration of about 15% to 45% (v / v). In some embodiments, the formulation includes a freezing point depressant, the freezing point depressant being at a concentration of about 10% to 25% (v / v). In some embodiments, the slurry is injectable through a needle. In other embodiments, the slurry is not injectable through a needle. In some embodiments, the slurry has a solid ice percentage of about 0.1% to about 75% of the slurry by weight. In some embodiments, the slurry has a solid ice percentage of about 0.1% to 1%, about 1% to 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, and greater than about 50%. In some embodiments, the slurry has a solid ice particle percentage that constitutes about 0.1% to about 50% of the slurry by weight.

[0018] In one aspect, the present disclosure provides a method for alleviating symptoms of ocular surface discomfort, comprising: applying a cold slurry formulation onto a patient's ocular surface adjacent to the limbus, the cold slurry formulation comprising water and a freezing point depressant, wherein application of the cold slurry formulation is configured to cause a degree of numbness of the cornea of ​​the eye for a period of time, after which ocular sensation in the eye is restored. In one embodiment, the cold slurry formulation further comprises a lipid. In a further embodiment, a method is provided in which the cold slurry formulation is applied posterior to the limbus. In a further embodiment, a method is provided in which the cold slurry is maintained on the ocular surface for more than about 4 hours without further application of the cold slurry formulation on any day after the first day of application. In one embodiment, a method is provided in which the cold slurry formulation comprises a freezing point depressant, the freezing point depressant being glycerol. In a further embodiment, a method is provided in which the cold slurry formulation comprises a lipid, the lipid comprising soybean phosphatidylcholine (soy-PC). In a further embodiment, a method is provided in which the cold slurry formulation comprises a lipid, the lipid comprising a fatty acid selected from the group consisting of stearic acid, palmitic acid, lauric acid, and myristic acid, and combinations thereof. In a further embodiment, a method is provided in which the cold slurry formulation comprises hyaluronic acid. In some embodiments, a method is provided in which the cold slurry formulation comprises an excipient. In some embodiments, a method is provided in which the cold slurry formulation comprises an excipient, the excipient being a poloxamer. In a further embodiment, a method is provided in which ocular sensation in the eye is restored about 21 days after application of the cold slurry formulation. In a further embodiment, a method is provided in which ocular sensation in the eye is restored about 7 days to about 90 days after application of the cold slurry formulation. In a further embodiment, a method is provided in which the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C during application of the cold slurry. In a further embodiment, a method is provided in which the cold slurry is applied for about 2 minutes to about 15 minutes. In a further embodiment, a method is provided in which an additional amount of cold slurry is reapplied about 90 seconds after the initial application of the cold slurry. In a further embodiment, a method is provided wherein the administration of the cold slurry formulation is a topical application.In a further embodiment, a method is provided wherein administration of the cold slurry formulation is via injection.

[0019] In one aspect, a device for protecting a cornea on the surface of an eye from the negative effects of a cooling treatment is provided, the device comprising: a structure configured to adhere to the surface of the eye by forming a vacuum, the structure comprising: a containment wall having an inner surface, an outer surface, and an open surface, the containment wall extending from a first end to a second end, the inner surface forming an internal cavity, the open surface configured to contact and surround the periphery of the cornea, and a vacuum being formed within the internal cavity when the structure is activated. In some embodiments, adhesion of the structure to the surface of the eye substantially seals the cornea within the open surface of the containment wall. In some embodiments, the structure includes a suction cup to ensure alignment of the structure with the eye and hold it in place. In some embodiments, the containment wall comprises a non-porous material with low thermal conductivity selected from the group consisting of polymers, polyvinyl chloride (PVC), neoprene, polyethylene (PE), polytetrafluoroethylene (PTFE), and combinations thereof. In some embodiments, the containment wall comprises a thermally insulating material selected from the group consisting of polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, and combinations thereof. In some embodiments, the containment wall comprises an optically transparent or translucent material. In some embodiments, the containment wall comprises an optically opaque material. In some embodiments, the structure is activated by contracting the interior cavity and then releasing the contraction of the interior cavity. In some embodiments, the structure is activated by squeezing the containment wall and then releasing the containment wall. In some embodiments, the vacuum is a partial vacuum.

[0020] In one embodiment, a method for protecting a cornea on the surface of a subject's eye is provided, the method comprising: a) placing a cornea-protecting device comprising an internal cavity on the cornea of ​​the subject; b) contracting and releasing a portion of the cornea-protecting device to form a vacuum within the internal cavity; and c) adhering the cornea-protecting device to the surface of the eye; the cornea-protecting device comprises a containment wall having an inner surface, an outer surface, and an open surface, the containment wall extending from a first end to a second end, the inner surface forming the internal cavity. In one embodiment, the method further comprises administering a cold slurry formulation to the surface of the eye after the cornea-protecting device is placed. In a further embodiment, the cornea-protecting device is configured to physically and thermally protect the cornea from the cold slurry formulation. In one embodiment, forming a vacuum within the internal cavity of the cornea-protecting device comprises squeezing the cornea-protecting device. In one embodiment, the vacuum is a partial vacuum.

[0021] In one aspect, the present disclosure provides a device for protecting the eyelids of a subject, the device comprising: a first surface configured to contact the upper eyelid; and a second surface configured to contact the lower eyelid, the first surface and the second surface being configured to reversibly couple with each other to create an opening between the first surface and the second surface, when inserted into the top of the eye, the device prevents the upper eyelid and the lower eyelid from closing, and protects the eyelid by physically and thermally isolating the eyelid from the surface of the eye or a material deposited on the surface of the eye.In some embodiments, the device further comprises a channel in one or more of the first surface and the second surface, the channel being configured to allow fluid to leak from the surface of the eye when the device is inserted into the top of the eye.In some embodiments, the device further comprises a platform on one or more of the first surface and the second surface, configured to facilitate handling and operation of the device. In further embodiments, the first surface comprises a first end and a second end, the second surface comprises a first end and a second end, the first end of the first surface attached to the first end of the second surface, and the second end of the first surface attached to the second end of the second surface. In some embodiments, the first surface and the second surface are curved. In further embodiments, one or more of the first and second surfaces are arc-shaped. In some embodiments, the first and second surfaces are adjustable in size. In some embodiments, the first and second surfaces are adjustable relative to one another to adjust the size of the opening. In some embodiments, the first and second surfaces are separate components of a device that can be assembled to form the device. In some embodiments, one or more of the first and second surfaces comprise connecting segments of a curve that can be connected relative to one another to adjust the size of the opening. In some embodiments, one or more spacings across the opening between the first and second surfaces can be adjusted to accommodate eyelids and eyes of various shapes and sizes. In some embodiments, the device comprises one or more plastics. In some embodiments, the device comprises one or more porous materials.In further embodiments, the one or more porous materials comprise a thermal insulating material selected from the group consisting of polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, and combinations thereof. In further embodiments, one or more of the first and second surfaces comprise a thermal insulating material and a wicking material. In further embodiments, the wicking material is selected from the group consisting of PVA, an open-cell foam material, and combinations thereof. In some embodiments, the device further comprises a receiving structure configured to receive the corneal protection device. In further embodiments, the corneal protection device comprises: a structure configured to adhere to the surface of the eye upon the formation of a vacuum, the structure comprising: a containment wall having an inner surface, an outer surface, and an open surface, the containment wall extending from a first end to a second end, the inner surface forming an internal cavity, the open surface configured to contact and surround the cornea, and a vacuum being formed within the internal cavity when the structure is activated. In further embodiments, the receiving structure occupies an opening in the device so that when the device is inserted into the apex of the eye, the receiving structure is positioned substantially above the cornea. In further embodiments, the receiving structure comprises a substantially circular shape and is adhered to the first surface and the second surface. In some embodiments, the device is configured to protect both the eyelid and the cornea. In some embodiments, the device further comprises one or more structures configured to act as an eyelid speculum to hold the eyelid open while the device is inserted into the eye.

[0022] In one aspect, a method for protecting the upper and lower eyelids of a subject is provided, the method comprising: inserting an eyelid protection device at the top of the subject's eye; contacting a first surface of the eyelid protection device around the contour of the upper eyelid; and contacting a second surface of the eyelid protection device around the contour of the lower eyelid; the first and second surfaces are configured to join together to create an opening between the first and second surfaces, and when inserted at the top of the eye, the device prevents the upper and lower eyelids from closing and protects the eyelids by physically and thermally isolating them from the surface of the eye or materials deposited on the surface of the eye. In one embodiment, the method further comprises administering a cold slurry formulation to the surface of the eye. In a further embodiment, the cold slurry formulation comprises water, a freezing point depressant, and optionally a lipid.

[0023] In one aspect, a kit is provided, the kit comprising: one or more syringes containing a cold slurry formulation; and a package enclosing the plurality of syringes, the package configured to store, seal, and provide thermal and humidity protection for the one or more syringes. In one embodiment, the kit comprises at least two syringes containing the cold slurry formulation. In one embodiment, the kit comprises 2-20, 2-15, 2-10, or 2-5 syringes. In a further embodiment, the one or more syringes containing the cold slurry formulation contain about 1-20 ml of the cold slurry formulation. In one embodiment, the package comprises a phase change material, a thermal insulator, a reflective barrier, or a combination thereof. In a further embodiment, the package is configured to protect the one or more syringes against contamination, temperature changes, environmental exposure, or a combination thereof. In one embodiment, the cold slurry formulation comprises water, a freezing point depressant, and optionally a lipid.

[0024] In one aspect, a kit is provided, the kit comprising: one or more syringes; a first package enclosing the one or more syringes; a container containing a cold slurry formulation; and a second package enclosing the one or more syringes and the container, the second package being configured to store, seal, and provide heat and humidity protection for the one or more syringes and the container. In some embodiments, the cold slurry formulation comprises water, a freezing point depressant, and optionally a lipid.

[0025] In one aspect, a self-contained cooling device for cooling a target tissue surface, such as the surface of an eye, is provided, the self-contained cooling device comprising: a formulation chamber including a hollow chamber with an open end and a closed end, the formulation chamber configured to receive and hold a cold slurry formulation or other formulation capable of maintaining a temperature below 0°C; a removable lid configured to fit over and seal the open end of the formulation chamber; and a target surface interface including a first surface and a second surface, the first surface configured to contact the target tissue surface and the second surface configured to form or contact the closed end of the formulation chamber. In one embodiment, the self-contained cooling device further comprises a movable plate disposed within the formulation chamber, wherein as the movable plate advances within the formulation chamber toward the closed end of the formulation chamber, a liquid phase of the cold slurry formulation is removed from the closed end of the formulation chamber and replaced with a substantially non-liquid phase of the cold slurry formulation, the movable plate being disposed within the formulation chamber and having a size smaller than the open end of the formulation chamber. In some embodiments, the self-contained cooling device further includes: a force spring having a first end and a second end, the first end being operably connected to the movable plate and the second end being operably connected to the removable lid; and one or more side pins operably connected to the hollow chamber; the one or more side pins are configured to, when depressed, extend the first end of the force spring beyond its original length and advance the movable plate within the formulation chamber toward the closed end of the formulation chamber. In some embodiments, the target surface interface is configured to contact the ocular surface, and the self-contained cooling device is configured to maintain the ocular surface at a temperature suitable for alleviating discomfort on the ocular surface. In some embodiments, the formulation chamber is configured to receive a cold slurry formulation according to the present disclosure. In some embodiments, the target surface interface is structurally integrated with the formulation chamber. In some embodiments, the target surface interface is configured to contact the sclera of the ocular surface.In some embodiments, the target surface interface includes an opening configured to conform to the cornea of ​​the ocular surface to avoid contact between the target surface interface and the cornea when the target surface interface contacts the ocular surface. In some embodiments, the target surface interface is configured to allow thermal energy to transfer from the target surface interface to the formulation chamber. In some embodiments, the target surface interface is configured to promote uniform cooling of the target tissue surface when the formulation chamber is filled with a cold slurry formulation. In some embodiments, the opening in the target surface interface is configured to receive a corneal protection device. In some embodiments, the corneal protection device is a corneal protection device according to the present disclosure. In some embodiments, the corneal protection device is disposed within the opening in the ocular surface interface and configured to physically and thermally protect the cornea when the ocular surface interface contacts the ocular surface. In further embodiments, the force spring is an extension spring, a torsion spring, or a combination thereof. In some embodiments, the target surface interface comprises a thermally conductive material selected from the group consisting of Al, Cu, stainless steel, a metal alloy, and combinations thereof. In certain embodiments, the target surface interface comprises one or more encapsulated phase change materials (PCMs), shape-stabilized PCMs, or combinations thereof. In certain embodiments, the first surface of the target surface interface comprises a non-stick coating. In further embodiments, the non-stick coating is PTFE. In certain embodiments, the first surface of the target surface interface comprises a hydrophobic coating. In certain embodiments, the first surface of the target surface interface comprises a surface coating that protects the target tissue from adhesion to the target surface interface. In certain embodiments, the first surface of the target surface interface comprises geometric design features that protect the target tissue from adhesion to the target surface interface. In further embodiments, the geometric design features comprise one or more of a hierarchical microstructure, a hierarchical nanostructure, a bioinspired surface pattern, or a combination thereof. In further embodiments, the first surface of the target surface interface comprises a hydrophilic surface coating.In some embodiments, the first surface of the target surface interface comprises a low surface energy material. In some embodiments, the target surface interface comprises an embedded thermoelectric Peltier cooler. In some embodiments, the target surface interface comprises a thin film of material.

[0026] In one aspect, a method for alleviating symptoms of ocular surface discomfort is provided, the method comprising: placing a self-contained cooling device on a target ocular surface; the self-contained cooling device comprising: a formulation chamber comprising a hollow chamber with an open end and a closed end, wherein the formulation chamber is configured to receive and hold a cold slurry formulation; a removable lid configured to fit and seal the open end of the formulation chamber; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target ocular surface and the second surface is configured to form or contact the closed end of the formulation chamber. In some embodiments, the cold slurry formulation comprises water, a freezing point depressant, and optionally a lipid. In some embodiments, the self-contained cooling device further comprises a movable plate disposed within the formulation chamber, wherein as the movable plate advances within the formulation chamber toward the closed end of the formulation chamber, the liquid phase of the cold slurry formulation is removed from the closed end of the formulation chamber and replaced with a substantially non-liquid phase of the cold slurry formulation, the movable plate being disposed within the formulation chamber and having a size smaller than the open end of the formulation chamber. In some embodiments, the method further includes advancing a movable plate of a self-contained cooling device disposed within the formulation chamber toward the closed end of the formulation chamber. In some embodiments, the self-contained cooling device further includes: a force spring having a first end and a second end, where the first end is operably connected to the movable plate and the second end is operably connected to the removable lid; and one or more side pins operably connected to the hollow chamber; the one or more side pins are configured, when depressed, to extend the first end of the force spring beyond its original length and advance the movable plate within the formulation chamber toward the closed end of the formulation chamber. In some embodiments, the method further includes depressing one or more side pins of the self-contained device operably connected to the hollow chamber to extend the first end of the force spring beyond its original length and advance the movable plate within the formulation chamber toward the closed end of the formulation chamber.

[0027] In one aspect, a self-contained cooling device for cooling a target tissue surface is provided, the self-contained cooling device comprising: a housing; a heat exchanger, wherein the heat exchanger comprises a formulation chamber configured to receive and hold a formulation, the formulation configured to freeze to a temperature below zero in a cold environment; a hole, wherein the hole is configured to allow a clinician to view the cornea of ​​a subject; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target tissue surface and the second surface is configured to form or contact the formulation chamber. In one embodiment, the cold environment is a standard freezer. In one embodiment, the formulation comprises water and a freezing point depressant. In one embodiment, the freezing point depressant is at a concentration of about 20% (wt / wt). In one embodiment, the freezing point depressant is glycerol. In one embodiment, the first surface is configured to adhere to the target tissue surface upon contact. In one embodiment, the target surface comprises the sclera. In a further embodiment, the sclera is adjacent to the limbus. In one embodiment, the temperature below zero is about -20°C to about 0°C. In one embodiment, the target surface interface comprises copper.

[0028] In some aspects, the self-contained cooling device is configured to receive an accessory. In some embodiments, the accessory is an eyelid speculum. In some embodiments, the accessory is configured to hold the subject's eye open during treatment. In some embodiments, the accessory is configured to protect the subject's eyelid from temperatures below 0 during treatment. In some embodiments, the accessory comprises silicone. In some embodiments, the accessory comprises thermoplastic elastomer (TPU) or thermoplastic polyurethane (TPE).

[0029] In certain aspects, the self-contained cooling device is further configured to receive a cap, where the cap is configured to prevent condensation from forming on the target surface interface prior to treatment.

[0030] In one aspect, a method for alleviating symptoms of ocular surface discomfort is provided, the method comprising: placing a self-contained cooling device on a target ocular surface; the self-contained cooling device comprising: a housing; a heat exchanger, wherein the heat exchanger comprises a formulation chamber configured to receive and hold a formulation, the formulation configured to freeze to a temperature below zero in a standard freezer; a hole, wherein the hole is configured to allow a clinician to view the subject's cornea; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target tissue surface and the second surface is configured to form or contact the formulation chamber. In one embodiment, the temperature below zero is about −20° C. to about 0° C. In one aspect, the formulation comprises water and a freezing point depressant. In one embodiment, the freezing point depressant is glycerol. In one embodiment, the treatment time is about 2 minutes to about 10 minutes.

[0031] In some aspects, the self-contained cooling device is configured to receive an appendage, the appendage configured to be positioned adjacent to the target ocular surface and prevent the subject's eye from closing. In some embodiments, the appendage is configured to thermally protect one or more eyelids from contacting the contact surface interface. In some embodiments, the appendage is configured to provide a hole for visualization of the cornea. In some embodiments, the appendage is configured to provide ease in device placement. In some embodiments, the appendage is configured to protect the subject's eyelids from temperatures below zero during treatment. In some embodiments, the target surface includes the sclera. In some embodiments, the sclera is adjacent to the limbus.

[0032] In some embodiments, the target surface interface comprises copper. In some embodiments, the target surface interface is configured to adhere to the target surface upon contact. In some embodiments, the target surface interface is configured to not adhere to the target surface interface upon contact. In some embodiments, the target surface interface is configured to be released from the target surface after a treatment period.

[0033] In some embodiments, the methods provided herein further comprise rinsing the target tissue surface with a liquid formulation prior to removing the target surface interface from the target tissue surface. In some embodiments, the liquid formulation comprises saline. In some embodiments, the liquid formulation is warmed prior to use. [Brief explanation of the drawings]

[0034] BRIEF DESCRIPTION OF THE DRAWINGS The following figures illustrate exemplary embodiments of the present invention. [Figure 1] FIG. 1 shows freezing point depression graphs for liquid water, a solution containing 10% glycerin volume / volume (v / v), and a solution containing 20% ​​glycerin (v / v). [Figure 2] FIG. 2 is a table showing the degradation by volume and weight of components of exemplary biomaterials that may form injectable cold slurries. [Figure 3] FIG. 3 is a graph showing the ice content characterization of cold slurries having crystallization set points of −5.5° C. and −8.1° C. [Figure 4] 4A and 4B show diagrams of the human eye showing different regions of the eye (4A) and degrees relative to anatomical references (4B). [Figure 5] FIG. 5 is a graph showing real-time scleral temperature monitoring in rabbits following ocular administration of topically applied (solid line) and injected (dashed line) cold slurry. [Figure 6] FIG. 6 is a graph showing the loss of sensation in rabbit eyes over time following administration of injected cold slurry (diamonds), topically applied cold slurry (triangles), and topically applied slurry at room temperature (squares) to the exposed cornea of ​​the eye. [Figure 7] FIG. 7 is a graph showing hypoesthesia in rabbit eyes over time following administration of topically applied cold slurry to the eye without exposing the cornea. [Figure 8]8A and 8B are images of fluorescein-stained rabbit corneas showing corneal healing over time after an intentional 8 mm corneal abrasion as a control (8A) and after topical application of cold slurry (8B). [Figure 9] 9 is a graph showing the decrease in sensation in the eyes of six rabbits over time after a combination treatment in which cold slurry was first applied topically and then injected. In three rabbits (indicated by diamonds, squares, and triangles), the injected slurry did not contain liposomes, while in the other three rabbits (indicated by "X," stars, and circles), the injected slurry contained liposomes. [Figure 10] FIG. 10 is a graph showing the degree of injectability of an embodiment of a cold slurry comprising ice, the freezing point depressant glycerol, and lipid as a function of the volumetric fraction of glycerol and lipid in the cold slurry. [Figure 11] FIG. 11 is a cross-sectional view of a corneal protection device according to certain embodiments described herein. [Figure 12] FIG. 12 is a perspective view of an exemplary corneal protection device according to certain embodiments described herein, where the corneal protection device is positioned on the surface of the eye around the circumference of the cornea so as to surround and seal the cornea. [Figure 13] 13A and 13B illustrate an exemplary corneal protection device described herein: FIG. 13A is a perspective view of the exemplary corneal protection device, and FIG. 13B illustrates the placement of the exemplary corneal protection device on the surface of the eye to surround and seal the circumference of the cornea. [Figure 14] 14A and 14B are perspective views of an exemplary eyelid protector device according to certain embodiments described herein. [Figure 15] 15A and 15B show an exemplary eyelid protector device in conjunction with an exemplary corneal protection device according to certain embodiments described herein. [Figure 16] FIG. 16 shows an exemplary kit including multiple syringes containing cold slurries according to certain embodiments described herein. [Figure 17]17A and 17B show a front perspective view (17A) and a perspective view (17B) of a self-contained ocular cooling device according to certain embodiments described herein. [Figure 18] 18A and 18B show front perspective views of an exemplary self-contained eye cooling device with (18A) and without (18B) an exemplary corneal protection device, according to certain embodiments described herein. [Figure 19] FIG. 19 illustrates an exemplary treatment protocol using an exemplary self-contained ocular cooling device according to certain embodiments described herein. [Figure 20] 20A and 20B show exploded views of an exemplary self-contained eye cooling device (20A) with a heat exchanger (20B) according to certain embodiments described herein. [Figure 21] 21A-E show an exemplary self-contained eye cooling device from multiple angles according to certain embodiments described herein. [Figure 22] 22A and 22B show an exemplary self-contained eye cooling device and attachment (e.g., an eye speculum) before and after placement of the self-contained eye cooling device with attachment (22A) and attachment (22B), respectively, according to certain embodiments described herein. [Figure 23] 23A-D show multiple views of an attachment (eg, an eye speculum) for use with a self-contained eye cooling device according to certain embodiments described herein. [Figure 24] FIG. 24 is a chart plotting treatment time in seconds versus removal time in seconds for treatment with a self-contained ocular cooling device according to certain embodiments described herein. [Figure 25] FIG. 25 is a diagram illustrating an exemplary treatment area 2500 on a diagram of the eye. [Figure 26] FIG. 26 is a graph showing a representative temperature profile comparing temperature (° C.) versus time (seconds) of the surface of a pig's eye upon contact with a self-contained cooling device according to certain embodiments described herein. [Figure 27]FIG. 27 shows temperature measurement locations 1 and 2 on a diagram of the eye along the treatment area 2500 (located under the contact surface of a self-contained cooling device according to the present disclosure). [Figure 28] FIG. 28 is a graph showing temperature (° C.) versus time (seconds) for temperatures taken from tissue at measurement locations 1 and 2 and under treatment area 2500. [Figure 29] FIG. 29 is a graph showing percent sensation in treated rabbit eyes compared to untreated time (days) over time. DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description The present disclosure describes apparatus, devices, systems, and methods for treating ocular surface discomfort using a biological material, such as a cold slurry or cooling device. In some embodiments, the biological material is a cold slurry (e.g., ice slurry) that can be delivered directly or indirectly to the ocular surface via topical application or injection to the eye of a human patient or subject (e.g., a non-patient human or non-human animal) for preventive or therapeutic purposes to reduce ocular discomfort. The systems and methods disclosed herein unexpectedly provide long-lasting ocular hypoesthesia (also referred to as hypoesthesia). Hypoesthesia can result in long-lasting corneal numbness and subsequent recovery of ocular sensation within days or weeks after application of the cold slurry treatment or cooling device, without causing permanent damage to the cornea or disrupting the progress of corneal healing.

[0036] The present disclosure provides novel cooling treatments for alleviating ocular surface discomfort by applying cooling treatment (e.g., −20° C. to 0° C.) to a subject's eye for a period of time (e.g., about 6 minutes to about 10 minutes, or about 2 minutes to about 10 minutes). For example, in certain embodiments, the present disclosure provides a self-contained cooling device and methods for using the same, wherein the self-contained cooling device includes an ocular (i.e., target) surface interface configured to rapidly freeze the ocular sclera upon contact, where the ocular surface interface adheres to the ocular surface for the duration of the treatment, thereby providing a subzero temperature (e.g., about −20° C. to about 0° C.) in a precise treatment area adjacent to the limbus. In certain embodiments, the self-contained cooling device reduces the temperature of the sclera to a cool temperature (e.g., −20° C. to about 4° C.) and maintains that cool temperature for a time sufficient to cause ocular surface hypoesthesia. This treatment does not cause adverse side effects to the eye or damage tissue in or around the eye.

[0037] In some embodiments, the cold slurry can be applied topically, directly or indirectly, to the ocular surface to achieve a desired therapeutic effect, such as ameliorating or treating ocular surface discomfort through long-term corneal numbing. In some embodiments, the therapeutically effective cold slurry is composed entirely of water and excipient materials (i.e., materials without active pharmaceutical compounds). In other embodiments, the cold slurry further comprises a known active pharmaceutical compound. In some embodiments, a protective layer, such as a contact lens or a corneal protection device that covers the cornea and provides a protective barrier around its circumference, is applied to the cornea before topical application of the slurry. In some embodiments, the eyelids are protected from topical application of the slurry by using an eyelid protection device, for example, by inserting a plastic or other thermally non-conductive material and / or a speculum into the subject's eye.

[0038] In some embodiments, the length of time that the slurry or cooling treatment is applied to the subject's eye can be varied to induce greater or more gradual loss of sensation. In some embodiments, the temperature of the slurry or cooling treatment applied directly or indirectly to the ocular surface or injected into the subject's eye can be varied to induce greater or more gradual loss of sensation. In some embodiments, the loss of sensation induced after treatment decreases over time to the point that it is no longer noticeable. In other embodiments, if the subject's eye may be particularly sensitive, greater loss of sensation is induced to numb more of the nerves in the subject's eye.

[0039] In some embodiments, the container containing the biomaterial (e.g., vial, syringe, self-contained cooling device) is received for clinical administration. The biomaterial may be received in a crystallized (or partially crystallized) state. In some embodiments, the final product administered to a human patient or subject (e.g., a human or non-human animal that is not a patient) via topical application or injection is a cold slurry composed of sterile ice particles in water and varying amounts of excipients or additives, such as freezing point depressants. For example, the percentage of ice particles in the cold slurry may comprise less than about 10% by weight of the slurry, between about 10% and about 20% by weight, between about 20% and about 30% by weight, between about 30% and about 40% by weight, between about 40% and about 60% by weight, greater than about 60% by weight, etc. In some embodiments, the size of the ice particles is controlled to allow the slurry to flow through various sized containers (e.g., needle gauge sizes from about 7 to about 43), as described in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated by reference in its entirety. Additionally, in some embodiments, other methods can be used to condition the size of the ice particles to allow the slurry to flow through various sized containers. In some embodiments, the majority of the ice particles have a diameter that is less than about half the inner diameter of the lumen or container used for application or injection. For example, in some embodiments, the ice particles can be about 1.5 mm or less in diameter for use with a 3 mm catheter.

[0040] There are various techniques that can be used to prepare cold slurry.The present disclosure is not limited to any particular method or technique.Exemplary cold slurry formulations and the method for preparing them have been previously disclosed in, for example, United States Patent No. 11,241,330; United States Patent No. 11,564,830; United States Patent No. 11,471,401; United States Patent Application Serial No. 18 / 358,795 (filed on July 25, 2023 but not yet published); International Application No. PCT / US2022 / 33095 (publication No. WO / 2022 / 261494); and International Application No. PCT / US2023 / 62443 (publication No. WO / 2023 / 154902), which are incorporated herein by reference in their entirety.

[0041] In some embodiments, one or more excipients may be included in the cold slurry. An excipient is any substance that is not itself a therapeutic agent but is used as a diluent, adjuvant, and / or vehicle for delivery of a therapeutic agent to a subject or patient, and / or is added to a composition to improve its handling, stability, and / or storage characteristics. In certain embodiments, an excipient may constitute less than about 10% volume / volume (v / v) of the cold slurry, from about 10% v / v to about 20% v / v, from about 20% v / v to about 30% v / v, from about 30% v / v to 40% v / v, or greater than about 40% v / v. Various added excipients may be used to alter the phase change temperature of the cold slurry (e.g., reduce the freezing point), alter the ice percentage of the cold slurry, alter the viscosity of the cold slurry, prevent agglomeration of ice particles, prevent dendritic ice formation (i.e., crystals with multiple branched "tree-like" morphologies such as those found in snowflakes), maintain separate ice particles, increase the thermal conductivity of the fluid phase, and / or improve the overall preventative, therapeutic, or cosmetic benefits of the cold slurry.

[0042] In some embodiments, one or more freezing point depressants can be added as an excipient to form a cold slurry having a freezing point below 0°C. In certain embodiments, lowering the freezing point of the slurry allows the slurry to remain flowable and applicable (e.g., injectable) through various sized containers while still containing a desired and effective proportion of ice particles. Suitable freezing point depressants include, but are not limited to, salts (e.g., sodium chloride, Betadex sulfobutylether sodium), ions, lactated Ringer's solution, sugars (e.g., glucose, sorbitol, mannitol, hetastarch, sucrose, (2-hydroxypropyl)-β-cyclodextrin, or combinations thereof), biocompatible surfactants such as glycerol (also known as glycerin or glycerine), other polyols (e.g., polyvinyl alcohol, polyethylene glycol 300, polyethylene glycol 400, propylene glycol), other sugar alcohols, or urea. Other exemplary freezing point depressants include, but are not limited to, those disclosed in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated by reference in its entirety. In other embodiments, a slurry paste is formed that has the consistency of toothpaste and may aid in topical application.

[0043] The concentration of the freezing point depressant determines the proportion of ice particles in the cold slurry as well as its flowability and ability to be applied through different sized containers (e.g., its injectability). The degree of freezing point depression is determined by the following formula, as set forth in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated herein by reference in its entirety: ΔT F = K F bi where ΔT F is the freezing point depression (T F (純粋溶媒) -T F (溶液) ), K Fis the freezing point depression constant, b is the molality, and i is the van't Hoff coefficient, which represents the number of ionic particles per individual molecule of solute. Other methods of calculating freezing point depression, such as those disclosed in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), may also be used.

[0044] Referring to FIG. 1, a graph of freezing point depression is shown for pure water T1, a mixture of water and 10% (v / v) glycerin T2, and a mixture of water and 20% (v / v) glycerin T3. In this graph, all materials were placed in a freezer with a constant temperature of -20°C. Temperatures were measured using thermometers placed within each material. The graph shows that the water and glycerin mixture has a different freezing point than pure water, meaning that the solution can be cooled below 0°C and only partially crystallize. The graph shows that upon cooling, pure water T1 crystallizes at its equilibrium freezing point of 0°C. This is indicated by the time that pure water T1 remains at a temperature of approximately 0°C from about 1.3 hours to about 4.4 hours, starting shortly after it passes its supercooling point of approximately -6°C. Having an equilibrium window of crystallization (i.e., the "flat, straight line" portion of pure water T1 in FIG. 1) is typical for pure solvents. For 10% glycerin solution T2, upon cooling, the solution begins to crystallize at a first freezing point of about −3° C. after about 2.2 hours, and crystallization continues as the solution's temperature further decreases to about −8° C. after about 6 hours. Initial crystallization occurs shortly after 10% glycerin solution T2 passes the supercooling point of about −8° C. (which may vary from sample to sample, e.g., from about −15° C. to about −3° C.), indicated at about 2.2 hours. Having a descending temperature window of crystallization for 10% glycerin solution T2 is typical for solutions (i.e., impure mixtures). Similarly, for 20% glycerin solution T3, upon cooling, the solution begins to crystallize at a first freezing point of about −7° C. after about 3.5 hours (which may vary from sample to sample, e.g., after the first supercooling point of about −25° C. to about −5° C.), and crystallization continues as the solution's temperature further decreases to about −11° C. after about 6 hours and continues to decrease over the next 6.5 hours. The first crystallization occurs shortly after the 20% glycerin solution T3 passes the supercooling point of about −14° C., shown at about 3.5 hours. Similar to the trace for the 10% glycerin solution T2, the falling temperature window of crystallization for the 20% glycerin solution T3 is typical for the solution.

[0045] Referring to FIG. 2, this chart shows the components of an exemplary biomaterial that can form a cold slurry. This chart shows how the ice percentage for an exemplary biomaterial can be calculated for a particular temperature. An exemplary slurry contains 30% ice by mass (weight / weight; w / w) at -10°C. This exemplary slurry has 80 mL of saline (0.9% NaCl) and 20 mL of glycerol (i.e., glycerin). By weight, such a slurry contains approximately 79.6 g of purified water, approximately 0.72 g of sodium chloride, and approximately 25.2 g of glycerol (approximately 20% v / v). In other embodiments, the slurry can contain a higher or lower percentage of glycerol by adjusting the relative volume of glycerol to the saline solution. For example, other suitable slurries contain about 10% glycerol (v / v), about 10% to about 20% glycerol, about 30% glycerol, or more than about 30% glycerol. Thus, when an active pharmaceutical compound is added to the slurry, the concentration of saline can be adjusted to maintain the desired concentration of excipients, such as glycerol. The percentage of ice will vary depending on the composition of the biomaterial.

[0046] Referring to Figure 3, different slurry compositions (batches) are characterized with respect to their temperature profile and ice content. The different slurry batches were placed on a copper plate heated to 40°C and had thermocouple wires measuring the change in temperature of the slurry over time. The plotted data shows the temperature change over time for three different slurry batches. The temperature was measured at two different locations for each slurry: the inside of the copper plate (trace A). C , B C and C C ) and the middle of the copper plate exposed on the outside of the plate (trace A M , B M and C M The temperature traces show three separately made slurry batches: a slurry composition with 15% glycerin (with a temperature setpoint of -8.1°C) is shown in trace A; C and A MTwo different slurry batches (with a freezing temperature of -5.5°C), both with 10% glycerin, are shown in trace B. C and B M and Trace C C and C M When the slurry batch is first introduced to the copper plate, the thermocouple wire (trace A) embedded inside the plate C , B C and C C ) is first measured by the heated plate (e.g., trace A at time 0). C A warm temperature of about 31 °C was measured, followed by a lower temperature (e.g., trace A at about 2 min) due to the cooling effect of the introduced slurry. C On the other hand, for a thermocouple wire placed in the middle of the plate, when the slurry is first introduced to the copper plate, the wire is exposed, so the slurry immediately comes into contact with the thermocouple wire. This results in a negative temperature reading at the middle position initially (e.g., 0°C for trace A at time 0) due to the crystallized slurry coming into contact with the wire. M about -5 °C), then when the slurry begins to melt on a heated plate at a warmer temperature (e.g., trace A at about 4 min). M Allow the plate to equilibrate at 18°C ​​(approximately 18°C). M , B M and C M ) can be used to detect phase transitions during the melting of a crystallized slurry. The graph shows that the two slurry compositions with 10% glycerin melt at similar time points (trace B). M About 4 minutes later, trace C M (approximately 2.7 minutes for the phase transition of the 15% glycerin slurry) M The graph also shows that the same composition (10% glycerin: Trace B) reaches its phase transition at a different time (occurring at approximately 0.2 min for C and B M and Trace C C and C MThe results show that two slurry batches with different compositions (15% glycerin, trace A) reach equilibrium in a similar time frame and at similar temperatures of approximately 15°C to 19°C depending on the thermocouple position (middle / bottom) (as measured by two thermocouple wire positions). C and A M The slurry with ) has a different temperature profile than the other two and reaches equilibrium faster at a temperature of about 19°C to 22°C depending on the thermocouple location (middle / bottom). Figure 3 therefore shows that slurries of different compositions have different temperature profiles and that there is consistency from batch to batch across slurries with the same composition (e.g., B C and B M and C C and C M The slurry represented by A C and A M (having a similar temperature profile that is different from the temperature profile of the slurry represented by

[0047] Referring to Figure 4A, a diagram of an eye is shown showing scleral zone 2, scleral zone 3, cornea 1, and limbus (the dotted line between cornea 1 and scleral zone 2). Figure 4A is reproduced from Andreoli CM, Gardiner MF. Open globe injuries: Emergent evaluation and initial management. In: https: / / eye.hms.harvard.edu / eyeinsights / 2014-april / benchmark-protocols-managing-eye-trauma. UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Figure 4B shows a diagram of the eye with a superimposed protractor indicating the angle in degrees (°) relative to the eye. In this diagram, 90° represents the most superior position along the eye.

[0048] In some embodiments, the cold slurries described herein can be applied directly or indirectly to the ocular surface, topically, or alternatively injected, to achieve long-lasting hypoesthesia that reduces discomfort on the ocular surface. Hypoesthesia, also referred to as hypoesthesia, refers to a reduction in discomfort or pain without complete loss of sensation, and in this disclosure, it specifically relates to the sensation on the ocular surface or to ocular structures. Hypoesthesia is therefore distinct from anesthesia, which is characterized by a more pronounced loss of ocular sensation. Hypoesthesia on the ocular surface can include corneal anesthesia, which causes a reduction in pain response while maintaining normal ocular function, including otherwise normal healing processes. On the other hand, anesthesia can cause abnormal ocular function due to the loss of all corneal sensation. Corneal sensation is important for normal ocular functions, such as the initiation of protective mechanisms such as blinking and tear production.

[0049] In certain embodiments, the cold slurries or devices described herein can be configured to induce complete loss of corneal sensation, i.e., numbness, which can be advantageous for surgical procedures or other ocular treatments.

[0050] In some embodiments, drops of the cold slurry are applied directly to the ocular surface. In some embodiments, the amount of slurry applied directly to the ocular surface can vary in volume from 1 to 100 milliliters. In some embodiments, the amount of slurry applied directly to the ocular surface can be approximately 10 to 80 milliliters. In some embodiments, the formulation can be administered directly to the ocular surface. In alternative embodiments, the cornea can be scraped first, and then drops can be administered directly to the ocular surface. In some embodiments, the topically applied cold slurry has a flowable paste consistency, and large amounts (e.g., 3 to 50 ml) can be applied topically to the ocular surface as a treatment.

[0051] In some embodiments, the cold slurry or self-contained cooling device described herein is applied topically, directly or indirectly, to the ocular surface for about 1 minute to about 20 minutes, about 2 minutes to about 5 minutes, about 10 minutes to about 15 minutes, or about 15 minutes to about 20 minutes. In some embodiments, the cold slurry or self-contained cooling device is applied for about 5 minutes to about 10 minutes. In some embodiments, the cold slurry or self-contained cooling device is administered to each eye every about 1 to about 10 seconds for about 1 to about 20 minutes. This treatment can be repeated several times over a short period of time (e.g., 5 to 20 minutes). In some embodiments, the cold slurry or self-contained cooling device is applied topically, directly or indirectly, to the ocular surface for about 10 minutes, with fresh slurry or a fresh device being reapplied about every 90 seconds until about 10 minutes have elapsed. In some embodiments, the slurry is applied directly or indirectly to the ocular surface posterior to the limbus, for example, in the area designated scleral region 2 in FIG. 4A.

[0052] In some embodiments, during topical application, sensitive ocular structures are protected from encountering the cold slurry to limit potential side effects. For example, protecting the corneal surface can limit some or all corneal cell damage or refractive changes caused by freezing the corneal tissue. Protecting the palpebral conjunctiva and eyelids can prevent redness, swelling, and inflammation unrelated to the therapeutic effect. By selectively applying the slurry directly or indirectly to the ocular surface posterior to the limbus on the bulbar conjunctiva (corresponding to the anterior anatomical region known as zone 2, FIG. 4A ), potential adverse effects on the cornea can be minimized.

[0053] In some embodiments, a protective contact lens or other protective cover, such as those further described herein, may be applied over the cornea to protect the cornea from potential damage from the slurry. In some embodiments, the corneal cover completely prevents the cold slurry from directly contacting the corneal surface. In some embodiments, a lid protecting the device is used to hold the eyelids open during topical cold slurry application. In some embodiments, the lid protecting the device is made of a thermally non-conductive material, such as plastic or another non-conductive material known in the art. A thermally non-conductive material may be used in the lid protecting the device to prevent the eyelids (inside and outside) from contacting the slurry and potentially freezing, which could cause damage to the eyelids during cold slurry treatment. In some embodiments, the lid protecting the device includes an eyelid speculum to help hold the eyelids open. In some embodiments, the cold slurry is applied only to the sclera, protecting the cornea from contacting the slurry and potentially freezing.

[0054] In some embodiments, as further described herein, a device can be used to limit exposure to the cold slurry to only the bulbar conjunctiva / sclera, so that the cold slurry does not physically contact or freeze adjacent tissues not related to the desired clinical effect. In some embodiments, the cold slurry formulation does not have any direct contact with the ocular surface. In some embodiments, the cold slurry formulation is contained within a device that is thermally conductive and may contact a material that contacts the ocular surface, such as a small metal or polymer donut-shaped object, other protective ring, or a recessed surface that may contact the ocular surface, thereby providing a barrier against direct contact between the formulation and the ocular surface but creating the need for cooling of the ocular surface. In some embodiments, to minimize potential undesirable side effects (e.g., potential ocular irritation due to direct application of a hyperosmotic solution to the eye), the device directs cooling only to the area of ​​potential therapeutic effect, preventing the device / cooling from contacting and affecting adjacent tissues.

[0055] In some embodiments, the cold slurry described herein is injected as a subconjunctival bolus. In some embodiments, the cold slurry is injected approximately every 2 minutes. In some embodiments, each injection provides approximately 0.5 to 1.5 ml of frozen slurry. In some embodiments, injections can be repeated approximately every 2 minutes for the desired duration of treatment. In some embodiments, the duration of treatment is a total of approximately 10 minutes, approximately 15 minutes, approximately 20 minutes, or longer than approximately 20 minutes. In some embodiments, the cold slurry is injected directly closer to the axons of the ciliary nerve. The ciliary nerve is located at approximately 0° and 180° of the eye (FIG. 4B).

[0056] In some embodiments, a standard syringe is used to inject the slurry. In some embodiments, a syringe pre-conditioned for injection of the slurry can be used. In some embodiments, the syringe can have a needle of about 18G to about 25G.

[0057] In some embodiments, real-time temperature sensing is performed on the surface of the eye during treatment (e.g., cold slurry injection, topical application of a slurry, or topical application of a self-contained cooling device). In some embodiments, the cold slurry or self-contained cooling device is applied to cool tissue (e.g., the corneal surface, conjunctiva, or any other part of the eye) to below about 0°C, below about -1°C, below about -2°C, below about -3°C, below about -4°C, or below about -5°C. In some embodiments, the cold slurry or self-contained cooling device is applied for about 1 minute, about 2 to about 10 minutes, about 5 to about 10 minutes, about 10 to about 20 minutes, about 10 to about 15 minutes, or about 15 to about 20 minutes. The temperature of the cooled tissue and the length of time the slurry or self-contained cooling device is applied can be varied to alter the reduced sensation experienced by the subject.

[0058] In some embodiments, the cold slurry or cooling treatment is periodically re-administered to the subject's eye over time to maintain the therapeutic effect.There is a range of possible frequencies for topical administration and / or injection.For example, the treatment can be administered at any one of the following times: once a week, once every two weeks; once a month; once every two months; once every three months, etc.

[0059] In some embodiments, the cold slurry is used as a safe corneal numbing therapy to treat corneal discomfort or pain. Various formulations of cold slurry can be used with the methods described herein, such as those described above. Further specific embodiments of cold slurry are described with reference to Figures 5-9. "ETX-4143" is a slurry formulation containing 15% glycerol, 30% L-α-phosphatidylcholine liposomes, and 0.9% saline (or phosphate-buffered saline). In some embodiments, ETX-4143 is administered to the eye (topically or via injection) at a temperature of approximately -25°C to -10°C (the temperature of the slurry). In some embodiments, ETX-4143 is administered to the eye (topically or via injection) at a temperature of approximately -18°C (the temperature of the slurry, such as in the embodiments described below with reference to Figures 5-9). ETX-4143 is administered at approximately 2-3 ml per application approximately every 90 seconds until a total treatment time of 10 minutes is reached.

[0060] "ECT-1719" is a slurry formulation containing 15% glycerol and 0.9% saline (or phosphate-buffered saline). In some embodiments, ECT-1719 is administered to the eye (topically or via injection) at a temperature of about -20°C to -5°C or about -15°C to about -10°C (the temperature of the slurry). In some embodiments, ECT-1719 is administered to the eye (topically or via injection) at a temperature of about -11°C (the temperature of the slurry, such as in the embodiments described below with reference to Figures 5-9). In some embodiments, ECT-1719 is injected in a volume of 0.7 ml per injection, for a total of four injections, for a total injection volume of 2.8 ml. ECT-1719 is administered approximately every 120 seconds until a total treatment of 10 minutes is reached.

[0061] Referring to Figure 5, real-time scleral temperature monitoring was performed in rabbits after ocular administration of topically applied cold slurry (ETX-4143, solid line) in one rabbit and injected cold slurry (ECT-1719, dashed line) in a second rabbit. Temperature monitoring was achieved by cannulating the subtenon space with a 25G needle containing a temperature probe at its distal end. As can be seen in Figure 5, the scleral temperature of the rabbit receiving injected cold slurry (ECT-1719) varied from approximately 0°C to approximately 8°C throughout the duration of the procedure (approximately 0 seconds after cold slurry injection to approximately 463 seconds after cold slurry injection). The sharp line on the graph at approximately 463 seconds represents the end of the study after 7.5 minutes and the removal of the temperature probe from the ocular tissue. The scleral temperature of rabbits receiving topically applied cold slurry (ETX-4143) was lower than that of injected cold slurry, fluctuating between approximately -6°C and approximately 4°C for the majority of the time during which temperatures were recorded (approximately 0 seconds after topical application to approximately 600 seconds after topical application). After topical application, the scleral temperature continued to decrease from approximately 4°C at the time of application (approximately 0 seconds in Figure 5) to approximately 0°C after approximately 120 seconds. After the initial period of scleral cooling, the temperature remained relatively stable at approximately 0°C to -5°C from approximately 120 seconds after topical application to approximately 520 seconds after topical application. Furthermore, for the duration of approximately 220 seconds to approximately 520 seconds after topical application, the scleral temperature remained stable at approximately -2°C to approximately -3°C with very little variability. Approximately 620 seconds after topical application, treatment was terminated and the temperature probe was removed, indicating a sharp increase in the measured temperature, as shown in Figure 5.

[0062] The hypoesthesia effect after cooling treatment (whether injection or application of a cold slurry or application of a self-contained cooling device) can be measured as a response to ocular contact stimulation using a monofilament / anesthesiometer. Starting with a 6 cm filament length, the eye is probed three times at each length, decreasing in 0.5 cm increments, until a blink response is elicited. As the filament shortens, it becomes stiffer, so more pressure is applied to the eye when probing. Hypoesthesia for each time point is based on a given length of monofilament. At each time point, the particular monofilament length recorded is the shortest length (highest pressure) that does not produce a blink response. For example, starting with the longest monofilament at 6 cm, if the rabbit does not blink when probed, the next monofilament at 5.5 cm is used to probe the eye. If the rabbit does not blink again, the next monofilament length at 5 cm is used. If the rabbit now blinks, the previous length of 5.5 cm is recorded, as this was the shortest length that did not produce a blink response (reflecting some degree of hypoesthesia). The deepest level of hypoesthesia is when the rabbit does not blink when probed with the shortest filament length (e.g., 0.5 cm). 0 degree hypoesthesia (no pain block / no numbness) is when the rabbit blinks when probed with the longest filament length (e.g., 6 cm). Filament length is related to the pressure (g / mm 2 ) and a 6cm filament can be converted to 0.4g / mm 2 pressure (lowest pressure), while the 0.5 cm filament produces 15.9 g / mm 2 The pressure recorded is therefore the pressure corresponding to the shortest filament length at which there is no blink response.

[0063] Referring to Figure 6, the hypoesthesia effect (degree of corneal numbness measured using a contact stimulus as described herein) was measured over time in rabbits following administration of injected cold slurry (ECT-1719, 3 rabbits in this group, indicated by diamonds), topically applied cold slurry (ETX-4143, 3 rabbits in this group, indicated by triangles), and room temperature topically applied slurry (ETX-4143, 1 rabbit in this group, indicated by squares) to the exposed cornea of ​​the eye. In Figure 6, the degree of hypoesthesia was measured at the highest possible pressure (i.e., 15.9 g / mm 2 The results are presented as a percentage of the recorded pressure (i.e., based on the shortest monofilament used, corresponding to a pressure of 0.5 cm) (i.e., based on the shortest monofilament with a lack of blink response). The degree of hypoesthesia is presented on days 1, 7, 14, and 28 after cold slurry administration. For injected cold slurries (ECT-1719, represented by diamonds), the hypoesthesia effect was approximately 20% on day 1, reached baseline levels by day 14, and continued to decrease (error bars overlap 0%). For topically applied cold slurries (ETX-4143, represented by triangles), the hypoesthesia effect was 100% on day 1 (maximum corneal numbness that could be measured), then continued to decrease and gradually ceased on day 28, during which time the pain response returned to baseline levels (error bars overlap 0%). For slurries applied topically at room temperature (ETX-4143, represented by squares), no hypoesthesia effect could be observed at any time point after treatment. Thus, Figure 6 shows an unexpectedly strong anesthesia effect for topically applied cold slurry, which produced long-lasting anesthesia (nearly one month). Injected cold slurry produced moderate anesthesia that also lasted longer than expected (e.g., approximately one to two weeks). Importantly, for both topical and injection methods, cold slurry treatment produced long-lasting anesthesia that normalized back to baseline levels without causing a permanent numbing effect.

[0064] Figure 7 shows the anesthetic effect over time in rabbits after ocular administration of topically applied cold slurry (6 rabbits, ETX-4143) similar to Figure 6, except that the cornea was not exposed (protected by a contact lens). The anesthetic effect was measured in the same manner as described above for Figure 6. The anesthetic effect is shown on days 1, 7, 14, 21, and 28 after treatment with the topically applied cold slurry. The anesthetic effect was approximately 50% on day 1 and gradually decreased, slowly reaching baseline levels by day 21 (error bars overlap 0%). Thus, Figure 7 shows an unexpected moderate to strong anesthetic effect for the topically applied cold slurry (with corneal protection), which produced long-lasting anesthetic reduction (approximately 3 weeks) without causing permanent corneal numbness or any corneal damage.

[0065] Referring to Figure 8, representative images of rabbit corneas using fluorescein staining show corneal healing over time after intentional 8 mm corneal abrasion applied in both the control group (Figure 8A) and after topical application of cold slurry in the treatment group where protection was applied to the cornea and eyelid (Figure 8B). The progression of the injury was determined by measuring the size of the injury over time. As can be seen in Figure 8A, corneal healing in the control group (3 rabbits) progressed by 1.31 mm in the first 24 hours after the abrasion. 2 / hour, and 0.62 mm 24 to 60 hours after corneal abrasion 2 8B, corneal healing was not impaired in rabbits receiving topically applied cold slurry (ETX-4143) compared to the control group. In this group (3 rabbits), corneal healing after cold slurry treatment increased by 1.09 mm in the first 24 hours after cold slurry treatment. 2 / hour, and 0.63 mm 24 to 60 hours after cold slurry treatment 2 The average healing rate was 1 / hour.

[0066] Referring to Figure 9, the graph shows the anesthetic effect over time in six rabbits after a combination treatment in which cold slurry was first applied topically and then injected. In three rabbits (indicated by diamonds, squares, and triangles), the topically applied cold slurry was ECT-1719 without liposomes, followed by an injection of the same cold slurry formulation (ECT-1719). In the other three rabbits (indicated by "X," stars, and circles), the topically applied cold slurry was again ECT-1719 (without liposomes) followed by an injection of cold slurry containing liposomes (ETX-4143). The anesthetic effect is indicated by the maximum pressure at which the rabbit did not blink (as described herein with reference to Figures 6 and 7). As shown in Figure 9, the anesthetic effect continued to increase after treatment and could peak anywhere from days 4 to 11, regardless of the combination treatment (liposome or non-liposome injection). The hypoesthesia effect gradually diminished, returning to baseline levels by about day 17. Surprisingly, a second, less pronounced period of hypoesthesia occurred spontaneously at about day 22, gradually ending with a return to baseline levels by day 26.

[0067] Cold slurry formulations containing one or more lipids In some embodiments, it is desirable to increase the amount of ice fragments in the slurry, because ice fragments are converted into a larger amount of heat energy that is removed from the surface of the eye.However, adding more ice to the cold slurry generally makes the slurry less flowable, making it difficult to inject or administer locally to the desired site.As further described herein, some embodiments of the present invention relate to the cold slurry formulations described herein, which further comprise one or more lipids that improve the fluidity of the slurry.In some embodiments, the one or more lipids improve the fluidity and flow properties of the slurry, while allowing the desired amount of ice fraction in the slurry.In some embodiments, the improved fluidity leads to improved slurry properties, which further allows the slurry to be applied via various sizes of devices (e.g., syringes) for injecting and / or local administration.

[0068] In some embodiments, the slurry contains one or more lipids that result in the formation of an emulsion with the ice and / or ice-freezing point depressant mixture in the slurry, preventing or reducing the aggregation of ice particles into larger crystal sizes that reduce the fluidity of the slurry. In some embodiments, the slurry contains one or more lipids that encapsulate the ice and / or ice-freezing point depressant crystals, preventing or reducing the amount of aggregation of smaller ice particles into larger crystals, resulting in smaller crystal sizes.

[0069] In some embodiments, the slurries contain varying amounts of lipid from about 0% to 45% (v / v). In some embodiments, the slurries contain varying amounts of lipid from about 0% to 10%, about 10% to 20%, about 20% to 30%, or about 30% to 45%. In some embodiments, the slurries contain varying amounts of freezing point depressant from about 0% to 10%, about 10% to 40%, about 10% to 30%, about 10% to 20%, or about 40% to 50% (v / v). In some embodiments, the slurries contain varying amounts of lipid and freezing point depressant (e.g., glycerol) from about 15% to 45% (v / v) and 10% to 25% (v / v), respectively. In some embodiments, the slurries contain about 0% to 45% (v / v) lipid and / or about 0% to 45% (v / v) freezing point depressant (e.g., glycerol).

[0070] In some embodiments, the slurry may contain water, one or more freezing point depressants, and / or one or more lipids, and is prepared by flash freezing. In some embodiments, the slurry may contain water, one or more freezing point depressants, and / or one or more lipids, and is prepared by freezing the slurry in a -20°C freezer, a -80°C freezer, an ultra-low temperature ("ULT") freezer, or flash freezing (e.g., using liquid nitrogen) to produce an emulsified slurry. In some embodiments, the emulsified slurry can be stored in a standard freezer and retains its fluidity when removed from the freezer for use (e.g., therapeutic treatment).

[0071] In some embodiments, the slurry, which may comprise water, one or more freezing point depressants and / or one or more lipids, can be contained in one or more syringes.In some embodiments, one or more slurry-containing syringes are prepared by flash-freezing one or more syringes containing the slurry.In some embodiments, one or more slurry-containing syringes are prepared by cooling the slurry-containing syringe in a -20°C freezer, a -80°C freezer, an ultra-low temperature ("ULT") freezer, or flash-freezing (such as using liquid nitrogen) to emulsify the slurry.In some embodiments, one or more slurry-containing syringes can be conveniently stored in a standard freezer without experiencing significant loss of flowability.

[0072] In some embodiments, the slurry contains one or more lipids with low degradability properties, resulting in long-term stability of the slurry mixture. In some embodiments, the slurry contains one or more lipids including soy phosphatidylcholine (soy-PC). In some embodiments, the slurry contains one or more lipids including one or more fatty acids. In some embodiments, the one or more fatty acids are selected from the group consisting of stearic acid, palmitic acid, lauric acid, and myristic acid. In some embodiments, the slurry contains one or more lipids from non-animal sources, such as soy-based and synthetic substitutes. In some embodiments, the slurry contains non-lipids, such as hyaluronic acid, polysorbates, and other hydroscopic molecules.

[0073] Referring to Figure 10, a diagram of the degree of injectability of an exemplary cold slurry containing ice, glycerol, and lipid as a function of the volumetric fractions of glycerol and lipid is shown. When the amounts of glycerol and lipid in the cold slurry are within the ranges of about 0%-10% (v / v) and about 0%-45% (v / v), respectively, the ice in the cold slurry aggregates into large chunks, making the slurry not flowable or injectable. When the amounts of glycerol and lipid in the cold slurry are within the ranges of about 10%-25% (v / v) and about 0%-15% (v / v), respectively, the ice in the cold slurry aggregates into crystals large enough to prevent the free flow of the cold slurry from an appropriately sized syringe, making the slurry not flowable or injectable. When the amounts of glycerol and lipid in the cold slurry are within the ranges of about 40%-50% (v / v) and about 0%-45% (v / v), respectively, the freezing point of water is depressed and any water present in the slurry is in liquid form, so no ice is present in the slurry, and the cold slurry becomes ineffective for cold slurry applications. When the amounts of glycerol and lipid in the cold slurry are within the ranges of about 25%-40% (v / v) and about 0%-45% (v / v), respectively, the ice crystals are small enough to allow free flow, making the cold slurry more flowable and injectable, but the amount of ice in the cold slurry remains low, making the cold slurry less effective at removing heat than required for cold slurry applications. When the amounts of glycerol and lipid in the cold slurry are within the ranges of about 10%-25% (v / v) and about 15%-45% (v / v), respectively, the cold slurry is flowable, injectable, and an effective heat carrier. In this performance range, the heat carrying capacity of the cold slurry can be maximized, depending on the desired degree of injectability of the cold slurry. In some embodiments, the lipid used in Figure 10 is soy-PC.

[0074] Generally, cold slurries containing greater amounts of ice remove more heat from the ocular surface but are less flowable due to the presence of ice particles. On the other hand, adding a freezing-point depressant (e.g., glycerol) and lipids to a slurry is expected to improve the slurry's flowability but reduce the amount of ice and, therefore, the slurry's heat-transporting capacity. When the amount of glycerol in a cold slurry is within the range of approximately 0% to 10% (v / v), the amount of glycerol is not sufficient to lower the freezing temperature sufficiently to prevent significant water freezing. Regardless of the amount of lipid added to the slurry, small ice crystals begin to form and then begin to aggregate into larger crystals, which further coalesce to produce large ice chunks. These large ice chunks render the slurry non-flowable, making the cold slurry mixture impractical for injection or direct topical administration into the eye; however, non-flowable cold slurries can be used in conjunction with self-contained cooling devices to apply cooling therapy to the ocular surface. When the amounts of glycerol and lipid in the slurry are within the ranges of approximately 10%-25% and 0%-15% (v / v), respectively, the cold slurry still lacks the fluidity required for injection or topical administration. When the amounts of glycerol and lipid in the slurry are within the ranges of approximately 25%-40% and 0%-40% (v / v), respectively, there is enough glycerol in the cold slurry to lower the freezing point of ice to the desired level, providing flow properties that allow for some degree of injectability. For example, in this range, even if the cold slurry does not contain lipid, the slurry still exhibits a lowered freezing point and fluidity that may enable its use in cold slurry therapy. When the amounts of glycerol and lipid in the slurry are within the ranges of approximately 25%-40% and 15%-45% (v / v), respectively, increasing the amount of lipid increases the fluidity of the slurry, but this also results in a decrease in the amount of ice and therefore a decrease in the heat-transporting capacity of the cold slurry. When the amount of glycerol in the slurry is greater than about 40% v / v, the water component of the slurry remains liquid at the target temperatures at which the ocular surface needs to be maintained (i.e., about -6°C and 4°C).This range is not appropriate for cold slurry treatments because cold slurry treatments rely on the latent heat of ice (rather than the sensible heat of liquid water, which results in significantly lower heat-carrying capacity for the temperature difference experienced during treatment) to maintain a low temperature at the ocular surface for extended periods of time. An optimized cold slurry consists of glycerol and lipid in amounts that vary from approximately 25% to 40% and 15% to 45% (v / v), respectively. Such a cold slurry maximizes the heat-carrying capacity of the cold slurry without compromising its fluidity and therefore the injectability required for slurry application (e.g., desired injectability depending on syringe size, treatment temperature, etc.).

[0075] In some embodiments, the present invention relates to a cold slurry formulation comprising water, one or more freezing point depressants, and one or more lipids. In some embodiments, the slurry formulation is configured to maintain a desired ocular surface temperature for an extended period of time. In some embodiments, the slurry formulation comprises about 25% to 40% (v / v) freezing point depressant. In some embodiments, the freezing point depressant is glycerol. In some embodiments, the slurry formulation comprises about 15% to 45% (v / v) lipid. In some embodiments, the lipid is soybean phosphatidylcholine (soybean-PC).

[0076] In some embodiments, the present invention relates to a method for alleviating symptoms of ocular surface discomfort, the method comprising: topically applying a cold slurry to a patient's eye adjacent to the limbus, the cold slurry comprising water, a freezing point depressant, and one or more lipids, the topical application of the cold slurry being configured to cause a degree of numbness of the cornea of ​​the eye for a period of time, and ocular sensation in the eye being restored after the period of time.

[0077] In some embodiments, the present invention relates to a method for preparing a cold slurry formulation, the method comprising mixing a desired fraction of water, one or more freezing point depressants, and one or more lipids at a mixing speed of 1 to 20,000 RPM. In some embodiments, the present invention relates to a method for preparing a cold slurry formulation by gently stirring a desired fraction of water, one or more freezing point depressants, and one or more lipids. In some embodiments, the slurry formulation comprises about 25% to 40% (v / v) of the freezing point depressant. In some embodiments, the freezing point depressant is glycerol. In some embodiments, the slurry formulation comprises about 15% to 45% (v / v) of lipid. In some embodiments, the lipid is soybean phosphatidylcholine (soy-PC). In some embodiments, such a method for preparing a cold slurry formulation provides an emulsified slurry comprising an emulsion of water and one or more lipids or water and one or more lipids with the freezing point depressant component. In some embodiments, this method for preparing slurry formulations provides a stable dispersion of one or more lipid particles or water and freezing point depressant components in water.In some embodiments, this method for preparing slurry formulations causes the water component to form small micro- and / or mm-sized droplets that are encapsulated in one or more lipids.In some embodiments, this method for preparing slurry formulations causes the water component to form small micro- and / or mm-sized droplets that are encapsulated in one or more lipids.

[0078] Devices for protecting the cornea In some embodiments, aspects of the present invention relate to devices for protecting the cornea. In some embodiments, the devices described herein for protecting the cornea can be used when applying the slurries described herein to the eye of a subject. In some embodiments, contacting certain parts of the eye (e.g., the cornea) with the cold slurries described herein can pose a risk of damage to the area (e.g., the cornea): for example, 1) cold slurries at temperatures below 0°C can freeze the cornea, and / or 2) chemicals used in the slurries can be harmful to the cornea (e.g., irritating). Therefore, in some embodiments in which the eye of a subject is contacted with the slurries described herein, physical and thermal protection / isolation of the cornea from the cold slurry can be desirable.

[0079] In some embodiments, the corneal protection devices described herein include a suction member, such as a suction cup. In some embodiments, the suction member is placed on the cornea, covering it and holding it in place by suction. In some embodiments, the suction member of the corneal protection device forms a seal around the circumference of the cornea. In some embodiments, the corneal protection device is used in conjunction with the application of a slurry to the ocular surface, the suction member provides a seal around the circumference of the cornea, preventing the deposited (i.e., topically administered or injected) slurry from coming into direct contact with the cornea. The diameter of the suction member (e.g., suction cup) of the corneal protection device can vary to accommodate corneas of different sizes, allowing the device to be used in different subjects, such as animals and humans of different ages and sizes (e.g., children, adults, etc.). For example, the diameter of the opening of the suction member (e.g., suction cup) can be 11-14 mm.

[0080] 11 , in some embodiments, the member of the corneal protection device 10 that provides the suction force comprises a suction cup 100 including one or more curved, rounded walls 110, the diameter of which gradually decreases until it reaches a tip 140, and an open surface 120 configured to contact the surface of the eye and surround the circumference of the cornea. In some embodiments, the corneal protection device comprises an internal cavity 130 that is configured such that when the one or more curved walls 110 are squeezed or pinched, air is expelled from the internal cavity 130, and after the open surface 120 of the suction cup is placed on the surface of the eye, the pinching or squeezing force on the one or more curved walls 110 is released, causing a vacuum or partial vacuum to form within the internal cavity 130, adhering the suction cup to the surface of the eye and sealing the cornea surrounded by the open surface 120 of the suction cup. In certain embodiments, one or more curved walls 110 and / or the entire corneal protection device 10 comprise a thermally insulating material to further protect the cornea from latent heat diffusion from the surrounding environment, such as when a cold slurry is applied to the sclera adjacent to the cornea. In some embodiments, an evacuated interior cavity 130, which may comprise a partial or complete vacuum, provides further thermal protection to the enclosed cornea from the surrounding environment by slowing conductive, convective, and radiative heat transfer from the surrounding environment. In some embodiments, one or more curved walls 110 and / or the entire corneal protection device 10 comprise a non-porous material with low thermal conductivity, such as polymer, polyvinyl chloride (PVC), neoprene, polyethylene (PE), polytetrafluoroethylene (PTFE), silicone, ethylene propylene diene monomer rubber (EPDM), elastomeric material, silicone, thermoplastic elastomer (TPE), thermoplastic polyurethane (TPU), etc.

[0081] In some embodiments, one or more curved walls 110 and / or the entire corneal protection device 10 comprise one or more layers of a low thermally conductive material. In certain embodiments, the thermally conductive material is selected from the group consisting of polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, silicone, EPDM, elastomeric materials, and the like.

[0082] In some embodiments, one or more of the suction-providing members (e.g., suction cups) and / or curved walls 110 of the corneal protection device provide high thermal resistance to slow the rate of heat transfer from the surrounding cold slurry to the cornea. In some embodiments, one or more walls of the suction cups and / or corneal protection device comprise an optically transparent or optically translucent material, such as optically clear silicone. In some embodiments, one or more walls of the suction cups and / or corneal protection device comprise an optically opaque material, such as silicone and colored elastomeric materials.

[0083] In some embodiments, the member providing the suction force (eg, suction cup) comprises the following design parameters: suction area / diameter, wall thickness, vertical height, etc.

[0084] In some embodiments, when the suction-providing member (e.g., suction cup) of the corneal protection device is held in place by suction, a vacuum or partial vacuum is formed between one or more walls 110 in the interior cavity 130 of the corneal protector. This vacuum or partial vacuum provides thermal protection for the cornea from its surroundings, such as a deposited cold slurry that may contact the exterior wall of the corneal protection device.

[0085] 12, in some embodiments, the corneal protection device includes an upper portion 212 for activating and deactivating suction. Suction can be activated by squeezing and releasing the walls of the corneal protection device in the region of the upper portion 212. In certain embodiments, the corneal protection device includes a bottom element 214 that forms a suction-providing member (e.g., a suction cup) that sits on the surface of the eye to cover the cornea and has an opening that creates a barrier between the circumference of the cornea and the sclera when held in place by suction.

[0086] In some embodiments, a suction member (e.g., a suction cup) containing an optional cold slurry applied to the ocular surface is used to protect the cornea from its surroundings by first pinching or squeezing the top element 212 of the device to activate the suction member (e.g., a suction cup), then placing the bottom element 214 on the ocular surface, so that the edge of the device that touches the eye surrounds the outer edge or circumference of the cornea, and then releasing the top element 212 to activate the suction, thereby adhering the suction member to the ocular surface. The suction ensures that the device is held in a position that covers and protects the cornea. The corneal protection device can then be removed from the ocular surface by pinching or squeezing the top element 212 to deactivate the suction, and then carefully removing the device from the ocular surface. In some embodiments, a suction-providing member (e.g., a suction cup) containing any cold slurry applied to the ocular surface is used to protect the cornea from its surroundings by first placing the bottom element 214 on the surface of the eye so that the edge of the device that touches the eye surrounds the outer edge or circumference of the cornea, and then pinching / squeezing and releasing the top element 212 of the device to force air out of the member (e.g., suction cup) and create a low-level vacuum inside the member that holds it in place.

[0087] 13A and 13B, a corneal protection device 300 and its application for sealing around the circumference of the cornea are shown. The corneal protection device 300 includes one or more walls 310, an open surface 330 that contacts the target surface (e.g., the surface of the eye) and surrounds the circumference of an area on the target surface (e.g., the cornea), and an interior cavity that is held under vacuum or partial vacuum when the device's suction force is activated. In one embodiment, the one or more walls 310 include a top element 312 and a bottom element 314, which are shaped as a cup. The bottom element 314 includes the open surface 330 that is positioned on the circumference of the target area (e.g., the cornea) as shown in FIG. 13B, and the top element 312 that can be squeezed or pinched to release air from the interior cavity, thereby creating a suction (i.e., vacuum) force within the cavity that holds the corneal protection device in place on the target surface (e.g., the area on the cornea shown in FIG. 13B).

[0088] Contact lenses to protect the cornea In some embodiments, aspects of the present invention relate to the use of contact lenses to protect the cornea both physically and thermally during cold slurry treatment. A contact lens can be placed on the cornea before applying the cold slurry to the eye. The contact lens can act as both a physical and thermal barrier between the cornea and the surrounding cold slurry. Potential advantages of using contact lenses to protect the cornea during cold slurry treatment include ease of use and patient familiarity with the product, helping to reduce anxiety during treatment. However, there are several difficulties associated with using contact lenses: 1) the contact lens can move during treatment, exposing the cornea to the slurry; 2) the slurry can still spread laterally, i.e., around the corners of the lens, from the sclera to the cornea; 3) typical contact lenses are porous, potentially allowing the surrounding slurry to find its way to the cornea; and 4) the contact lens must be thin to be placed on the corneal surface, limiting the thermal resistance provided by the contact lens from the surrounding cold slurry.

[0089] In some embodiments, contact lenses comprising materials that have low thermal conductivity but still allow sufficient suction force, such as polymethyl methacrylate (PMMA), silicone, hydrogels, etc., may be used.

[0090] Eyelid protection device When a subject's eyelids come into contact with the slurries described herein, the subzero temperature and duration of contact of the cold slurry with the eyelids can potentially cause inflammation and / or physical damage to the eyelids. Described herein are eyelid protection devices that can be used alone or in combination with cold slurry treatment to physically and thermally separate the eyelids from the material applied to the eye surface, such as the cold slurry. The eyelid protection device is generally shaped to fit between the patient's upper and lower eyelids and act as a physical and thermal barrier between the eyelids and the material (e.g., cold slurry) deposited on the eye surface. In some embodiments, the eyelid protection device also acts as an eyelid retractor to keep the eye open during treatment.

[0091] 14A and 14B, in some embodiments, eyelid protection device 400, 500 includes a surface 410, 510 that contacts the upper eyelid and a surface 420, 520 that contacts the lower eyelid. In some embodiments, one or both of surfaces 410, 510 and 420, 520 are curved (e.g., convex) to better conform to the contours of the eyelid and eye. In some embodiments, one or more of surfaces 410, 510 and 420, 520 of the eyelid protection device include members (e.g., platforms) 470, 570 to assist the practitioner in handling and manipulating the device, for example, for insertion into and removal from the eye. In some embodiments, one or more of surfaces 410, 510 and 420, 520 of the eyelid protection device include one or more structures 430 that act as eyelid speculum to hold the eyelid open while the device is inserted into the eye. In some embodiments, the eyelid protector device includes an opening between or surrounded by surfaces 410, 510 and 420, 520 that conform to the surface of the eye. The size of the opening can vary depending on the size of the subject's eye. In some embodiments, the eyelid protector device includes a single continuous component that includes both surfaces 410, 510 and 420, 520. In some embodiments, the eyelid protector device includes more than one component, where surfaces 410, 510 and 420, 520 separate components that can be reversibly attached to each other to form a complete device. In some embodiments, one or more of the surface components 410, 510 and 420, 520 of the eyelid protector device include curvilinear connecting segments that can move relative to each other to adjust the size of the opening of the device to accommodate eyelids of various shapes and sizes. In some embodiments, the distance across the opening of the eyelid protection device between or surrounded by surfaces 410, 510 and 420, 520 can be adjusted to accommodate eyelids and eyes of various shapes and sizes.

[0092] The size of each surface of the eyelid protection device can be adjusted to accommodate various shapes and sizes of eyelids and eyes. In some embodiments, the eyelid protection device includes dimensions that allow eyelid opening in the range of 0 to 20.83 mm or 17.25 to 20.83 mm. In some embodiments, the protrusion depth of the eyelid protection device inserted under the eyelid ranges from 2.54 to 5.85 mm. In some embodiments, the eyelid protection device includes one or more plastics, extruded plastics, silicone, EPDM, etc. In some embodiments, the eyelid protection device includes one or more low thermal conductivity materials, such as silicone and EPDM. In some embodiments, the eyelid protection device includes one or more porous materials that are both thermal insulators and wicking materials, such as open-cell foam, PVA, etc.

[0093] In some embodiments, the eyelid protector device is configured to drain molten, i.e., liquid or less viscous, slurry from the surface of the eye. For example, in some embodiments, the eyelid protector device includes gaps or channels 440, 540 in one or more of surfaces 410, 510 and 420, 520 that allow molten slurry to drain from the surface of the eye. Removing warm molten slurry from the surface of the eye is advantageous in some embodiments because it provides a fresh batch of cold slurry to the surface of the eye while holding the eyelid protector in place. Such removal of molten slurry during treatment is desirable in some embodiments to ensure that the surface of the eye remains in contact with ice crystal-containing slurry at the desired temperature (as opposed to being covered by warm molten slurry), improving the efficiency and effectiveness of treatment. In some embodiments, the eyelid protector device includes a wick structure and / or wicking material to aid in the removal of molten slurry from the surface of the eye. Examples of wick materials and structures that may be integrated into the eyelid protection device include, but are not limited to, PVA, open cell foam materials, and the like.

[0094] Referring to Figure 14B, in some embodiments, the eyelid protection device includes a structure, e.g., feature 550, for receiving and holding a corneal protection device, such as a corneal protection device described herein and shown, e.g., in Figures 11-13. Such an eyelid protection device, as related to a corneal protection device, can be used to protect both the eyelid and the cornea while applying, e.g., a cold slurry described herein to the surface of the eye. Examples of eyelid protection devices and corneal protection devices used in conjunction are shown in Figures 15A and 15B.

[0095] kit For a more effective cold slurry treatment, the ocular surface should be maintained at a temperature below zero for the entire duration of the treatment. In some situations, the topically administered cold slurry warms above a critical temperature and melts on the ocular surface before treatment is complete, necessitating the administration of additional doses to maintain the desired sub-zero temperature at the ocular surface. Accordingly, kits are described herein for providing multiple cold slurry doses that enable treatments involving multiple administrations of slurry to maintain the ocular surface at a sub-zero temperature over the course of treatment. Referring to FIG. 16 , in some embodiments, kit 600 includes multiple syringes 610 pre-filled with slurry. In some embodiments, the kit includes an external package 620 containing multiple syringes 610. In some embodiments, external package 620 is configured to store, seal, and provide thermal and humidity protection for multiple syringes 610. In some embodiments, kit 600 includes at least two syringes pre-filled with slurry. In some embodiments, the kit 600 includes 2-20, 2-15, 2-10, or 2-5 syringes prefilled with slurry. In some embodiments, the kit 600 includes one syringe prefilled with slurry. The number of syringes in the kit can vary depending on various factors, such as the duration of the planned treatment, the size of the eye, and the ability to store different sized kits (e.g., available freezer size). The amount of slurry in each syringe can also vary (e.g., 1-20 ml) depending on the same types of factors listed above regarding the desired treatment and storage source details. Before and during use in a cold slurry procedure, the kit can be stored in a freezer to ensure that the cold slurry in each syringe is initiated and substantially maintained at the desired temperature (e.g., a temperature below 0°C) during treatment. Such kits can also help promote the proper use and effectiveness of cold slurry treatment, as clinicians are more informed about how many new doses and at what time intervals new doses should be administered to the treatment area.

[0096] In some embodiments, kit 600 includes a thermal package configured to maintain the cold slurry at a temperature below zero for a desired period of time after the kit is removed from the freezer and placed in ambient temperature conditions (e.g., during transport or prior to upcoming use). This is particularly useful in locations where freezers are not available during cold slurry treatment, such as in remote, underdeveloped areas. In some embodiments, the thermal package of the kit includes a phase change material, insulation, a reflective barrier, reflective foil, polystyrene foam, or a combination thereof.

[0097] In some embodiments, the kit includes one or more empty syringes and a separate container with a slurry. Prior to treatment, one or more of the empty syringes can be filled with cold slurry by withdrawing the slurry from the container. In some embodiments, the slurry can be withdrawn into one or more empty syringes under ambient temperature conditions, where the liquid slurry can be easily withdrawn by the syringe. In such embodiments, the filled syringes can be returned to the kit and placed and / or stored in a freezer before use.

[0098] In some embodiments, the kit includes an outer package made of an air and / or moisture barrier, e.g., a metallized polymer film, a thin metal film, a polymer film, Styrofoam, etc., to impart a long shelf life to the slurry. In certain embodiments, the outer package seals the kit and provides some protection against, e.g., potential contamination, temperature changes, and / or other environmental conditions.

[0099] Methods for making and transporting cold slurry formulations have been previously described, for example, in U.S. Pat. No. 11,241,330; U.S. Pat. No. 11,564,830; U.S. Pat. No. 11,471,401; U.S. Patent Application No. 18 / 358,795 (filed July 25, 2023, not yet published); International Application No. PCT / US2022 / 33095 (Publication No. WO / 2022 / 261494); and International Application No. PCT / US2023 / 62443 (Publication No. WO / 2023 / 154902), which are incorporated by reference herein in their entireties. In some embodiments, the kit comprises a pre-filled syringe, and the syringe is pre-filled with a composition according to Patent No. 11,471,401; International Application No. PCT / US2022 / 33095 (Publication No. WO / 2022 / 261494); or International Application No. PCT / US2023 / 62443 (Publication No. WO / 2023 / 154902), which are incorporated herein by reference in their entirety. In some embodiments, the kit is compatible with the manufacturing systems and methods previously described in, for example, U.S. Patent No. 11,241,330 and U.S. Patent No. 11,564,830, which are incorporated herein by reference in their entirety. In some embodiments, the kit comprises at least one pre-filled syringe, and the kit can be transported, and the contents of the syringe can be transformed into a slurry, and the slurry can be administered according to the disclosure of Patent No. 11,471,401, which is incorporated herein by reference in its entirety.

[0100] Self-contained cooling device In some embodiments, aspects of the invention relate to self-contained cooling devices that transfer thermal energy away from a target surface (e.g., the surface of the eye) using cold slurry therapy. In certain embodiments, the self-contained cooling devices are used for cryoneurolysis. In some embodiments, such self-contained cooling devices are configured to protect the cornea, eyelid, and potentially other sensitive structures (e.g., tissue, skin) from the sub-zero temperatures required during cryoneurolysis procedures and any physical damage that may potentially occur during the application of the therapy.

[0101] In some embodiments, aspects of the present invention relate to a self-contained cooling device comprising a container containing a thermal mass (e.g., a liquid, solid, or cold slurry formulation) having a freezing point lower than that of water. In some embodiments, such devices can be transported and stored in a sterile package or in a standard freezer at ambient temperature. In some embodiments, such packages are frozen prior to use. In some embodiments, when ready for use, the device is removed from the freezer and its packaging (e.g., sterile barrier) and applied to the target ocular surface to achieve cryoneuropathy. In some embodiments, the device is discarded after use. In some embodiments, the liquid or cold slurry formulation is sealed within the container so that it cannot directly contact and therefore cause any damage to the target ocular surface or surrounding tissues and body parts (e.g., cornea, eyelid, skin).

[0102] In some embodiments, the self-contained cooling device comprises a thermal mass (e.g., a liquid, solid, or cold slurry formulation). In some embodiments, the thermal mass is contained within a heat exchanger. In some embodiments, the thermal mass comprises a formulation of about 20% wt / wt glycerol in water (e.g., purified water).

[0103] In some aspects, the self-contained cooling device according to the present disclosure can be sterilized. In some embodiments, the self-contained cooling device is placed in a package after being sterilized. In some embodiments, the self-contained cooling device is sterilized after being placed in the package. In some embodiments, the self-contained cooling device is sterilized before shipping. In some embodiments, the self-contained cooling device and optionally the package are sterilized, shipped, received at the point of interest, placed in a freezer, and then opened for use, thereby maintaining sterility throughout preparation and shipping prior to treatment.

[0104] In some embodiments, the self-contained cooling device is configured to administer a cryoneuropalsy treatment to provide long-term ocular pain relief. In some embodiments, such a self-contained cooling device is intended for use by a clinician or by a patient in an out-of-clinic setting without the need for a physician. In some embodiments, the self-contained cooling device is used in conjunction with an eyelid protection device to protect the subject's eyelid from damage from the cooling treatment. In some embodiments, the self-contained cooling device is shaped to balance on the subject's eye while the subject is in a supine position.

[0105] In some embodiments, aspects of the present invention relate to self-contained cooling devices capable of maintaining the ocular surface at a temperature below zero. Referring to FIG. 17 , in some embodiments, a self-contained device 700 includes a target (e.g., ocular) surface interface 710 configured to contact a desired portion of the target (e.g., ocular) surface and act as an effective thermal interface capable of efficiently transferring thermal energy from the ocular surface to a thermal mass to cool and maintain the ocular surface at a desired sub-zero temperature for prolonged sensation reduction. In some embodiments in which a thermal mass is used to remove thermal energy from the ocular surface, the device's ocular surface interface 710 acts as a physical barrier between the ocular surface and the thermal mass. In some embodiments, the thermal mass comprises a cold slurry, solid ice, or a liquid formulation. Some of the benefits of such self-contained cooling devices are that the biocompatibility or flowability of the thermal mass (e.g., cold slurry, liquid formulation) is not a concern because the thermal mass does not directly physically contact the ocular surface, which can result in a more streamlined and simplified procedure.

[0106] In some embodiments, the self-contained cooling device includes a formulation chamber or reservoir 720 for holding a thermal mass (e.g., a liquid or slurry formulation), such as the cold slurries described herein, that may have a freezing point lower than that of water. In certain embodiments, the formulation may be a liquid that can be cooled or frozen within the chamber or reservoir 720 of the device prior to use, for example, by placing the entire device containing the formulation or the reservoir or chamber 720 portion of the device inside a standard freezer. As shown in Figures 17A and 17B, the ocular surface interface 710 can either be an integral part of the reservoir or chamber 720 or be attached to the bottom of the reservoir or chamber 720. In such a configuration, thermal energy from the ocular surface is dissipated through the ocular surface interface 710 to the formulation within the chamber or reservoir 720.

[0107] In certain embodiments, the ocular (i.e., target) surface interface 710 is curved (e.g., concave) in shape to better fit the contours of the ocular surface. In some embodiments, the ocular surface interface 710 has an opening or hole (e.g., circular, rectangular, oval, irregularly sized opening) 712 configured to be aligned over the target area of ​​the eye (e.g., the cornea) to prevent direct cooling of the cornea by the cold slurry in the chamber 720 via the ocular surface interface 710.

[0108] In some embodiments, the formulation in chamber 720 utilizes the latent heat (i.e., volume-controlled amount of thermal energy transfer) of a phase change (e.g., solid-liquid phase transformation) to maintain a temperature below 0 on the target ocular surface for a predetermined duration.

[0109] In some embodiments, the ocular (i.e., target) surface interface 710 comprises one or more highly thermally conductive materials, such as Al, Cu, Au, Ni, stainless steel, a metal alloy, a thermally conductive plastic, e.g., a metal-impregnated polyimide, or a combination thereof. In some embodiments, the ocular surface interface 710 comprises one or more encapsulated phase change materials (PCMs), shape-stabilized PCMs, or a combination thereof. In some embodiments, the surface of the ocular surface interface 710 that contacts the ocular surface comprises a non-stick coating, e.g., PTFE, a hard coating, an anodized coating, a diamond-like coating (DLC). In some embodiments, the surface of the ocular surface interface 710 that contacts the ocular surface comprises a hydrophobic surface coating, including nanocoatings and composites. In some embodiments, the surface of the ocular surface interface 710 that contacts the ocular surface comprises a surface coating that protects the ocular surface from adhering to the frozen ocular surface interface 710, e.g., a hard coating, an anodized coating, DLC, a nanocoating, a composite, PTFE, etc. In some embodiments, the surface of the ocular surface interface 710 that contacts the ocular surface comprises geometric design features (e.g., hierarchical micro / nanostructures and surfaces, bio-inspired hydrophobic surface patterns) that protect the ocular surface from adhering to the frozen ocular surface interface 710. In some embodiments, the ocular surface interface 710 that contacts the ocular surface comprises a thin film material.

[0110] In some embodiments, the surface of the ocular surface interface 710 that contacts the ocular surface comprises a hydrophilic surface coating. In some embodiments, the surface of the ocular surface interface 710 that contacts the ocular surface comprises a low surface energy material. In some embodiments, the ocular surface interface 710 comprises an embedded thermoelectric Peltier cooler. In some embodiments, the self-contained cooling device comprises one or more electromechanical systems that circulate coolant (or cool air) through the ocular surface interface 710. In some embodiments, the self-contained cooling device comprises one or more mechanical systems that deliver coolant to the ocular surface interface 710. In some embodiments, the self-contained cooling device comprises one or more mechanical systems that facilitate manual administration of coolant to the ocular surface interface.

[0111] To ensure that the target surface remains at the desired sub-zero temperature during treatment, the ocular surface interface 710 should remain in contact with the portion of the formulation (e.g., frozen or slurry formulation) that is at the desired temperature within the chamber or reservoir 720. In some embodiments, the portion of the slurry or frozen formulation in contact with the ocular surface interface 710 begins to melt as it warms due to the transfer of heat from the ocular surface to the ocular surface interface 710 and then to the formulation within the chamber or reservoir 720. For example, in embodiments where the formulation comprises water, because liquid water is denser than ice, the melted (i.e., liquid, molten) portion of the formulation will tend to settle to the bottom of the chamber or reservoir 720 in contact with the ocular surface interface 710, while the more solid (e.g., ice portion) formulation will tend to float to the top of the chamber or reservoir 720, losing contact with the ocular surface interface 710 and resulting in a reduced ability of the formulation in contact with the ocular surface interface 710 to retain heat.

[0112] In some embodiments, the self-contained cooling device includes a mechanism 730 that pushes down the frozen portion of the formulation within the chamber or reservoir 720 to maintain contact between the colder (e.g., ice or frozen) portion of the formulation and the ocular surface interface 710 in contact with the bottom of the chamber or reservoir 720 by pushing down the formulation and forcing the colder (e.g., ice or frozen) portion of the formulation to the bottom of the chamber or reservoir 720 where it contacts the ocular surface interface 710, causing the warmer (e.g., molten or melted liquid) portion of the formulation, which has a lower heat retention capacity than the colder portion of the formulation, to flow out of the bottom of the chamber or reservoir 720 where it contacts the ocular surface interface 710 toward the top of the chamber or reservoir 720. In some embodiments, the mechanism for depressing the formulation within the chamber or reservoir 720 to maintain contact between the cooler (e.g., ice or frozen) portion of the formulation and the ocular surface interface includes one or more lateral pins 734 that can be pushed into or out of the aforementioned hollow chamber 732 or form the upper portion of the formulation chamber or reservoir 720, an extension spring 736 having two ends operably coupled to or physically attached to the hollow chamber 732 and a removable lid 733 of a movable plate 738 or form the upper portion of the formulation chamber or reservoir 720, and a movable plate 738 that fits within an opening 724 at the top of the formulation chamber or reservoir 720 and contacts or is in proximal proximity to a wall 722 of the formulation chamber or reservoir 720. In some embodiments, the movable plate 738 can slide up and down within the formulation chamber or reservoir 720 while maintaining contact with or in proximal proximity to the interior of the vertical wall 722 of the formulation chamber or reservoir 720. In some embodiments, the sliding plate includes one or more holes to allow the molten liquid to pass through the sliding plate as it moves up and down inside the chamber or reservoir 720.In certain embodiments, when lateral pin 734 is pushed into or pulled from the interior of hollow chamber 732, it releases spring 736, causing movable plate 738 to move downward within formulation chamber or reservoir 720, forcing the cooler (e.g., ice or frozen) portion of formulation toward the bottom of formulation chamber or reservoir 720 and into contact with the ocular surface interface 710 of the device, while the warmer (e.g., molten or melted) portion of formulation is pushed toward the upper portion of formulation chamber or reservoir 720. In some embodiments, the mechanism used to maintain contact between the cooler (e.g., ice or frozen) portion of formulation and the ocular surface interface 710 relies on vacuum, gravity, capillary force, magnetism, or a combination thereof.

[0113] In some embodiments, self-contained cooling device 700 may further include a structure 740 for receiving additional devices or structures, such as an eyelid protection device and / or a corneal protection device described herein. In some embodiments, such a self-contained cooling device further includes an eyelid protection and a corneal protection device. Such a self-contained cooling device may simplify treatment with the cold slurries described herein by reducing the number of devices and associated steps that a clinician assembles / handles and uses during a procedure.

[0114] In some embodiments, the self-contained cooling device includes features (eg, suction, physical location features) that prevent the self-contained device from moving during treatment once it is loaded onto the surface of the eye.

[0115] 18A and 18B, in some embodiments, a self-contained cooling device 800 includes a corneal protection device 850 that is integrated with a structure 840 of the self-contained cooling device 800. Such a self-contained cooling device may be used in conjunction with a corneal protection device to prevent both the cornea and the target ocular surface from coming into direct contact with the cold slurry, for example, while relying on the cold slurry described herein to affect cooling of the target ocular surface.

[0116] In certain embodiments, when self-contained cooling device 800 is placed on the ocular surface such that ocular surface interface 810 is in contact with a desired portion of the ocular surface, corneal protector device 850 contacts the cornea in a manner that prevents the cornea from physical or thermal contact with any exogenous material (e.g., cold slurry). In some embodiments, corneal protector device 840 maintains its position on the cornea when lateral pins 834 are pushed toward hollow chamber 832 to activate mechanism 830, which allows ocular surface interface 810 to remain in contact with the frozen cold slurry and allows liquid slurry to be forced out of ocular surface interface 810.

[0117] In one embodiment, a method for treating ocular surface discomfort using a self-contained cooling device is provided. An exemplary method according to one embodiment of the present disclosure is provided in FIG. 19. First, an anesthetic may be applied to the subject's eye. Then, an accessory (e.g., an eyelid speculum) may be placed to hold the eye open. After the eyelid speculum is placed, the self-contained cooling device is placed. Optionally, the eyelid speculum includes a guide configured to ensure proper placement of the self-contained cooling device. The self-contained cooling device may include holes configured to allow the clinician to view the subject's cornea and to maintain proper device positioning. Once the self-contained cooling device is in contact with the subject's eye, the device is left in contact with the eye for a treatment period (e.g., about 2 minutes to about 10 minutes). After the treatment period, the eye is rinsed (e.g., with saline) to avoid adhesion between the eye and the self-contained cooling device after treatment. After rinsing, the device and eyelid speculum are removed. FIG. 24 provides a chart showing treatment time versus removal time after treatment using a method according to the present disclosure.

[0118] In some embodiments, the self-contained cooling device achieves cooling of the target surface by conduction. In some embodiments, the self-contained cooling device initially contacts the target surface, e.g., the sclera, and conducts heat from the target surface to the device, e.g., the target surface interface and heat exchanger, and finally from the heat exchanger to the thermal mass (e.g., a liquid, solid, or partially solid cold slurry formulation), where the latent heat of fusion (e.g., solid-liquid phase transformation) maintains the therapeutic temperature.

[0119] In some aspects, the self-contained cooling device is left in contact with the eye during the treatment time. In some embodiments, the treatment time is about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In some embodiments, the treatment time is longer than 10 minutes. In some embodiments, the treatment time is about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or longer than about 60 minutes. In certain embodiments, the treatment time is about 1 to about 2 minutes, about 2 to about 3 minutes, about 3 to about 4 minutes, about 4 to about 5 minutes, about 5 to about 6 minutes, about 6 to about 7 minutes, about 7 to about 8 minutes, about 8 to about 9 minutes, about 9 to about 10 minutes, about 2 to about 4 minutes, about 3 to about 5 minutes, about 4 to about 6 minutes, about 5 to about 7 minutes, about 6 to about 8 minutes, about 7 to about 9 minutes, about 8 to about 10 minutes, about 2 to about 5 minutes, about 3 to about 6 minutes, about 4 to about 7 minutes, about 5 to about 8 minutes, about 6 to about 9 minutes, about 7 to about 10 minutes, or about 2 to about 10 minutes. In certain embodiments, the treatment time is about 10 to about 15 minutes, about 15 to about 20 minutes, about 20 to about 25 minutes, about 25 to about 30 minutes, about 30 to about 35 minutes, about 35 to about 40 minutes, about 40 to about 45 minutes, about 45 to about 50 minutes, about 50 to about 55 minutes, or about 55 to about 60 minutes.

[0120] In some aspects, the self-contained cooling device is placed in a cold environment before use. In some embodiments, the cold environment is a standard freezer, a -20°C freezer, a -80°C freezer, an ultra-low temperature ("ULT") freezer, flash freezing (e.g., using liquid nitrogen, etc.), or any other suitable cold environment. In some embodiments, the self-contained cooling device is placed in a standard freezer for at least about 12 hours before use in the methods for treating ocular surface discomfort using a self-contained cooling device provided herein. In some embodiments, the self-contained cooling device is placed in a standard freezer for at least about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours before use in the methods for treating ocular surface discomfort using a self-contained cooling device provided herein.

[0121] In some aspects, the self-contained cooling device is at a predetermined temperature prior to use in the methods provided herein. In some embodiments, the predetermined temperature is a temperature less than 0. In some embodiments, the predetermined temperature is about -20°C to about 0°C. In some embodiments, the predetermined temperature is about -20°C, about -19°C, about -18°C, about -17°C, about -16°C, about -15°C, about -14°C, about -13°C, about -12°C, about -11°C, about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about -5°C, about -4°C, about -3°C, about -2°C, about -1°C, or about 0°C. In one embodiment, the predetermined temperature is about -20°C to about -18°C, about -19°C to about -17°C, about -18°C to about -16°C, about -17°C to about -15°C, about -16°C to about -14°C, about -15°C to about -13°C, about -14°C to about -12°C, about -13°C to about -11°C, about -12°C to about -10°C, about -11°C to about -9°C, about -10°C to about -8°C, about -9°C to about -7°C, about -8°C and about -7°C, about -6°C to about -4°C, about -5°C to about -3°C, about -4°C to about -2°C, about -3°C to about -1°C, or about -2°C to about 0°C.

[0122] In some aspects, when the self-contained cooling device contacts the subject's eye, the eye reaches a therapeutic temperature. In some embodiments, the therapeutic temperature is a temperature below 0°C. In some embodiments, the therapeutic temperature is about -6°C to about 4°C. In some embodiments, the therapeutic temperature is about -6°C. In some embodiments, the therapeutic temperature is about 4°C. In some embodiments, the therapeutic temperature is about -20°C, about -19°C, about -18°C, about -17°C, about -16°C, about -15°C, about -14°C, about -13°C, about -12°C, about -11°C, about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about -5°C, about -4°C, about -3°C, about -2°C, about -1°C, about 0°C, about 1°C, about 2°C, about 3°C, or about 4°C. In certain embodiments, the treatment temperature is about -20°C to about -18°C, about -19°C to about -17°C, about -18°C to about -16°C, about -17°C to about -15°C, about -16°C to about -14°C, about -15°C to about -13°C, about -14°C to about -12°C, about -13°C to about -11°C, about -12°C to about -10°C, about -11°C to about -9°C, about -10°C to about -8°C, about -9°C to about -7°C, about -8°C, and about -7°C, about -6°C to about -4°C, about -5°C to about -3°C, about -4°C to about -2°C, about -3°C to about -1°C, about -2°C to about 0°C, about -1°C to about 1°C, about 0°C to about 2°C, or about 2°C to about 4°C.

[0123] In certain aspects, the methods and devices provided herein achieve rapid temperature reduction after contacting the eye with a self-contained cooling device according to the present disclosure. In some embodiments, the ocular (i.e., target) surface interface of the self-contained cooling device contacts the sclera of the eye, and the sclera reaches a therapeutic temperature (e.g., below 0° C.) after about 30 seconds. In certain embodiments, the sclera is irradiated for about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 60 seconds, about 70 seconds, about 80 seconds, about 90 seconds, about 100 seconds, about 110 seconds, about 120 seconds, about 130 seconds, about 140 seconds, about 150 seconds, about 160 seconds, about 170 seconds, about 180 seconds, about 190 seconds, about 200 seconds, about 210 seconds, about 220 seconds, about 230 seconds, about 240 seconds, about 250 seconds, about 260 seconds, about 270 seconds, about 280 seconds, about 290 seconds, about 300 seconds, about 310 seconds, about 320 seconds, about 330 seconds, about 340 seconds, about 350 seconds, about 360 seconds, about 370 seconds, about 380 seconds, about 390 seconds, about 400 seconds, about 410 seconds, about 420 seconds, about 430 seconds, about 440 seconds, about 450 seconds, about 460 seconds, about 470 seconds, about 480 seconds, about 490 seconds, about 500 seconds, about 510 seconds, about 520 seconds, about 530 seconds, about 540 seconds, about 550 seconds, about 560 seconds, about 570 seconds, about 580 seconds, about 590 seconds, about 600 seconds, about 610 seconds, about 620 seconds, about 630 seconds, about 640 seconds, about 650 seconds, about 660 seconds, about 670 seconds, about 680 seconds The therapeutic temperature (e.g., below 0°C) is reached after about 00 seconds, about 310 seconds, about 320 seconds, about 330 seconds, about 340 seconds, about 350 seconds, about 360 seconds, about 370 seconds, about 380 seconds, about 390 seconds, about 400 seconds, about 410 seconds, about 420 seconds, about 430 seconds, about 440 seconds, about 450 seconds, about 460 seconds, about 470 seconds, about 480 seconds, about 490 seconds, about 500 seconds, about 510 seconds, about 520 seconds, about 530 seconds, about 540 seconds, about 550 seconds, about 560 seconds, about 570 seconds, about 580 seconds, about 590 seconds, or about 600 seconds.

[0124] In some aspects, the self-contained cooling device includes an insulating feature. In some embodiments, the insulating feature is a gap between the housing of the self-contained cooling device and a heat exchanger. In some embodiments, the gap is an air gap. In some embodiments, the gap is filled with an insulating material. Insulating the self-contained cooling device provides benefits by minimizing condensation on the self-contained cooling device, maintaining a desired temperature of the self-contained cooling device including one or more contact surfaces, and / or maintaining the volume of the thermal mass (e.g., within a heat exchanger).

[0125] In certain aspects, the self-contained cooling device is configured to be balanced. A balanced self-contained cooling device can be advantageous because it allows for ease of positioning for the clinician during use.

[0126] 20A and 20B, exploded views of a self-contained cooling device according to the present disclosure are provided. In some embodiments, the self-contained cooling device 900 includes a housing 910 that houses a heat exchanger 920. In some embodiments, the housing 910 includes multiple sections, e.g., a top and bottom section. In some embodiments, the housing 910 includes one or more polycarbonate sections. In some embodiments, the self-contained cooling device includes a gap between the housing 910 and the heat exchanger 920. In some embodiments, the gap provides insulation, e.g., an air gap, for the heat exchanger 920. In some embodiments, the heat exchanger 920 is made of a thermally conductive material. Exemplary thermally conductive materials include, but are not limited to, Al, Cu, Au, Ni, Ag, stainless steel, metal alloys, diamond, thermally conductive plastics, e.g., metal-impregnated polyimide, or combinations thereof. In some embodiments, the heat exchanger 920 includes a cavity, the cavity containing a thermal mass (e.g., a liquid, solid, or partially solid cold slurry formulation). In some embodiments, the thermal mass is contained within the heat exchanger 920. In some embodiments, the thermal mass is frozen in a standard freezer. In some embodiments, the heat exchanger 920 includes a bottom portion and a top portion, which can be separate components that can be joined together. In some embodiments, the thermal mass is sealed within the heat exchanger 920, for example, using an adhesive to join the top and bottom portions after placing the thermal mass within the heat exchanger 920 chamber. In some embodiments, the heat exchanger 920 is formed from a single piece of metal by machining copper. This allows the self-contained cooling device to reach a cold temperature at the surface of the eye very quickly by facilitating heat exchange between the surface of the eye and the heat exchanger 920. In some embodiments, the heat exchanger 920 further includes conductive structures 930 (e.g., fins or walls) for conducting heat from the surface of the eye to the frozen thermal mass. In some embodiments, the self-contained cooling device includes an ocular (i.e., target) surface interface 940 configured to freeze the sclera of the eye upon contact. In some embodiments, the self-contained cooling device includes an ocular (ie, target) surface interface 940 configured to prevent freezing of the sclera of the eye upon contact.In some embodiments, the self-contained cooling device includes a cap 950 configured to prevent condensation on the ocular (ie, target) surface interface prior to use.

[0127] 21A-E, several exterior views of the self-contained cooling device shown in FIGS. 20A and 20B are provided. In some embodiments, the self-contained cooling device includes a housing 910. In some embodiments, the housing 910 includes a grip interface 1020. In some embodiments, the grip interface 1020 is configured to assist the clinician in holding the device, for example, by indicating proper finger placement or making the device easier to hold. In some embodiments, the self-contained cooling device includes holes 1030 configured to provide visibility of the cornea during the procedure. In some embodiments, the self-contained cooling device includes an ocular (i.e., target) surface interface 940 configured to freeze the sclera of the eye upon contact.

[0128] 22A and 22B, diagrams of the self-contained cooling device and accessories provided in FIGS. 20A, 20B, and 21A-E are provided in accordance with the present disclosure. In some embodiments, the self-contained cooling device includes a housing 910, a grip interface 1020, an aperture 1030, and an eye (i.e., target) surface interface 940 configured to freeze the sclera of the eye upon contact. In some embodiments, an appendage 1150 (e.g., an eyelid speculum) is provided, configured to assist in holding the subject's eye open during the procedure and to assist in proper placement of the self-contained cooling device. In further embodiments, the appendage insulates the eyelid from the eye surface interface 940. In some embodiments, the appendage includes a flexible insulating material (e.g., silicone). Diagrams of an accessory according to some embodiments of the present disclosure are provided in FIGS. 23A-D. In some embodiments, the appendage includes an aperture 1230 configured to allow a clinician to view the subject's cornea. In some embodiments, the appendage includes one or more guide features 1235 (e.g., cutouts) configured to assist the clinician in positioning the self-contained cooling device during a procedure. In some embodiments, the appendage includes one or more surfaces 1260 configured to conform to the subject's eyelid to hold the eyelid open during a procedure. In some embodiments, the appendage includes one or more features 1270 configured to push the patient's eyelashes away from the self-contained cooling device. In some embodiments, the appendage further includes an appendage grip interface 1220. In some embodiments, the appendage grip interface 1220 is configured to assist the clinician in proper positioning of the appendage.

[0129] In some embodiments, the self-contained cooling device is reusable. In some embodiments, the self-contained device is disposable.

[0130] 25, the figure illustrates an exemplary treatment area 2500 on a schematic diagram of an eye. In some embodiments, the surface interface 940 of the eye (i.e., the target) is configured to contact the treatment area 2500.

[0131] In certain aspects, a self-contained cooling device can be used in conjunction with the methods for treating ocular surface discomfort provided herein. In certain embodiments, the self-contained cooling device is placed in a cold environment (e.g., a standard freezer) before use, as described herein. In certain embodiments, the self-contained cooling device is placed in a standard freezer for at least 12 hours before use. In certain embodiments, the self-contained cooling device is configured to be used in conjunction with an accessory. For example, the accessory (e.g., an eyelid speculum) can be positioned to hold the subject's eye open. A clinician can place the accessory on the subject's eye, for example, by squeezing the accessory, so that surface 1260 can be placed under the subject's eyelid to hold the eye open while holding the accessory grip interface 1220. After placing the eyelid speculum, the self-contained cooling device is placed. Optionally, feature 1270 can push the patient's eyelashes away from the self-contained cooling device during use. In some embodiments, the accessory (e.g., an eye speculum) includes guide features 1235 configured to ensure proper placement of the self-contained cooling device, for example, a clinician may position the ocular (i.e., target) surface interface 940 of the self-contained cooling device via the guide features 1235. The clinician may then view the patient's eye (e.g., including the cornea of ​​the eye) through the aperture 1030 / 1230 and maintain proper device positioning before contacting the eye with the ocular surface interface 940. Upon contact, the ocular surface interface 940 may adhere to the eye and remain in contact with the eye for a treatment period (e.g., about 2 minutes to about 10 minutes). After the treatment period, steps may be taken to prevent adhesion between the eye and the self-contained cooling device's ocular surface interface 940 after treatment. In some embodiments, the eye is rinsed (e.g., with saline and optionally warm saline or other suitable fluid and optionally warm fluid) to prevent adhesion between the eye and the self-contained cooling device's ocular surface interface 940 after treatment. After rinsing, the self-contained cooling device and accessory are removed from the eye.In some embodiments, the self-contained cooling device is warmed after treatment, for example, by using an electric heating element or system, removing thermal mass, flushing the interior of the device with a fluid and optionally a warm fluid, or by a chemical (exothermic) reaction. In some embodiments, the ocular surface interface 940 or appendage includes one or more channels configured to facilitate rinsing.

[0132] Mechanism of action Without being bound by any theory, the basic premise is that application of temperatures below zero (e.g., about −20°C to about 0°C) stops the signaling of pain stimuli by causing the degeneration of the myelin sheath across the nerve. Myelin is a fatty, lipid-rich substance that rapidly and efficiently transports electrical impulses down nerve axons. By administering cold slurry or other cooling therapy (e.g., using a self-contained cooling device according to the present disclosure) across both the free nerve endings and the myelinated portion of the nerve, the cold temperature freezes or crystallizes the lipid components of adipocytes, inducing apoptosis and degenerating the myelin sheath, a process known as Wallerian degeneration. This process significantly reduces the ciliary nerve's ability to transmit pain stimuli from the cornea to the brainstem. Because not all peripheral nerves are affected due to the thin volume of distal nerve endings on the surface of the eye, not all sensation from the surface of the eye is eliminated, thereby inducing relative hypoesthesia instead of complete numbness. Furthermore, the effects subside after approximately 4-8 weeks, at which point ocular sensation is fully restored. Other options for inducing Wallerian degeneration include radiofrequency ablation and cryoneuropathy (freezing at temperatures reaching -80°C), but these procedures present the risk of damaging surrounding tissues and structures. Furthermore, the inert vehicle containing the ice crystals does not harm other components of the eye, making this a reasonable application for treating nerves that cause pain on the ocular surface. This approach preserves vision and normal function of the ocular surface.

[0133] Without being bound by any particular theory, injection into the subconjunctival space around the limbus distributes the cold slurry around the free nerve endings of the ciliary nerve. Furthermore, local administration or application of cold slurry (e.g., using the self-contained cooling device provided herein) can be used to target the ciliary nerve and its free nerve endings with cold temperatures. There are two main ciliary nerves with free nerve endings that branch off into the cornea of ​​both eyes. Each ciliary nerve is myelinated along its axon and located downstream from its free nerve ending within the cornea. The cold temperature from the cold slurry injection and / or locally applied cold slurry and / or self-contained cooling device spreads downstream to the myelinated axons of the ciliary nerve. As the cold temperature from the cold slurry and / or locally applied cold slurry and / or self-contained cooling device spreads to the axons of the ciliary nerve, it causes crystallization and apoptosis of the myelin sheath, demyelinating the ciliary nerve. Demyelination prevents nerves from transmitting pain signals to the brain. Alternatively, cold slurries and / or cold temperatures from locally applied cold slurries and / or self-contained cooling devices can cause Wallerian degeneration of nerves, which can also prevent pain signals from being transmitted to the brain. Alternatively, cold slurries and / or cold temperatures from locally applied cold slurries and / or self-contained cooling devices can target the free nerve endings of the ciliary nerve.

[0134] Topically applied and / or injected cold slurries or self-contained cooling devices have advantages over other administration methods because they do not damage the surface of the cornea.

[0135] The systems and methods disclosed herein are not limited in scope to the specific embodiments described herein. Indeed, various modifications of the devices, systems, and methods in addition to those described will be apparent to those skilled in the art from the foregoing description. The data described herein support the application of cold slurries (topical and injectable) and self-contained cooling devices as long-term, safe corneal numbing treatments that produce reduced sensation without permanent corneal numbness or damage. [Example]

[0136] Example 1 - In vivo testing of cold slurry treatment for corneal paralysis The results of the studies described in this example can be seen in Figures 5-9. Preclinical animal studies were conducted to determine the efficacy of the treatment, including the best means for delivering the treatment, the duration of the treatment's effect, and to examine any potential side effects. For ocular investigations, New Zealand White rabbits are an ideal model because their cornea and corneal innervation system are very similar to humans, and they are the standard accepted model for corneal testing in the literature.

[0137] Preparation of the procedure The animals were given preanesthesia (rabbit xylazine 1.1 mg / kg IM, buprenorphine HCl 0.01-0.05 mg / kg IM) and pre-surgery antibiotics (cefazolin 25-50 mg / kg IM). The animals were then anesthetized (rabbit ketamine 33 mg / kg IM). The animals were placed on a heating pad and vital signs were monitored. Two drops of proparacaine HCl 0.5% and 5% phenylephrine / 0.5% tropicamide (expanded drops) were administered to the eye to be examined. The animals were subjected to inhalation anesthesia (1.5-2% isoflurane concentration) with O2 supplementation.

[0138] Test Procedure The animals are prepped and draped in the usual sterile fashion, including instillation of povidone-iodide drops onto the surface of the eye, an eyelid speculum is placed, and topical or subconjunctival injection of the slurry is administered.

[0139] Injection To evaluate the sensitivity of ECT-1719, approximately 0.7 mL of cold slurry was injected into the subconjunctival space around the limbus. Due in part to corneal pressure, injection force, and the natural potential space, the injected cold slurry was uniformly distributed 360° around the limbus. The injection procedure was repeated every 120 seconds for a total of 10 minutes.

[0140] Control animals received treatment with sterile saline (control) or vehicle control (uncooled slurry). At the end of the procedure, the eyes were carefully examined, the eye speculum removed, the sterile drape removed, and the eyes washed with sterile saline. There was an additional control group in which conventional anesthetic drops were applied to the cornea. All surgical procedures were performed on the left eye only (for control purposes) and lasted approximately 10 minutes.

[0141] The above surgical procedures are commonly performed in humans with the use of injections of a variety of different medications (eg, steroids, antibiotics, etc.) depending on the condition.

[0142] Topical administration To evaluate the sensitivity-reducing potential of ETX-4143, the slurry was applied topically to the ocular surface, posterior to the limbus. The cornea was protected with a contact lens and the eyelids with a plastic speculum. Approximately 2 mL of cold slurry was applied topically approximately every 30 seconds for the first 4 minutes, then approximately every 2 minutes until a total treatment time of 10 minutes was achieved. At the end of the procedure, the eye was carefully inspected, the speculum removed, the sterile drape removed, and the eye was washed with sterile saline.

[0143] Post-procedures for surviving animals Neomycin / Polymyxin / Bacitracin eye ointment was applied to the operated eye and a few drops of prednisone acetate were applied postoperatively. The animals were removed from the operating table and placed on a heating pad. The animals were monitored for their vital signs (e.g., heart rate, respiration, SPO2) while they recovered. The animals continued to be monitored until muscle control was restored. The animals were returned to their home cages.

[0144] Post-surgical animal monitoring Animals underwent comprehensive eye examinations, including corneal sensation measurements, one day after surgery and weekly thereafter. Intraocular pressure measurements were also performed if beneficial reductions in intraocular pressure could be observed in treated animals. Additionally, slit lamp examinations using fluorescein staining and dilated fundus examinations (i.e., the eyes were dilated with 5% phenylephrine and 0.5% tropicamide) were performed. The animals were placed in a restrictive cage for a few seconds while eye drops were applied one at a time.

[0145] Effect of administration Several techniques were used to test the effect of cold slurry administration.

[0146] The paralytic effect of the cold slurry was tested using an anesthesiometer. A filament with a specific stiffness was stretched from the device. Animals treated with the cold slurry were able to withstand a stronger force from the anesthesiometer than animals in the control group. This was indicated by whether the animals recoiled when the eye was poked with the anesthesiometer filament. The test was performed multiple times over the course of the test to determine the duration of the paralytic effect.

[0147] The effect of the cold slurry on the eye's ability to heal was also examined. Epithelial defects were created in the cornea using a trephine and corneal brush. The wound was verified by fluorescein staining and photo-documented. Fluorescein staining was used to measure wound size and wound progression. The cold slurry did not affect the eye's ability to heal.

[0148] Example 2 - In vitro testing of a self-contained cooling device treatment for corneal paralysis The results of the studies described in this example can be seen in Figures 26, 27 and 28. Preclinical studies using animal studies were conducted to determine the thermal effects of the self-contained cooling devices according to the present disclosure.

[0149] Referring to Figure 26, a pig eye surface was used in this example to generate a representative temperature profile of the temperature taken from the surface of a pig eye. The pig eye was contacted with the ocular surface interface of a self-contained cooling device according to the present disclosure. In this example, the ocular surface interface was a copper ocular surface interface coupled with a heat exchanger to form one piece, and the self-contained cooling device included a thermal mass comprising 20% ​​by weight glycerol in purified water. The temperature of the pig eye was measured over time and is shown in Figure 26. As shown in Figure 26, the temperature reached 0°C after 29 seconds. A minimum temperature of -3.5°C was recorded. Finally, after 536 seconds (8 minutes 56 seconds), the temperature rose above 0°C again.

[0150] Temperature measurements were also taken from the pig's eye at three locations, as shown in Figure 27 and described below. The pig's eye was partially immersed in a water bath, and the eye was heated to a representative surface temperature of approximately 33°C. Temperature was monitored at three locations as shown in Figure 27: location 1 (located 0° from horizontal and 1.5 mm from treatment area 2500); location 2 (located 45° from horizontal and 1.5 mm from treatment area 2500) and below treatment area 2500.

[0151] As described above with respect to Figure 26, a pig's eye was contacted with the self-contained cooling device and measurements were recorded over time. As shown in Figure 28, the temperature under the treatment area 2500 reached 0°C after 29 seconds and rose above 0°C again after 536 seconds (8 minutes 58 seconds). A representative temperature profile under the treatment area 2500 shown in Figure 26 is also shown in Figure 28. Temperatures were also recorded at Position 1 (located 0° from horizontal and 1.5 mm from the treatment area 2500) and Position 2 (located 45° from horizontal and 1.5 mm from the treatment area 2500). Results showed that Position 1 reached a lower temperature than Position 2.

[0152] Example 3 - In vivo testing of a self-contained cooling device treatment for corneal paralysis The results of the studies described in this example can be seen in Figure 29. Preclinical studies using animal studies were conducted to determine the effectiveness of treatment using the self-contained cooling device, including examining its ability to cool the eye, and evaluating its effect on numbing / anesthetizing the corneal surface, the duration of the treatment effect, and any potential side effects. As shown in Example 1, for ocular research, the New Zealand White rabbit is an ideal model because its cornea and corneal innervation system are very similar to humans, and it is the standard accepted model for corneal testing in the literature.

[0153] Self-contained cooling device The self-contained cooling device was designed for use in treating rabbit eyes similar to that in humans. The self-contained cooling device contained a thermocouple embedded in the ocular contact surface to measure the ocular surface temperature during the procedure. The device was designed to contact and treat the rabbit eye at 200° (220° total, minus a 20° gap), specifically treating the portion of the sclera just outside the cornea. Previous testing showed that it was difficult to treat the entire periphery of the cornea in this model. The contact surface (copper) was protected from the rabbit's eyelids. The contact surface was configured to conduct heat directly to the device's chamber, which was filled with ice with a depressed freezing point. In this example, the ice was a mixture of purified water and glycerol (20% wt / wt). Prior to use, the device was placed in a freezer set at -20°C for at least 12 hours, or alternatively, at -27°C for 2 hours and -20°C for at least 2 hours (4-hour freezer).

[0154] Self-Contained Cooling Device Procedure Prior to anesthesia, a corneal sensitivity test was performed. Subjects were anesthetized in a standard manner consistent with approved IACUC protocols. Topical proparacaine was administered to both the treatment and control eyes. The subject's eyelids were opened, and the cornea and lid speculum were used to expose as much of the sclera as possible. If necessary, a corneal protector device (contact lens suction device) was placed by suctioning the cornea. When using the device, the cornea was centered between the two contact surfaces. The device was positioned to cover approximately 240° of the scleral surface around the cornea, and care was taken to ensure minimal interference with the subject's eyelids. Contact between the device and the eye was maintained for 10 minutes. At the end of the contact period, the eye and device were rinsed with warm water or saline, and the device was removed from the eye.

[0155] Post-procedure monitoring After the procedure, subjects were monitored for one week for general health. One week after the procedure and weekly thereafter (+ / - 3 days), subjects also underwent a comprehensive eye examination, which included corneal sensitivity testing using an aesthesiometer and intraocular pressure ("IOP") measurement.

[0156] Effect of self-contained cooling device procedures The rabbits showed a significant reduction in sensation compared to their respective untreated eyes, with an average reduction of approximately 75% at week 1 and 63% at week 2. See Figure 29. The greatest reduction in sensation was measured near one week after treatment, with five of eight rabbits showing a greater than 85% reduction in sensation compared to the control eye. No adverse effects were observed as a result of the treatment.

Claims

1. Water; and Freezing point depressants 1. A cold slurry formulation for relieving symptoms of ocular surface discomfort, comprising: A cold slurry formulation, wherein ocular sensation in the eye is restored following application of the cold slurry to the targeted ocular surface.

2. 10. The cold slurry formulation of claim 1, further comprising a lipid.

3. 3. The formulation of claim 1 or 2, wherein the freezing point depressant is at a concentration of about 10% to 40% (v / v).

4. 4. The formulation of claim 2 or 3, wherein the lipid is at a concentration of about 0.1% to 10%, 10% to 20%, 20% to 30%, or 30% to 45% (v / v).

5. 5. The formulation of claim 1, wherein the freezing point depressant is at a concentration of about 10% to 20%, 20% to 30%, or 30% to 40% (v / v).

6. 6. The formulation of claim 2, 3 or 5, wherein the lipid is at a concentration of about 15% to 45% (v / v).

7. 7. The formulation of any one of claims 1 or 4-6, wherein the freezing point depressant is at a concentration of about 10% to 25% (v / v).

8. 1. A method of relieving symptoms of ocular surface discomfort, comprising applying a cold slurry formulation to a patient's ocular surface adjacent the limbus, the cold slurry formulation comprises water and a freezing point depressant; A method wherein application of the cold slurry formulation is configured to cause a degree of numbness of the cornea of ​​the eye, and ocular sensation in the eye is restored following application of the cold slurry to the targeted ocular surface.

9. 10. The method of claim 8, wherein the cold slurry formulation further comprises a lipid.

10. 9. The method of claim 8, wherein the cold slurry formulation is applied posterior to the limbus.

11. 11. The method of any of claims 8 to 10, wherein the cold slurry remains on the surface of the eye for more than about 4 hours without further applications of the cold slurry formulation on any day after the first day of application.

12. 12. The method of any one of claims 8 to 11, wherein the freezing point depressant is glycerol.

13. 13. The method of any one of claims 9 to 12, wherein the lipid comprises soybean phosphatidylcholine (soybean-PC).

14. 13. The method of any one of claims 9 to 12, wherein the lipid comprises a fatty acid selected from the group consisting of stearic acid, palmitic acid, lauric acid, and myristic acid, and combinations thereof.

15. The method of any one of claims 8 to 14, wherein the cold slurry formulation further comprises hyaluronic acid.

16. 16. The method of any one of claims 8 to 15, wherein the cold slurry formulation further comprises a poloxamer.

17. 17. The method of any one of claims 8 to 16, wherein ocular sensation in the eye is restored about 21 days after application of the cold slurry formulation.

18. 18. The method of any one of claims 8 to 17, wherein the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C during application of the cold slurry.

19. 19. The method of any one of claims 8 to 18, wherein the cold slurry is applied for about 2 minutes to about 15 minutes.

20. 20. The method of any one of claims 7 to 19, wherein a further amount of cold slurry is reapplied about 90 seconds after the first application.

21. 21. The method of any one of claims 8 to 20, wherein the application is topical.

22. 21. The method of any one of claims 8 to 20, wherein the application is via injection.

23. 1. A device for protecting a cornea on a surface of an eye, comprising a structure configured to adhere to a surface of an eye via the formation of a vacuum, the structure comprising: a containment wall having an inner surface, an outer surface, and an open surface, the containment wall extending from a first end to a second end, the inner surface defining an interior cavity; A device wherein the open surface is configured to contact and surround the circumference of the cornea, and wherein a vacuum is formed within the internal cavity when the structure is activated.

24. 24. The device of claim 23, wherein adhesion of the structure to the surface of the eye substantially seals the cornea within the open surface of the containment wall.

25. 25. The device of claim 23 or 24, wherein the structure comprises a suction cup.

26. 26. The device of any one of claims 23 to 25, wherein the containment wall comprises a non-porous material with low thermal conductivity selected from the group consisting of polymers, polyvinyl chloride (PVC), neoprene, polyethylene (PE), polytetrafluoroethylene (PTFE), silicone, thermoplastic elastomers (TPU), thermoplastic polyurethanes (TPE), and combinations thereof.

27. 27. The device of any one of claims 23 to 26, wherein the containment wall comprises a thermal insulating material selected from the group consisting of polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, and combinations thereof.

28. The device of any one of claims 23 to 27, wherein the containment walls comprise an optically transparent or translucent material.

29. The device of any one of claims 23 to 28, wherein the containment walls comprise an optically opaque material.

30. 30. The device of any one of claims 23 to 29, wherein the structure is activated by contracting the internal cavity and then releasing the contraction of the internal cavity.

31. A device according to any one of claims 23 to 30, wherein the structure is activated by squeezing the containment wall and then releasing the containment wall.

32. A device according to any one of claims 23 to 31, wherein the vacuum is a partial vacuum.

33. a) placing a corneal protection device comprising an internal cavity onto the cornea of ​​a subject; b) contracting and releasing a portion of the corneal protection device to create a vacuum within the interior cavity; and c) Adhering the corneal protection device to the surface of the eye 1. A method for protecting a cornea on an eye surface of a subject, comprising: The method, wherein the corneal protection device includes a containment wall having an inner surface, an outer surface, and an open surface, the containment wall extending from a first end to a second end, the inner surface forming an interior cavity.

34. 34. The method of claim 33, further comprising administering a cold slurry formulation to the surface of the eye.

35. 35. The method of claim 34, wherein the corneal protection device is configured to physically and thermally protect the cornea from the cold slurry formulation.

36. The method of any one of claims 33 to 35, wherein creating a vacuum within the interior cavity of the corneal protection device comprises squeezing the corneal protection device.

37. The method of any one of claims 33 to 36, wherein the vacuum is a partial vacuum.

38. a first surface configured to contact the upper eyelid; and a second surface configured to contact the lower eyelid.

1. A device for protecting an eyelid of a subject, comprising: the first surface and the second surface are configured to reversibly bond with each other to create an opening between the first surface and the second surface; A device that, when inserted into the top of the eye, prevents the upper and lower eyelids from closing and protects the eyelids by physically and thermally isolating the eyelids from the surface of the eye or materials placed on the surface of the eye.

39. 40. The device of claim 38, further comprising a channel in one or more of the first and second surfaces, the channel configured to allow fluid to escape from the surface of the eye when the device is inserted into the top of the eye.

40. 40. The device of claim 38 or 39, further comprising a platform on one or more of the first and second surfaces configured to facilitate handling and manipulation of the device.

41. the first surface comprises a first end and a second end, the second surface comprises a first end and a second end; 41. The device of any one of claims 38 to 40, wherein a first end of the first surface is attached to a first end of the second surface and a second end of the first surface is attached to a second end of the second surface.

42. The device of any one of claims 38 to 41, wherein the first surface and the second surface are curved in shape.

43. 43. The device of any one of claims 38 to 42, wherein one or more of the first surface and the second surface are arcuate.

44. 44. The device of any one of claims 38 to 43, wherein the first surface and the second surface are of adjustable size.

45. 45. The device of any one of claims 38 to 44, wherein the first surface and the second surface are adjustable relative to each other to adjust the size of the aperture.

46. 46. ​​The device of any one of claims 38 to 45, wherein the first surface and the second surface are separate components of the device that can be assembled to form the device.

47. 47. A device according to any one of claims 38 to 46, wherein one or more of the first surface and second surface comprise connecting segments of a curve that can be connected relative to one another to adjust the size of the aperture.

48. 48. The device of any one of claims 38 to 47, wherein one or more distances across the opening between the first and second surfaces can be adjusted to accommodate eyelids and eyes of various shapes and sizes.

49. 49. The device of any one of claims 38 to 48, comprising one or more plastics.

50. 50. The device of any one of claims 38 to 49, comprising one or more porous materials.

51. 51. The device of claim 50, wherein the one or more porous materials comprise a thermal insulating material selected from the group consisting of polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, and combinations thereof.

52. 52. The device of any one of claims 38 to 51, wherein one or more of the first surface and second surface comprises a thermal insulating material and a wicking material.

53. 53. The device of claim 52, wherein the wicking material is selected from the group consisting of PVA, open cell foam material, and combinations thereof.

54. 54. The device of any one of claims 38 to 53, further comprising a receiving structure configured to receive a corneal protection device.

55. Corneal protection devices: a structure configured to adhere to a surface of an eye via the formation of a vacuum, the structure comprising: a containment wall having an inner surface, an outer surface, and an open surface, the containment wall extending from a first end to a second end, the inner surface defining an interior cavity; 55. The device of claim 54, wherein the open surface is configured to contact and circumferentially surround the cornea, and wherein a vacuum is created within the interior cavity when the structure is activated.

56. 56. The device of claim 54 or 55, wherein the receiving structure is positioned in the opening of the device such that when the device is inserted into the top of the eye, the receiving structure is positioned substantially above the cornea.

57. 57. The device of any of claims 54 to 56, wherein the receiving structure comprises a substantially circular shape and is attached to the first surface and the second surface.

58. 58. A device according to any one of claims 54 to 57, configured to protect both the eyelid and the cornea.

59. 59. The device of any one of claims 38 to 58, further comprising one or more structures configured to act as an eyelid speculum to hold the eyelid open while the device is inserted into the eye.

60. inserting an eyelid protection device into the top of the subject's eye; contacting a first surface of the eyelid protector device around the contour of the upper eyelid; contacting the second surface of the eyelid protector device around the contour of the lower eyelid; 1. A method for protecting the upper and lower eyelids of a subject, comprising: the first surface and the second surface are configured to mate with one another to create an opening between the first surface and the second surface; A method in which the device, when inserted into the top of the eye, protects the eyelids by preventing the upper and lower eyelids from closing and physically and thermally isolating the eyelids from the surface of the eye or materials placed on the surface of the eye.

61. 61. The method of claim 60, further comprising administering a cold slurry formulation to the ocular surface.

62. 62. The method of claim 61, wherein the cold slurry formulation comprises water and a freezing point depressant.

63. 63. The method of claim 62, wherein the cold slurry formulation further comprises a lipid.

64. one or more syringes containing the cold slurry formulation; and Package containing multiple syringes wherein the package is configured to store, seal, and provide heat and humidity protection for one or more syringes.

65. 65. The kit of claim 64, comprising at least two syringes containing the cold slurry formulation.

66. 66. The kit of claim 64 or 65, comprising 2 to 20, 2 to 15, 2 to 10, or 2 to 5 syringes.

67. 67. The kit of any one of claims 64 to 66, wherein one or more of the syringes containing the cold slurry formulation contains about 1 to 20 ml of the cold slurry formulation.

68. 68. The kit of any one of claims 64 to 67, wherein the package comprises a phase change material, a thermal insulator, a reflective barrier, or a combination thereof.

69. 69. The kit of any of claims 64-68, wherein the package is configured to protect the one or more syringes against contamination, temperature changes, environmental exposure, or a combination thereof.

70. 70. The kit of any one of claims 64 to 69, wherein the cold slurry formulation comprises water and a freezing point depressant.

71. 71. The kit of any one of claims 64 to 70, wherein the cold slurry formulation further comprises a lipid.

72. one or more syringes; a first package enclosing one or more syringes; a container containing the cold slurry formulation; and a second package enclosing one or more syringes and a container; wherein a second package is configured to store and seal one or more syringes and containers and provide heat and humidity protection therefor.

73. 73. The kit of claim 72, wherein the cold slurry formulation comprises water and a freezing point depressant.

74. 74. The kit of claim 73, wherein the cold slurry formulation further comprises a lipid.

75. a formulation chamber comprising a hollow chamber having an open end and a closed end, wherein the formulation chamber is configured to receive and hold a cold slurry formulation; a removable lid configured to fit over and seal the open end of the formulation chamber; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target tissue surface and the second surface is configured to form or contact a closed end of the formulation chamber; 1. A self-contained cooling device for cooling a target tissue surface, comprising:

76. A self-contained cooling device further comprising a movable plate disposed within the formulation chamber, when the movable plate is advanced within the formulation chamber toward the closed end of the formulation chamber, a liquid phase of the cold slurry formulation is removed from the closed end of the formulation chamber and replaced with a substantially non-liquid phase of the cold slurry formulation; 76. The self-contained cooling device of claim 75, wherein the movable plate is disposed within the formulation chamber and has a size smaller than the open end of the formulation chamber.

77. a force spring having a first end and a second end, wherein the first end is operably connected to the movable plate and the second end is operably connected to the removable lid; and one or more lateral pins operably coupled to the hollow chamber; A self-contained cooling device further comprising:

77. A self-contained cooling device as described in any one of claims 74 to 76, wherein the one or more lateral pins are configured to, when depressed, extend a first end of the force spring beyond its original length to allow the movable plate to advance within the formulation chamber toward the closed end of the formulation chamber.

78. the target surface interface is configured to contact the surface of the eye; 78. A self-contained cooling device according to any one of claims 74 to 77, wherein the self-contained cooling device is configured to maintain the surface of the eye at a temperature suitable to alleviate discomfort to the surface of the eye.

79. 79. The self-contained cooling device of any one of claims 74 to 78, wherein the formulation chamber is configured to receive a cold slurry formulation of any one of claims 1 to 6.

80. 80. The self-contained cooling device of any one of claims 74 to 79, wherein the target surface interface is structurally integrated with the formulation chamber.

81. 81. The self-contained cooling device of any one of claims 78 to 80, wherein the target surface interface is configured to contact the sclera of the surface of the eye.

82. 82. A self-contained cooling device as described in any one of claims 78 to 81, wherein the target surface interface includes an opening configured to conform to the cornea of ​​the surface of the eye to avoid contact between the target surface interface and the cornea when the target surface interface contacts the surface of the eye.

83. 83. The self-contained cooling device of any one of claims 74 to 82, wherein the target surface interface is configured to allow thermal energy transfer from the target surface interface to the formulation chamber.

84. 84. The self-contained cooling device of any one of claims 74 to 83, wherein the target surface interface is configured to promote uniform cooling of the target tissue surface when the formulation chamber is filled with the cold slurry formulation.

85. 85. The self-contained cooling device of any one of claims 82 to 84, wherein the opening in the target surface interface is configured to receive a corneal protection device.

86. The self-contained cooling device of claim 85, wherein the corneal protection device is a device according to any one of claims 23 to 32.

87. 87. The self-contained cooling device of claim 85 or 86, wherein the corneal protection device is positioned within the opening of the ocular surface interface and configured to physically and thermally protect the cornea when the ocular surface interface contacts the surface of the eye.

88. 88. The self-contained cooling device of any one of claims 77 to 87, wherein the force spring is an extension spring, a torsion spring, or a combination thereof.

89. 89. The self-contained cooling device of any of claims 74-88, wherein the target surface interface comprises a thermally conductive material selected from the group consisting of Al, Cu, stainless steel, metal alloys, and combinations thereof.

90. 90. The self-contained cooling device of any one of claims 74 to 89, wherein the target surface interface comprises one or more encapsulated phase change materials (PCMs), shape-stabilized PCMs, or combinations thereof.

91. 91. The self-contained device of any one of claims 74 to 90, wherein the first surface of the target surface interface comprises a non-stick coating.

92. 92. The self-contained device of claim 91, wherein the non-tacky coating is PTFE.

93. 93. The self-contained cooling device of any one of claims 74 to 92, wherein the first surface of the target surface interface comprises a hydrophobic coating.

94. 94. The self-contained cooling device of any one of claims 74 to 93, wherein the first surface of the target-surface interface comprises a surface coating that protects the target tissue from adhering to the target-surface interface.

95. 95. The self-contained cooling device of any one of claims 74 to 94, wherein the first surface of the target surface interface comprises geometric design features that protect the target tissue from adhering to the target surface interface.

96. 96. The self-contained cooling device of claim 95, wherein the geometric design features include one or more of a hierarchical microstructure, a hierarchical nanostructure, a bio-inspired surface pattern, or a combination thereof.

97. 97. The self-contained cooling device of any one of claims 74 to 96, wherein the first surface of the target surface interface comprises a hydrophilic surface coating.

98. 98. The self-contained cooling device of any one of claims 74 to 97, wherein the first surface of the target surface interface comprises a low surface energy material.

99. 99. The self-contained cooling device of any one of claims 74 to 98, wherein the target surface interface comprises an embedded thermoelectric Peltier cooler.

100. 100. The self-contained cooling device of any one of claims 74 to 99, wherein the target surface interface comprises a thin film of material.

101. Placing the self-contained cooling device on the surface of the target eye.

1. A method for relieving symptoms of ocular surface discomfort, comprising: A self-contained cooling device: a formulation chamber comprising a hollow chamber having an open end and a closed end, wherein the formulation chamber is configured to receive and hold a cold slurry formulation; a removable lid configured to fit over and seal the open end of the formulation chamber; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target ocular surface and the second surface is configured to form or be attached to a closed end of the formulation chamber; A method comprising:

102. 102. The method of claim 101, wherein the cold slurry formulation comprises water and a freezing point depressant.

103. 103. The method of claim 102, wherein the cold slurry formulation further comprises a lipid.

104. the self-contained cooling device further comprises a movable plate disposed within the formulation chamber; when the movable plate advances within the formulation chamber toward the closed end of the formulation chamber, a liquid phase of the cold slurry formulation is removed from the closed end of the formulation chamber and replaced with a substantially non-liquid phase of the cold slurry formulation; 104. The method of any one of claims 101 to 103, wherein the movable plate is disposed within the formulation chamber and has a size smaller than the open end of the formulation chamber.

105. 105. The method of claim 104, further comprising advancing a movable plate of a self-contained cooling device disposed within the formulation chamber to a closed end of the formulation chamber.

106. A self-contained cooling device: a force spring having a first end and a second end, wherein the first end is operably connected to the movable plate and the second end is operably connected to the removable lid; and one or more lateral pins operably coupled to the hollow chamber; further comprising 106. The method of claim 104 or 105, wherein the one or more lateral pins are configured to, when depressed, extend a first end of the force spring beyond its original length to allow the movable plate to advance within the formulation chamber toward the closed end of the formulation chamber.

107. The method of claim 106, further comprising depressing one or more lateral pins of a self-contained device operably connected to the hollow chamber to extend a first end of the force spring beyond its original length and advance the movable plate within the formulation chamber toward the closed end of the formulation chamber.

108. housing; a heat exchanger, wherein the heat exchanger comprises a formulation chamber configured to receive and hold a formulation, the formulation being configured to be frozen to a temperature below zero in a cold environment; a hole, wherein the hole is configured to allow a clinician to view the subject's cornea; a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact a target tissue surface and the second surface is configured to form or contact a formulation chamber; 1. A self-contained cooling device for cooling a target tissue surface, comprising:

109. 109. The self-contained cooling device of claim 108, wherein the cold environment is a standard freezer.

110. 109. The self-contained cooling device of claim 108, wherein the formulation comprises water and a freezing point depressant.

111. 111. The self-contained cooling device of claim 110, wherein the freezing point depressant is at a concentration of about 20% (wt / wt).

112. 112. The self-contained cooling device of claim 111, wherein the freezing point depressant is glycerol.

113. 109. The self-contained cooling device of claim 108, wherein the first surface is configured to adhere to the target tissue surface upon contact.

114. 109. The self-contained cooling device of claim 108, wherein the target surface comprises the sclera.

115. 115. The self-contained cooling device of claim 114, wherein the sclera is adjacent to the limbus.

116. 109. The self-contained cooling device of claim 108, wherein the temperature below 0 is from about -20°C to about 0°C.

117. 109. The self-contained cooling device of claim 108, wherein the target surface interface comprises copper.

118. 118. A self-contained cooling device according to any one of claims 108 to 117, configured to receive an attachment.

119. 119. The self-contained cooling device of claim 118, wherein the attachment is an eyelid speculum.

120. 119. The self-contained cooling device of claim 118, wherein the appendage is configured to hold the subject's eye open during the procedure.

121. 121. The self-contained cooling device of any one of claims 118 to 120, wherein the attachment is configured to protect the subject's eyelid from temperatures below 0 during the procedure.

122. 122. The self-contained cooling device of claim 121, wherein the appendage comprises silicone.

123. 123. The self-contained cooling device of any one of claims 108 to 122, wherein the self-contained cooling device is further configured to receive a cap, the cap configured to prevent condensation from forming on the target surface interface prior to the procedure.

124. Positioning the self-contained cooling device over the target ocular surface.

1. A method for relieving symptoms of ocular surface discomfort, comprising: A self-contained cooling device: housing; a heat exchanger, wherein the heat exchanger comprises a formulation chamber configured to receive and hold a formulation, the formulation being configured to be frozen to a temperature below zero in a standard freezer; a hole, wherein the hole is configured to allow a clinician to view the subject's cornea; a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target tissue surface and the second surface is configured to form or contact a formulation chamber; A method comprising:

125. 125. The method of claim 124, wherein the self-contained cooling device is configured to receive an appendage, the appendage being configured to be positioned adjacent to the surface of the target eye and to prevent the subject's eye from closing.

126. 126. The method of claim 125, wherein the attachment is configured to protect the subject's eyelid from temperatures below 0 during the procedure.

127. 125. The method of claim 124, wherein the target surface comprises the sclera.

128. 128. The method of claim 127, wherein the sclera is adjacent to the limbus.

129. 125. The method of claim 124, wherein the formulation comprises water and a freezing point depressant.

130. 130. The method of claim 129, wherein the freezing point depressant is glycerol.

131. 125. The method of claim 124, wherein the temperature below 0 is from about -20°C to about 0°C.

132. 125. The method of claim 124, wherein the target surface interface comprises copper.

133. 133. The method of any of claims 124-132, wherein the target surface interface is configured to adhere to the target surface upon contact.

134. 134. The method of claim 133, wherein the target surface interface is configured to be separated from the target surface after a treatment period.

135. 135. The method of claim 134, wherein the treatment time is from about 2 minutes to about 10 minutes.

136. 136. The method of any of claims 133 to 135, further comprising rinsing the target tissue surface with the liquid formulation prior to removing the target surface interface from the target tissue surface.

137. 137. The method of claim 136, wherein the liquid formulation comprises saline.

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