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

Abstract

Disclosed herein are cold slurry formulations, devices, and methods for reducing symptoms of ocular surface discomfort. Cold slurry formulations containing ice, a freezing temperature reducing agent, and optionally a lipid are disclosed. Disclosed are devices and methods for protecting a target ocular surface from contact with a cold slurry formulation for maintaining the target ocular surface at a temperature desired to alleviate symptoms of ocular surface discomfort. A stand-alone device configured to receive a cold slurry formulation for maintaining a target ocular surface at a temperature desired to alleviate symptoms of ocular surface discomfort is disclosed. Devices and methods for protecting the cornea and / or eyelids of a subject from frozen cold plasma formulations applied or injected directly or indirectly to the target ocular surface are disclosed. A kit containing a plurality of syringes for applying multiple doses of cold slurry to a target ocular surface is disclosed.

Description

Technical Field

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

[0002] This invention generally relates to apparatus, systems, and methods for generating and applying biological materials such as cold slurry. More particularly, this invention relates to apparatus, systems, and methods for treating ocular surface discomfort by safely and effectively lowering the ocular surface temperature of a subject to a sufficiently low temperature for a duration sufficient to cause decreased or reduced ocular sensation. Background Technology

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

[0004] The cornea is innervated by the brainstem, where the large sensory root branches from the pons and attaches to the trigeminal nucleus caudalis, located in the lateral part of the medulla. From the trigeminal nucleus caudalis, the trigeminal nerve branches into three branches, one of which is an ophthalmic branch. This root further divides into three branches, one of which extends and is called the nasociliary nerve. This purely sensory nerve travels along the upper part of the orbit and contributes smaller branches to the cornea. Two types of branches from this nerve are called the short ciliary nerves and the long ciliary nerves. The short ciliary nerve enters the ciliary ganglion through the sensory root, then leaves the nucleus to pierce the sclera and enter the perchoroidal space, where it can enter the cornea. Belmonte, C., Tervo, TT, & Gallar, J. (2011), CHAPTER 16 - Sensory Innervation of the Eye, Adler's Physiology of the Eye (11th ed., pp. 363-384), Elsevier Inc.

[0005] The perchoroidal space lies between the sclera (the outermost layer of the eyeball) and the choroid (a vascularized layer responsible for supplying nutrients to the eye structures). Approximately 8 to 10 short ciliary nerves pierce the sclera, but once inside the perchoroidal space, they branch into about 15 to 20 branches. Regarding long ciliary nerves, more than 50 branches pierce the sclera and further divide within the perchoroidal space. At the limbus, the junction of the sclera and cornea, the nerves lose their myelin sheath and continue as free nerve endings. The nerves collect sensory signals from the cornea and transmit them posteriorly to the brainstem. (Belmonte, C., Tervo, TT, & Gallar, J. (2011). CHAPTER 16 - Sensory Innervation of the Eye, Adler's Physiology of the Eye (11th ed., pp. 363-384), Elsevier Inc.) Not all the details of corneal nerve innervation are fully understood, and they can vary from patient to patient. Some normal anatomical variations in other nerve fibers or nerve innervation pathways may contribute to this understanding.

[0006] Free nerve endings located beneath the corneal epithelium (the anterior layer protecting the corneal structure) often cause painful eye sensations. When patients are troubled by these symptoms, the condition is called dry eye syndrome (DES), also known as ocular surface disease (OSD). The causes of this condition are multifaceted. A significant cause is insufficient production of aqueous tears, leading to a lack of hydration and lubrication of the eye. 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 input may have significant consequences for both the regulation of tearing and ocular pain." (McMonnies, CW, The potential role of neuropathic mechanisms in dryeye syndromes, Journal of Optometry, 10, 5‒13 (2017)). Importantly, some patients continue to experience ocular surface pain even after their ocular surface has recovered to a clinically normal appearance. This condition presents a clinical challenge because its cause is believed to be persistent somatosensory dysfunction of corneal innervation following the initial damage to the stimulating nerves.

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

[0009] There are three different types of nociceptive receptors that innervate the cornea. Twenty percent of corneal nociceptors are Aδ mechanoreceptors, responsible for rapidly transmitting sharp, painful stimuli caused by deterioration of the ocular surface. Seventy percent of corneal nociceptors are polysensory receptors, which are stimulated by corneal nerve damage and cause neuropathic pain and “reflexive tearing”. (Levitt, AE, et al., Chronicdry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders, Molecular Pain, 11:21 (2015)). The final ten percent of corneal nociceptors are C-fiber cold receptors, which play a crucial role in maintaining basal tear secretion. These receptors are highly sensitive to temperature changes within the corneal tissue, and LASIK surgery can cause tear evaporation at the tear film surface, lowering the temperature by approximately 0.3 degrees Celsius per second, thus affecting C-fiber signaling. (Levitt et al., 2015)

[0010] Many mechanisms, including dryness, prior surgery, meibomian gland dysfunction, or prior chemical irritation, can lead to a clinical syndrome of OSD, marked by signs and characteristics of ocular irritation such as dryness, burning, or discomfort. Even after the initial damage to this mechanism has been addressed and the normal lubrication of the eye has been restored, patients may still report significant symptoms of ocular surface discomfort, despite their ocular surface showing only minimal signs of disease indicating components that cause hypersensitivity or abnormal pain. In fact, the reference states that "the status of the ocular surface alone is not sufficient to understand dry eye and that corneal somatosensory function…must be considered when evaluating a patient 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 dilemma for treating physicians—patients have residual pain and discomfort, but the ocular surface appears normal (corneal somatosensory dysfunction). As expected, additional lubrication and other treatments aimed at improving the ocular surface are no longer helpful for these patients.

[0011] Current treatments for eye pain are limited, offer only temporary relief, or are associated with adverse side effects. This includes eye pain related to dry eye syndrome / ocular surface disease, PRK or LASIK surgery, or corneal somatosensory dysfunction. Dry eye syndrome is most commonly treated with warm compresses, over-the-counter artificial tears, or prescription eye drops, aimed at improving tear production or reducing inflammation. Physicians may also recommend topical ocular lubricants, hygiene products that remove debris from under the eyelids. These methods work by softening meibum (an oily, lipid-rich secretion from the meibomian glands) to help distribute tear production across the cornea. The limitations of these treatments are short-term relief and the need for continuous use. Lubricants or artificial tears relieve irritation but do not actually address the underlying cause of dry eye and can even lead to increased debris buildup under the eyelids. Shen Lee, B., et al., Managing dry eye disease and facilitating realistic patient expectations: Areview and appraisal of current therapies, Clinical Ophthalmology, 14 119–126 (January 2020).

[0012] For postoperative pain management in photorefractive keratology (PRK) and LASIK eye surgery, surface NSAIDs and soft bandage contact lenses are the most common treatments. NSAIDs block the production of prostaglandins (hormone-like substances that are involved in inflammation and are produced in the event of corneal tissue damage). Pathak, AK, & Karacal, H., (2019), Painreduction after photoablation, EyeWiki by the American Academy of Ophthalmology. Surface NSAIDs carry the risk of corneal damage, such as erosion, defects, delayed corneal epithelial healing, or corneal ablation (which can lead to vision loss). With soft bandage contact lenses, this approach can stimulate the regeneration of epithelial cells and serves as a delivery system for antibiotics or surface NSAIDs. However, bandage contact lenses can promote bacterial growth and are generally not effective in relieving pain. Shetty, R., et al., Pain management after photorefractive keratology, Journal of Cataract Refract Surgery, 45(7):972-976 (2019).

[0013] Acute eye pain can also be treated with topical anesthetic eye drops, such as proparacaine hydrochloride and tetracaine hydrochloride. These aqueous solutions are given as short-term pain relief, or when measuring intraocular pressure, removing foreign bodies, smoothing sutures in the cornea, or as preoperative anesthetics for ophthalmic surgery. Topical anesthetics block the transmission of pain stimuli to corneal nerves for approximately 15 to 20 minutes per dose. While this provides short-term pain relief, continuous application is necessary, but prolonged use can ultimately lead to corneal toxicity. Corneal toxicity includes damage to the stromal corneal cells, which play a crucial role in healing corneal wounds. If epithelial cells cannot migrate across the cornea, the epithelium will eventually begin to shed, leading to chronic non-healing of the corneal epithelium.

[0014] However, maintaining some sensation of pain is essential for the normal function of a healthy cornea. Neurokeratopathy (also known as neurotrophic keratitis) is a syndrome in which the ocular surface undergoes a progression from tear film abnormalities to epithelial lesions and ultimately stromal lysis due to pathological loss of sensation in the cornea and conjunctiva. For true neurokeratopathy, the eye must have a lack of sensation in the cornea and conjunctiva due to pathological destruction of the trigeminal nerve, which can occur due to surgery intended to treat trigeminal neuralgia, surgery for acoustic neuroma, or infections such as ocular herpes zoster ophthalmicus or leprosy. Other forms of neurokeratopathy occur due to the misuse of topical anesthetics. In rabbit models, typical trophic changes in the corneal epithelium have been shown following controlled thermal coagulation of the trigeminal ganglion in rabbits. This denervation was found to significantly affect epithelial proliferative activity and result in sparse mitosis.

[0015] As mentioned above, the cornea is extremely sensitive to pain or disturbance. Many individuals present with clinical conditions leading to mild to severe corneal pain and discomfort, all of which could potentially be addressed by developing safe and effective treatments for corneal pain. The current state of topical numbing drops only provides corneal numbness for a few minutes, and long-term use is associated with serious complications, including corneal infection and corneal ablation. Furthermore, traditional methods for treating ocular pain result in complete anesthesia of the eye's sensation, which can be highly problematic in the long term due to the risk of developing neurogenic keratopathy. Moreover, in chronically inflamed and painful eyes, corneal somatosensory dysfunction becomes a major feature of the pain syndrome. In summary, many patients suffer from debilitating ocular surface discomfort that can be associated with active keratopathy or persist for a long time after the initial injury without detectable persistent lesions. Clearly, there is a significant unmet clinical need to develop long-acting and safe corneal anesthesia that partially blocks corneal sensation and significantly reduces patient discomfort. Summary of the Invention

[0016] The following embodiments describe non-limiting arrangements of the feature combinations of the invention described herein. Other arrangements of feature combinations are also contemplated and / or described throughout this disclosure. In particular, each of these numbered embodiments is considered to be subordinate to or relating to each preceding or following numbered embodiment, regardless of the order in which they are listed.

[0017] In some aspects, this disclosure provides a cold plasma formulation for relieving symptoms of ocular surface discomfort, the cold plasma formulation comprising: water and a freezing point depressant, wherein the cold plasma formulation is configured to be applied directly or indirectly to the target ocular surface to induce numbness of the target ocular surface, and wherein ocular sensation of the eye is restored after the cold plasma is applied to the target ocular surface. In some embodiments, the cold plasma formulation further comprises lipids. In some embodiments, the formulation comprises a freezing point depressant, wherein the concentration of the freezing point depressant is about 10% to 40% (v / v). In some embodiments, the formulation comprises lipids, wherein the concentration of the lipids is about 0.1% to 10%, 10% to 20%, 20% to 30%, or 30% to 45% (v / v). In other embodiments, the formulation comprises a freezing point depressant, wherein the concentration of the freezing point depressant is about 10% to 20%, 20% to 30%, or 30% to 40% (v / v). In some embodiments, the formulation comprises lipids, wherein the concentration of the lipids is about 15% to 45% (v / v). In some embodiments, the formulation comprises a freezing point depressant at a concentration of about 10% to 25% (v / v). In some embodiments, the slurry can be injected via a needle. In other embodiments, the slurry cannot be injected via a needle. In some embodiments, the percentage of solid ice in the slurry is about 0.1% to about 75% by weight of the slurry. In some embodiments, the percentage of solid ice in the slurry is 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 percentage of solid ice particles in the slurry is about 0.1% to about 50% by weight of the slurry.

[0018] In some aspects, this disclosure provides a method for relieving symptoms of ocular surface discomfort, the method comprising: applying a cryosol preparation to a surface adjacent to the limbus of a patient's eye, wherein the cryosol preparation comprises water and a freezing point depressant, wherein the application of the cryosol preparation is configured to cause a degree of numbness in the cornea of ​​the eye for a period of time, and after which ocular sensation is restored. In some embodiments, the cryosol preparation further comprises lipids. In other embodiments, a method is provided in which the cryosol preparation is applied to the posterior portion of the limbus. In other embodiments, a method is provided in which the cryosol remains on the surface of the eye for more than about 4 hours if the cryosol preparation is not reapplied on any day after the first day of application. In some embodiments, a method is provided in which the cryosol preparation comprises a freezing point depressant, wherein the freezing point depressant is glycerol. In other embodiments, a method is provided in which the cryosol preparation comprises lipids, wherein the lipids comprise soy-phosphatidylcholine (soy-PC). In other embodiments, a method is provided in which the cold plasma preparation comprises lipids, wherein the lipids comprise fatty acids selected from stearic acid, palmitic acid, lauric acid, and myristic acid, and combinations thereof. In other embodiments, a method is provided in which the cold plasma preparation comprises hyaluronic acid. In some embodiments, a method is provided in which the cold plasma preparation comprises an excipient. In some embodiments, a method is provided in which the cold plasma preparation comprises an excipient, wherein the excipient is poloxamer. In other embodiments, a method is provided in which ocular sensation recovers approximately 21 days after application of the cold plasma preparation. In other embodiments, a method is provided in which ocular sensation recovers approximately 7 to approximately 90 days after application of the cold plasma preparation. In other embodiments, a method is provided in which the sclera of the patient's eye is cooled to a temperature of approximately -6°C to approximately 4°C during application of the cold plasma. In other embodiments, a method is provided in which the cold plasma is applied for approximately 2 minutes to approximately 15 minutes. In other embodiments, a method is provided in which an additional amount of cold paste is applied approximately 90 seconds after the initial application. In other embodiments, a method is provided in which the application of the cold paste formulation is surface-applied. In still other embodiments, a method is provided in which the application of the cold paste formulation is performed by injection.

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

[0020] In some embodiments, a method is provided for protecting the cornea on the surface of an object's eye, the method comprising: a) positioning a corneal protection device including an internal cavity on the object's cornea; b) contracting and releasing a portion of the corneal protection device to create a vacuum within the internal cavity; and c) adhering the corneal protection device to the surface of the eye; wherein the corneal protection device includes a sealing wall having an inner surface, an outer surface, and an opening surface, the sealing wall extending from a first end to a second end, wherein the inner surface forms the internal cavity. In some embodiments, the method further includes applying a cryo-gel agent to the surface of the eye after placement of the corneal protection device. In other embodiments, the corneal protection device is configured to protect the cornea physically and thermally from the effects of the cryo-gel agent. In some embodiments, creating a vacuum within the internal cavity of the corneal protection device includes squeezing the corneal protection device. In some embodiments, the vacuum is a partial vacuum.

[0021] In some aspects, this disclosure provides a device for protecting the eyelids of an object, the device comprising: a first surface configured to contact the upper eyelid; and a second surface configured to contact the lower eyelid, wherein the first and second surfaces are configured to be reversibly connected to each other to create an opening between the first and second surfaces, and wherein, upon insertion into the eye, the device prevents the upper and lower eyelids from closing and protects the eyelids from the ocular surface or substances deposited on the ocular surface by physically and thermally isolating the eyelids. In some embodiments, the device further comprises channels in one or more of the first and second surfaces, wherein the channels are configured to allow fluid to escape from the ocular surface when the device is inserted into the eye. In some embodiments, the device further comprises platforms on one or more of the first and second surfaces, the platforms being configured to facilitate handling and manipulation of the device. In other embodiments, the first surface comprises a first end and a second end, and the second surface comprises a first end and a second end, wherein the first end of the first surface is connected to the first end of the second surface, and the second end of the first surface is connected to the second end of the second surface. In some embodiments, the first and second surfaces are curved in shape. In some embodiments, one or more of the first and second surfaces are arcuate. In some embodiments, the dimensions of the first and second surfaces are adjustable. In some embodiments, the first and second surfaces are adjustable relative to each other to adjust the size of the opening. In some embodiments, the first and second surfaces are separate components of the device, which can be assembled to form the device. In some embodiments, one or more of the first and second surfaces include curved connecting sections that can be hinged relative to each other to adjust the size of the opening. In some embodiments, one or more segments of distance spanning 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 types of plastic. In some embodiments, the device comprises one or more porous materials. In other embodiments, one or more porous materials comprise an insulating material selected from polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, and combinations thereof. In other embodiments, one or more of the first and second surfaces comprise an insulating material and a wicking material. In other embodiments, the wicking material is selected from PVA, open-cell foam materials, and combinations thereof. In some embodiments, the device also includes a receiving structure configured to receive a corneal protection device.In other embodiments, the corneal protection device includes a structure configured to adhere to the ocular surface by forming a vacuum. The structure includes a sealing wall having an inner surface, an outer surface, and an opening surface extending from a first end to a second end. The inner surface forms an internal cavity, and the opening surface is configured to contact and surround the periphery of the cornea, creating a vacuum within the internal cavity when the structure is activated. In other embodiments, a receiving structure is located in the opening of the device such that the receiving structure is substantially on the cornea when the device is inserted into the eye. In other embodiments, the receiving structure has a substantially circular shape and is connected to the first and second surfaces. In some embodiments, the device is configured to protect both the eyelids and the cornea. In some embodiments, the device also includes one or more structures configured to function as a speculum to keep the eyelids open when the device is inserted into the eye.

[0022] In some aspects, a method for protecting the upper and lower eyelids of an object is provided, the method comprising: inserting an eyelid protection device into the object's eye; bringing a first surface of the eyelid protection device into contact with the contour of the upper eyelid; bringing a second surface of the eyelid protection device into contact with the contour of the lower eyelid; wherein the first and second surfaces are configured to be connected to each other to create an opening between the first and second surfaces, and wherein, when inserted into the eye, the device prevents the upper and lower eyelids from closing and protects the eyelids from the ocular surface or substances deposited on the ocular surface by physically and thermally isolating them. In some embodiments, the method further comprises applying a cryo-slurry preparation to the ocular surface. In other embodiments, the cryo-slurry preparation comprises water, a freezing point depressant, and optionally lipids.

[0023] In some aspects, a kit is provided comprising: one or more syringes containing a cold-slurry formulation; and a package enclosing the syringes, wherein the package is configured to store, seal, and provide thermal and moisture protection for the syringes. In some embodiments, the kit comprises at least two syringes containing a cold-slurry formulation. In some embodiments, the kit comprises 2 to 20, 2 to 15, 2 to 10, or 2 to 5 syringes. In other embodiments, one or more of the syringes containing the cold-slurry formulation contains about 1 to 20 ml of the cold-slurry formulation. In some embodiments, the package comprises a phase change material, a thermal insulation material, a reflective barrier, or a combination thereof. In other embodiments, the package is configured to protect one or more syringes from contamination, temperature changes, environmental exposure, or a combination thereof. In some embodiments, the cold-slurry formulation comprises water, a freezing point depressant, and optionally a lipid.

[0024] In some aspects, a kit is provided 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, wherein the second package is configured to store, seal, and provide thermal and moisture 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, lipids.

[0025] In some aspects, a separate cooling device is provided for cooling a target tissue surface (e.g., the ocular surface), the separate cooling device comprising: a formulation chamber including a hollow chamber having an open end and a closed end, wherein the formulation chamber is configured to receive and contain a cryo-slurry formulation or other formulation capable of maintaining a temperature below 0°C; a removable cover 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, wherein the first surface is configured to contact the target tissue surface, and the second surface is configured to form or contact the closed end of the formulation chamber. In some embodiments, the separate cooling device further includes a movable plate disposed within the formulation chamber, wherein, as the movable plate is advanced within the formulation chamber toward the closed end of the formulation chamber, a liquid-phase cryo-slurry formulation is displaced away from the closed end of the formulation chamber and replaced by a substantially non-liquid-phase cryo-slurry formulation, and wherein the movable plate is disposed within the formulation chamber and has a smaller dimension than the open end of the formulation chamber. In some embodiments, the independent cooling device further includes: a force spring having a first end and a second end, wherein the first end is operatively connected to a movable plate and the second end is operatively connected to a removable cover; and one or more side pins operatively connected to a hollow chamber; one or more side pins are configured to cause the first end of the force spring to extend beyond its original length upon being pressed, so as to allow the movable plate to be advanced within the formulation chamber toward a closed end of the formulation chamber. In some embodiments, the target surface interface is configured to contact the ocular surface, and the independent cooling device is configured to maintain the ocular surface at a temperature suitable for alleviating ocular surface discomfort. In some embodiments, the formulation chamber is configured to receive a cryopreservation 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 adapt to the cornea of ​​the ocular surface to prevent contact between the target surface interface and the cornea when the target surface interface is in contact with the ocular surface. In some embodiments, the target surface interface is configured to allow thermal energy 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 plasma formulation. In some embodiments, an 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 this disclosure. In some embodiments, the corneal protection device is configured to be disposed within an opening in the ocular surface interface and to physically and thermally protect the cornea when the ocular surface interface is in contact with the ocular surface. In other embodiments, the force spring is a tension spring, a torsion spring, or a combination thereof. In some embodiments, the target surface interface comprises a thermally conductive material selected from Al, Cu, stainless steel, metal alloys, and combinations thereof.In some embodiments, the target surface interface comprises one or more encapsulated phase change materials (PCMs), shape-stabilized PCMs, or combinations thereof. In some embodiments, the first surface of the target surface interface comprises a non-stick coating. In other embodiments, the non-stick coating is PTFE. In some embodiments, the first surface of the target surface interface comprises a hydrophobic coating. In some embodiments, the first surface of the target surface interface comprises a surface coating that protects the target tissue from adhering to the target surface interface. In some embodiments, the first surface of the target surface interface comprises a geometric design feature that protects the target tissue from adhering to the target surface interface. In other embodiments, the geometric design feature comprises one or more of hierarchical microstructures, hierarchical nanostructures, bio-inspired surface patterns, or combinations thereof. In other 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 some aspects, a method for relieving symptoms of ocular surface discomfort is provided, the method comprising: positioning an independent cooling device on a target ocular surface; wherein the independent cooling device comprises: a formulation chamber having a hollow chamber having an open end and a closed end, wherein the formulation chamber is configured to receive and contain a cryopreservation formulation; a removable cap configured to fit over and seal the open end of the formulation chamber; and a target surface interface having 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 cryopreservation formulation comprises water, a freezing point depressant, and optionally lipids. In some embodiments, the independent cooling device further comprises a movable plate disposed within the formulation chamber, wherein, as the movable plate is advanced within the formulation chamber toward the closed end of the formulation chamber, a liquid-phase cryopreservation formulation is displaced away from the closed end of the formulation chamber and replaced by a substantially non-liquid-phase cryopreservation formulation, and wherein the movable plate is disposed within the formulation chamber and has a smaller dimension than the open end of the formulation chamber. In some embodiments, the method further includes advancing a movable plate disposed within the formulation chamber of an independent cooling device toward the closed end of the formulation chamber. In some embodiments, the independent cooling device further includes: a force spring having a first end and a second end, wherein the first end is operatively connected to the movable plate and the second end is operatively connected to a removable cap; and one or more side pins operatively connected to the hollow chamber; one or more side pins being configured to cause the first end of the force spring to extend beyond its original length upon being pressed, thereby allowing the movable plate to advance toward the closed end of the formulation chamber within the formulation chamber. In some embodiments, the method further includes pressing one or more side pins operatively connected to the hollow chamber of the independent device to cause the first end of the force spring to extend beyond its original length, thereby causing the movable plate to advance toward the closed end of the formulation chamber within the formulation chamber.

[0027] In some aspects, a separate cooling device is provided for cooling a target tissue surface, the separate cooling device comprising: a housing; a heat exchanger, wherein the heat exchanger includes a formulation chamber configured to receive and contain a formulation, wherein the formulation is configured to freeze to sub-zero temperatures in a cold environment; an orifice, wherein the orifice is configured to allow a clinician to visualize the cornea of ​​the object; and a target surface interface including 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 some embodiments, the cold environment is a standard cryostat. In some embodiments, the formulation comprises water and a freezing point depressant. In some embodiments, the concentration of the freezing point depressant is about 20% (w / w). In some embodiments, the freezing point depressant is glycerol. In some embodiments, the first surface is configured to adhere to the target tissue surface after contact. In some embodiments, the target surface comprises the sclera. In other embodiments, the sclera is adjacent to the limbus. In some embodiments, the sub-zero temperature is about -20°C to about 0°C. In some embodiments, the target surface interface comprises copper.

[0028] In some aspects, an independent cooling device is configured to receive an accessory. In some embodiments, the accessory is a speculum. In some embodiments, the accessory is configured to keep the subject's eye open during surgery. In some embodiments, the accessory is configured to protect the subject's eyelids from sub-zero temperatures during surgery. In some embodiments, the accessory comprises silicone. In some embodiments, the accessory comprises thermoplastic elastomer (TPU) or thermoplastic polyurethane (TPE).

[0029] In some respects, the independent cooling device is also configured as a receiving cap, wherein the cap is configured to prevent condensation from forming on the target surface interface prior to surgery.

[0030] In some aspects, a method for relieving symptoms of ocular surface discomfort is provided, the method comprising: positioning an independent cooling device on a target ocular surface; wherein the independent cooling device comprises: a housing; a heat exchanger, wherein the heat exchanger includes a formulation chamber configured to receive and contain a formulation, wherein the formulation is configured to be frozen to sub-zero temperatures in a standard cryostat; an orifice, wherein the orifice is configured to allow a clinician to visualize 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 a target tissue surface, and the second surface is configured to form or contact the formulation chamber. In some embodiments, the sub-zero temperature is from about -20°C to about 0°C. In some aspects, the formulation comprises water and a freezing point depressant. In some embodiments, the freezing point depressant is glycerin. In some embodiments, the treatment time is from about 2 minutes to about 10 minutes.

[0031] In some aspects, an independent cooling device is configured to receive an accessory, wherein the accessory is configured to be positioned adjacent to the target ocular surface and prevent the subject's eye from closing. In some embodiments, the accessory is configured to thermally protect one or more eyelids from contact with the contact surface interface. In some embodiments, the accessory is configured to provide an aperture for visualization of the cornea. In some embodiments, the accessory is configured to facilitate positioning of the device. In some embodiments, the accessory is configured to protect the subject's eyelids from sub-zero temperatures during surgery. In some embodiments, the target surface comprises 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 after contact. In some embodiments, the target surface interface is configured not to adhere to the target surface after contact. In some embodiments, the target surface interface is configured to detach from the target surface after treatment time.

[0033] In some embodiments, the method provided herein further includes rinsing the target tissue surface with a liquid formulation before 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. Attached Figure Description

[0034] The following figures depict some illustrative embodiments of the present invention.

[0035] Figure 1 Freezing point depression plots were depicted for liquid water, a solution containing 10% glycerol (volume by volume, v / v) and a solution containing 20% ​​glycerol (v / v).

[0036] Figure 2 This is a table showing the degradation of the components of an exemplary biomaterial that can form an injectable cold slurry by volume and weight.

[0037] Figure 3 This is a graph characterizing the ice content of cold slurries with crystallization setpoints of -5.5℃ and -8.1℃.

[0038] Figure 4A and 4B A diagram of the human eye is shown, illustrating different regions of the eye (4A) and degrees used for anatomical reference (4B).

[0039] Figure 5 This is a graph showing real-time scleral temperature monitoring in rabbits after applying cold gel to the eye surface (solid line) and injecting cold gel (dashed line).

[0040] Figure 6 This diagram illustrates the decrease in sensory perception in rabbit eyes over time after applying injected cold paste (diamond), surface-applied cold paste (triangle), and surface-applied paste at room temperature (square) with corneal exposure.

[0041] Figure 7 This figure shows the decrease in sensory perception in a rabbit eye over time after applying a surface-applied cold paste to the eye without exposing the cornea.

[0042] Figure 8A and 8B These are images of rabbit corneas stained with fluorescein, showing corneal healing over time after an intentional 8 mm corneal abrasion (8A) (as a control group) and after the application of a cold gel to the surface (8B).

[0043] Figure 9 This figure shows the decline in eye sensation over time in six rabbits after a combined treatment in which a cold paste was first applied to the surface and then injected. In three rabbits (shown as rhombuses, squares, and triangles), the injected paste did not contain liposomes, while in the other three rabbits (shown as "X", stars, and circles), the injected paste contained liposomes.

[0044] Figure 10 This is a graph showing the injectability of one embodiment of a cold slurry containing ice, the freezing point depressant glycerol, and lipids as a function of the volume fraction of glycerol and lipids in the cold slurry.

[0045] Figure 11 This is a cross-sectional view of a corneal protection device according to certain embodiments described herein.

[0046] Figure 12 This is a perspective view of an exemplary corneal protection device according to certain embodiments described herein, wherein the corneal protection device is placed on the ocular surface around the periphery of the cornea to enclose and seal the cornea.

[0047] Figure 13A and 13B An exemplary corneal protection device as described herein is shown. Figure 13A This is a perspective view of an exemplary corneal protection device and Figure 13B An exemplary corneal protection device is shown placed on the ocular surface to enclose and seal the periphery of the cornea.

[0048] Figure 14A and 14B This is a perspective view of an exemplary eyelid protector device according to certain embodiments described herein.

[0049] Figure 15A and 15BAn exemplary eyelid protector device combined with an exemplary corneal protection device is shown according to certain embodiments described herein.

[0050] Figure 16 An exemplary kit comprising multiple syringes containing cold slurry is shown according to certain embodiments described herein.

[0051] Figures 17A and 17B show a front perspective view (17A) and a perspective view (17B) of an independent eye cooling device according to certain embodiments described herein.

[0052] Figures 18A and 18B show front perspective views of exemplary independent eye cooling devices with an exemplary corneal protection device (18A) and without an exemplary corneal protection device (18B) according to certain embodiments described herein.

[0053] Figure 19 An exemplary treatment protocol using an exemplary independent eye cooling device is shown according to certain embodiments described herein.

[0054] Figures 20A and 20B show exploded views of an exemplary independent eye cooling device (20A) with a heat exchanger (20B) according to certain embodiments described herein.

[0055] Figure 21A Figures E illustrate exemplary independent eye cooling devices from multiple angles according to certain embodiments described herein.

[0056] Figures 22A and 22B illustrate exemplary independent eye cooling devices and accessories (e.g., specters) before (22A) and after (22B) placement of the independent eye cooling device through the accessory, according to certain embodiments described herein.

[0057] Figure 23A Figures D to D show multiple views of an accessory (e.g., a spectral) used with an independent eye cooling device according to certain embodiments described herein.

[0058] Figure 24 It is a graph showing the treatment time in seconds versus the removal time in seconds for treatment with an independent eye cooling device according to some embodiments described herein.

[0059] Figure 25 It is a diagram depicting an exemplary treatment area 2500 on a drawing of the eye.

[0060] Figure 26This is a graph showing a representative temperature curve comparing the temperature (°C) of a pig's eye surface with respect to the time (seconds) following contact with an independent cooling device according to some embodiments described herein.

[0061] Figure 27 It is a drawing showing the temperature measurement locations 1 and 2 on the eye and the treatment area 2500 (located below the contact surface of the independent cooling device according to this disclosure).

[0062] Figure 28 It is a graph showing the temperature (°C) relative to the time (seconds) taken at measurement locations 1 and 2 and from the tissue below the treatment area 2500.

[0063] Figure 29 It is a graph showing the percentage of sensation in treated rabbit eyes over time (in days) compared to the untreated time. Detailed Implementation

[0064] This disclosure relates to devices, apparatus, systems, and methods for treating ocular surface discomfort using biological materials (e.g., cryopreservatives) or cooling devices. In some embodiments, the biological material is a cryopreservative (e.g., ice plasma), which can be delivered by direct or indirect surface application to the surface of the eye of a human patient or subject (e.g., a person who is not a patient or a non-human animal) or by injection into the eye of a human patient or subject (e.g., a person who is not a patient or a non-human animal) for preventative or therapeutic purposes to alleviate ocular discomfort. The systems and methods disclosed herein provide unexpectedly long-term hypoesthesia (also known as hypoesthesia). Hypopesthesia can cause prolonged corneal numbness, followed by restoration of ocular sensation within days or weeks after application of cryopreservative treatment or a cooling device, without causing permanent corneal damage or disrupting the corneal healing process.

[0065] This disclosure provides novel cooling treatments that relieve ocular surface discomfort by applying cold therapy (e.g., -20°C to 0°C) to the 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 some embodiments, this disclosure provides a stand-alone cooling device and a method of using it, wherein the stand-alone cooling device includes an ocular surface (i.e., target surface) interface configured to rapidly freeze to the sclera upon contact, wherein the ocular surface interface adheres to the surface of the eye for sustained treatment, thereby providing a sub-zero temperature (e.g., about -20°C to about 0°C) to a precise treatment area adjacent to the limbus. In some embodiments, the stand-alone cooling device lowers the temperature of the sclera to a cold temperature (e.g., -20°C to about 4°C) and maintains this low temperature for a period of time sufficient to cause reduced ocular surface sensation. This treatment does not cause harmful side effects to the eye or damage to tissues in or around the eye.

[0066] In some embodiments, a cold paste may be applied directly or indirectly to the surface of the eye to achieve a desired therapeutic effect, such as improving or treating ocular surface discomfort by alleviating prolonged corneal numbness. In some embodiments, the therapeutically effective cold paste consists entirely of water and excipient materials (i.e., materials free of active pharmaceutical compounds). In other embodiments, the cold paste also contains known active pharmaceutical compounds. In some embodiments, a protective layer (such as a contact lens or corneal protection device that covers the cornea and provides a protective barrier around the corneal periphery) is applied to the cornea prior to the surface application of the paste. In some embodiments, the eyelids are protected from the surface-applied paste by using an eyelid protection device, such as by inserting a plastic or other non-thermally conductive material and / or a speculum into the subject's eye.

[0067] In some embodiments, the duration of application of the slurry or cooling treatment to the subject's eye can be varied to induce a greater or lesser degree of sensory deprivation. In some embodiments, the temperature of the slurry or cooling treatment applied directly or indirectly to the surface of the eye or injected into the subject's eye can be varied to induce a greater or lesser degree of sensory deprivation. In some embodiments, the sensory deprivation induced after treatment decreases to an imperceptible point over time. In other embodiments, where the subject's eye may be particularly sensitive, a greater degree of sensory deprivation can be induced to cause more nerve numbness in the subject's eye.

[0068] In some embodiments, containers (e.g., vials, syringes, individual cooling devices) containing biological materials are received at the point of clinical care. The biological materials may be received in a crystalline (or partially crystalline) state. In some embodiments, the final product to be administered to a human patient or object (e.g., a person who is not a patient or a non-human animal) by surface application or injection is a cold slurry consisting of sterile ice particles of water and varying amounts of excipients or additives (e.g., freezing point depressants). For example, the percentage of ice particles in the cold slurry may be less than about 10% by weight, about 10% to about 20% by weight, about 20% to about 30% by weight, about 30% to about 40% by weight, about 40% to about 60% by weight, greater than about 60% by weight, etc. In some embodiments, the size of the ice pellets is controlled to allow flow of the slurry through containers of various sizes (e.g., needle gauge sizes of about 7 to about 43), as described in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated herein by reference in its entirety. Furthermore, in some embodiments, other methods may be used to adjust the size of the ice pellets to allow flow of the slurry through containers of various sizes. In some embodiments, the diameter of most of the ice pellets is smaller than about half the inner diameter of the application or injection lumen or container. For example, in some embodiments, the diameter of the ice pellets may be about 1.5 mm or less for use with 3 mm catheters.

[0069] Various techniques exist for preparing cold slurries. This disclosure is not limited to any particular method or technique. Exemplary cold slurry formulations and methods for their preparation have previously been disclosed, for example, in the following: U.S. Patent Nos. 11,241,330; 11,564,830; 11,471,401; U.S. Patent Application Serial 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), all of which are incorporated herein by reference in their entirety.

[0070] In some embodiments, the cold paste may contain one or more excipients. Excipients are any substances that are not therapeutic agents themselves but are used as diluents, excipients, and / or carriers for delivering therapeutic agents to a subject or patient, and / or substances added to the composition to improve its handling properties, stability properties, and / or storage properties. In some embodiments, excipients may constitute less than about 10% v / v of the cold paste, about 10% v / v to about 20% v / v of the paste, about 20% v / v to about 30% v / v, about 30% v / v to 40% v / v, and more than about 40% v / v. A variety of added excipients can be used to alter the phase transition temperature of cold slurry (e.g., lower the freezing point), change the ice content of cold slurry, change the viscosity of cold slurry, prevent ice particle aggregation, prevent the formation of dendritic ice (i.e., crystals with multi-branched "tree-like" formations, such as those seen in snowflakes), maintain ice particle separation, improve the thermal conductivity of the fluid phase, and / or improve the overall preventive, therapeutic, or aesthetic efficacy of cold slurry.

[0071] In some embodiments, one or more freezing point depressants may be added as excipients to form a cold slurry with a freezing point below 0°C. In some embodiments, lowering the freezing point of the slurry allows it to maintain fluidity and remain suitable for use in containers of various sizes (e.g., maintaining injectability) while still containing the desired and effective percentage of ice particles. Suitable freezing point depressants include, but are not limited to, salts (e.g., sodium chloride, betaadex sulfobutyl ethersodium), ions, lactated Ringer's solution, sugars (e.g., glucose, sorbitol, mannitol, hydroxyethyl starch, sucrose, (2-hydroxypropyl)-β-cyclodextrin, or combinations thereof), biocompatible surfactants such as glycerol (also known as glycerol), other polyols (e.g., polyvinyl alcohol, polyethylene glycol 300, polyethylene glycol 400, propylene glycol), other sugar alcohols, or urea, etc. Other exemplary freezing point lowering agents include, but are not limited to, those disclosed in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which are incorporated herein by reference in their entirety. In other embodiments, a slurry paste with the consistency of toothpaste is formed, which can facilitate surface application.

[0072] The concentration of the freezing point lowering agent will determine the percentage of ice particles in the cold slurry and its flowability and ability (e.g., its injectability) when applied through containers of different sizes. The degree of freezing point reduction can be calculated using the following formula, as described in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011) (which is incorporated herein by reference in its entirety):

[0073]

[0074] in It is the decrease in freezing point (as from) definition), It is the freezing point depression constant. It is the molality, and This is the van't Hoff factor, representing the number of ionic particles per individual solute molecule. Other methods for calculating freezing point depression can also be used, such as those disclosed in U.S. Application No. 15 / 505,042 (Publication No. US2017 / 0274011).

[0075] Reference Figure 1 This is a graph showing the freezing point depression of pure water T1, a mixture of water and 10% (v / v) glycerol T2, and a mixture of water and 20% (v / v) glycerol T3. In this graph, all substances were placed in a freezer at a constant temperature of -20°C. Temperatures were measured using thermometers placed in each substance. The graph shows that the water-glycerol mixture has a different freezing point compared to pure water, meaning the solution can be cooled below 0°C and only partially crystallizes. The graph shows that cooling causes pure water T1 to crystallize at its equilibrium freezing point of 0°C. This is indicated by the time pure water is held at approximately 0°C for approximately 1.3 hours to approximately 4.4 hours, starting immediately after pure water T1 passes its supercooling point of approximately -6°C. For the pure solvent, there is an equilibrium window for crystallization (i.e., ...). Figure 1The "flat" portion (of the pure water T1) is typical. For the 10% glycerol solution T2, cooling causes the solution to begin crystallizing at an initial freezing point of approximately -3°C after approximately 2.2 hours, and crystallization continues after approximately 6 hours as the solution temperature further decreases to approximately -8°C. Initial crystallization occurs immediately after the 10% glycerol solution T2 passes through its supercooling point of approximately -8°C (this can vary depending on the sample, e.g., from approximately -15°C to approximately -3°C), as shown at approximately 2.2 hours. For solutions (i.e., impure mixtures), a decreasing crystallization temperature window is typical for the 10% glycerol solution T2. Similarly, for the 20% glycerol solution T3, cooling caused the solution to begin crystallizing at an initial freezing point of approximately -7°C after approximately 3.5 hours (after which the initial supercooling point can vary from sample to sample, e.g., from approximately -25°C to approximately -5°C), and continued crystallizing after approximately 6 hours as the solution temperature further decreased to approximately -11°C, and thereafter continued to decrease for more than 6.5 hours. Initial crystallization occurred immediately after the 20% glycerol solution T3 passed its supercooling point of approximately -14°C, as shown at approximately 3.5 hours. Similar to the trace of the 10% glycerol solution T2, the decreasing crystallization temperature window of the 20% glycerol solution T3 is typical for the solution.

[0076] Reference Figure 2 This chart illustrates the composition of an exemplary biomaterial capable of forming a cold slurry. The chart shows that the ice percentage of the exemplary biomaterial can be calculated for a specific temperature. The exemplary slurry contains 30% ice by mass (w / w) at -10°C. This exemplary slurry has 80 mL of brine (0.9% NaCl) and 20 mL of glycerol (i.e., glycerol). By weight, such a slurry contains approximately 79.6 g of pure water, approximately 0.72 g of sodium chloride, and approximately 25.2 g of glycerol (approximately 20% v / v). In other embodiments, the slurry may contain a higher or lower percentage of glycerol by adjusting the relative volume of glycerol to brine. For example, other suitable slurries contain approximately 10% glycerol (v / v), approximately 10% to approximately 20% glycerol, approximately 30% glycerol, or more than approximately 30% glycerol. If an active pharmaceutical compound is added to the slurry, the concentration of the brine can be adjusted accordingly to maintain a desired concentration of the excipient, such as glycerol. The ice percentage will vary depending on the composition of the biomaterial.

[0077] Reference Figure 3 Different slurry compositions (batches) were characterized based on their temperature spectra and ice content. Different slurry batches were placed on a copper plate heated to 40°C and equipped with thermocouple wires for measuring the temperature change of the slurry over time. The plotted data shows the temperature changes of three different slurry batches over time. For each slurry, the temperature was measured at two different locations: embedded inside the copper plate (trace A). CB C and C C ) and the middle of the copper plate exposed outside the plate (trace A) M B M and C M The temperature traces show three separately produced slurry batches: a slurry composition with 15% glycerol (with a temperature setpoint of -8.1°C) produced by trace A. C and A M This indicates that two different slurry batches, both containing 10% glycerol (with a temperature setpoint of -5.5°C), were produced by trace B. C and B M and trace C C and C M This indicates that when the first batch of paste is introduced into the copper plate, the thermocouple wires (trace A) embedded inside the plate... C B C and C C The initial measurement of the temperature of the heating plate (e.g., trace A) C At time point 0, the temperature is 31°C, and subsequently, due to the cooling effect of the introduced slurry, equilibrium is reached at a lower temperature (e.g., trace A). C At approximately 2 minutes, the temperature is 22°C. On the other hand, for the thermocouple wire located in the middle of the plate, when the paste is first introduced into the copper plate, the paste immediately contacts the thermocouple wire because the wire is exposed. This results in an initial negative temperature reading at the middle position (e.g., trace A) due to the contact between the crystalline paste and the wire. M At time point 0, the temperature is -5°C. Subsequently, as the slurry begins to melt on the heating plate, it reaches equilibrium at a warmer temperature (e.g., trace A). M (At approximately 4 minutes, the temperature is 18°C). Thermocouple wires exposed outside the plate (trace A) M B M and C M This can be used to detect the phase transition during the initial melting of a crystallizing slurry. The figure shows two slurry compositions containing 10% glycerol at similar time points (trace B). M At approximately 4 minutes, and along trace C M It reaches its phase transition at approximately 2.7 minutes, which differs from the phase transition of the 15% glycerol slurry (trace A). M The phase transition occurs at approximately 0.2 minutes. The figure also shows that, depending on the thermocouple position (middle / bottom), traces with the same composition (10% glycerol: trace B) are observed. C and B M and trace C C and C MTwo slurry batches reached equilibrium within similar timeframes and at similar temperatures ranging from approximately 15°C to 19°C (as measured by the positions of the two thermocouple lines). On the other hand, depending on the position of the thermocouples (middle / bottom), different compositions (15% glycerol: trace A) were produced. C and A M The slurry of this type has a different temperature spectrum than the other two slurries, reaching equilibrium more quickly at temperatures between approximately 19°C and 22°C. Therefore, Figure 3 This indicates that slurries with different compositions have different temperature spectra, and that batch-to-batch consistency exists in slurries with the same composition (e.g., by B). C and B M The slurry and the slurry composed of C C and C M The slurry represented has a similar temperature spectrum to that of A. C and A M (The different types of slurry are indicated).

[0078] Reference Figure 4A The diagram shows the eye, which depicts scleral region 2, scleral region 3, cornea 1, and limbus (the dashed line between cornea 1 and scleral region 2). Figure 4A Reprinted from Andreoli CM, Gardiner MF. Open globe injuries: Emergent evaluation and initial management. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA, available at https: / / eye.hms.harvard.edu / eyeinsights / 2014-april / benchmark-protocols-managing-eye-trauma. Figure 4B A diagram of the eye with an overlay protractor is shown, displaying the angles relative to the eye in degrees (°). In this diagram, 90° represents the highest position of the eye.

[0079] In some embodiments, the cooling plasma described herein may be applied directly or indirectly to the surface of the eye, or alternatively, injected, to achieve long-term hypoesthesia to alleviate ocular surface discomfort. Hypesthesia, also known as hypoesthesia, refers to the reduction of discomfort or pain without complete blockage of sensation, which in this disclosure specifically relates to sensation on the ocular surface or ocular structures. Therefore, hypoesthesia differs from anesthesia, which is characterized by a deeper blockage of ocular sensation. Ocular surface hypoesthesia may include corneal numbness leading to a reduced pain response while maintaining other normal ocular functions, including normal healing processes. On the other hand, anesthesia can lead to abnormal ocular function due to the loss of all corneal sensation. Corneal sensation is important for normal ocular function, including initiating protective mechanisms such as blinking and tear production.

[0080] In some embodiments, the cooling plasma or device described herein can be configured to induce complete loss of corneal sensation, i.e., anesthesia. This can be advantageous for surgical procedures or other ocular treatments.

[0081] In some embodiments, the cold plasma drops are applied directly to the ocular surface. In some embodiments, the amount of plasma applied directly to the ocular surface can range from 1 to 100 ml by volume. In some embodiments, the amount of plasma applied directly to the ocular surface can be about 10 to 80 ml. In some embodiments, the formulation can be applied directly to the ocular surface. In some alternative embodiments, the cornea can be scraped first, and then the drops can be applied directly to the ocular surface. In some embodiments, the surface-applied cold plasma has a free-flowing paste consistency and can be applied in large quantities (e.g., 3 to 50 ml) to the ocular surface as a therapeutic agent.

[0082] In some embodiments, a cold paste or independent cooling device, as described herein, is applied directly or indirectly to the surface of the eye 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 application of the cold paste or independent cooling device lasts for about 5 minutes to about 10 minutes. In some embodiments, the cold paste or independent cooling device is applied to each eye for about 1 to about 10 seconds for about 1 to about 20 minutes. This treatment may be repeated several times in a short period of time (e.g., 5 to 20 minutes). In some embodiments, the cold paste or independent cooling device is applied directly or indirectly to the surface of the eye for about 10 minutes, and then fresh paste or a new device is applied for about 90 seconds until about 10 minutes are reached. In some embodiments, the paste is applied directly or indirectly to the ocular surface behind the limbus, for example, Figure 4A The area marked as scleral region 2.

[0083] In some implementations, sensitive ocular structures are protected from the cold gel during surface application to limit potential side effects. For example, protection of the corneal surface can limit some or all corneal cell damage or refractive changes caused by freezing corneal tissue. Protection of the palpebral conjunctiva and eyelids can prevent redness, swelling, and inflammation unrelated to the therapeutic effect. This is achieved by selectively applying the gel directly or indirectly to the ocular surface above the bulbar conjunctiva, posterior to the limbus (corresponding to the anterior anatomical region referred to as Zone 2). Figure 4A This can minimize potential adverse effects on the cornea.

[0084] In some embodiments, a protective contact lens or other protective covering (such as those otherwise described herein) may be applied to the cornea to protect it from potential damage from the gel. In some embodiments, the corneal covering completely prevents the cold gel from directly contacting the corneal surface. In some embodiments, an eyelid protection device is used to keep the eyelids open during the application of the cold gel to the surface. In some embodiments, the eyelid protection device is made of a non-thermally conductive material such as plastic or other non-conductive materials known in the art. Non-thermally conductive materials may be used in eyelid protection devices to prevent the eyelids (inner and outer) from contacting the gel and potentially freezing during cold gel treatment, which can lead to eyelid damage. In some embodiments, the eyelid protection device includes a speculum to help keep the eyelids open. In some embodiments, the cold gel is applied only to the sclera and the cornea is protected from contact with the gel and potential freezing.

[0085] In some embodiments, as further described herein, a device may be used to control the area exposed to the cold plasma to be only the bulbar conjunctiva / sclera, so that the cold plasma does not physically contact or freeze adjacent tissues unrelated to the desired clinical effect. In some embodiments, the cold plasma formulation does not come into direct contact with the ocular surface at all. In some embodiments, the cold plasma formulation may be contained within a device and contacted with a thermally conductive material that contacts the ocular surface, such as small metal or polymer donuts, other protective rings, or concave surfaces capable of contacting the ocular surface, thereby providing a barrier to prevent direct contact between the formulation and the ocular surface, but allowing necessary ocular surface cooling to occur. In some embodiments, the device directs cooling only to areas with potential therapeutic effects and prevents the device / cooling from contacting and affecting adjacent tissues, thereby minimizing potential undesirable side effects (e.g., potential irritation to the eye due to direct application of a hypertonic solution to the eye).

[0086] In some embodiments, the cryosol described herein is injected as a subconjunctival bolus. In some embodiments, the cryosol is injected approximately every 2 minutes. In some embodiments, each injection provides approximately 0.5 to 1.5 ml of cryosol. In some embodiments, the injection may be repeated approximately every 2 minutes for the desired duration of treatment. In some embodiments, the total duration of treatment is approximately 10 minutes, approximately 15 minutes, approximately 20 minutes, or more than approximately 20 minutes. In some embodiments, the cryosol is injected more closely adjacent to the axon of the ciliary nerve. The ciliary nerve is located at approximately 0° and 180° of the eye (…). Figure 4B ).

[0087] In some embodiments, a standard syringe is used to inject the slurry. In some embodiments, a syringe adjusted to fit the slurry injection may be used. In some embodiments, the syringe may have a needle with a weight of about 18G to about 25G.

[0088] In some embodiments, real-time temperature sensing of the ocular surface is performed during treatment (e.g., injection of cold plasma, surface application of a paste, or surface application of a stand-alone cooling device). In some embodiments, a cold plasma or stand-alone 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 application of the cold plasma or stand-alone cooling device is sustained for more than about 1 minute, for about 2 minutes to about 10 minutes, for about 5 minutes to about 10 minutes, for about 10 minutes to about 20 minutes, for about 10 minutes to about 15 minutes, or for about 15 minutes to about 20 minutes. The temperature of the cooled tissue and the duration of application of the paste or stand-alone cooling device can be varied to alter the sensory loss experienced by the subject.

[0089] In some implementations, the cold plasma or cold treatment is periodically reapplied to the subject's eye over time to maintain the therapeutic effect. A range of possible frequencies exist for surface application and / or injection. For example, treatment can be administered in any of the following ways: weekly, every other week; monthly; every other month; every three months, etc.

[0090] In some implementations, cold plasma is used as a safe treatment for corneal numbness to treat corneal discomfort or pain. A variety of cold plasma formulations can be used in conjunction with the methods described herein, including those mentioned above. (See reference...) Figures 5 to 9Some other specific embodiments of the cold slurry are described. "ETX-4143" is a slurry formulation comprising 15% glycerol, 30% L-α-phosphatidylcholine liposomes, and 0.9% saline (or phosphate-buffered saline). In some embodiments, ETX-4143 is applied to the eye (surface or by injection) at a temperature of about -25°C to -10°C (the temperature of the slurry). In some embodiments, it is applied at a temperature of about -18°C (the temperature of the slurry, e.g., referred to below). Figures 5 to 9 In the described implementation method, ETX-4143 is applied to the eye (surface or by injection). ETX-4143 is administered every approximately 90 seconds, with each application being approximately 2 to 3 ml, until a total treatment time of 10 minutes is achieved.

[0091] “ECT-1719” is a slurry formulation comprising 15% glycerol and 0.9% saline (or phosphate-buffered saline). In some embodiments, ECT-1719 is applied to the eye (surface or by 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, it is applied at a temperature of about -11°C (the temperature of the slurry, e.g., as referred to below). Figures 5 to 9 In the described implementation, ECT-1719 is applied to the eye (surface or by injection). In some implementations, ECT-1719 is injected in 0.7 ml volumes per injection, with four injections constituting a total injection volume of 2.8 ml. ECT-1719 is administered every approximately 120 seconds until a total treatment time of 10 minutes is achieved.

[0092] Reference Figure 5 Real-time scleral temperature monitoring was performed in rabbits after the following administration of a cooling gel (ETX-4143, solid line) to the eye and an injection of a cooling gel (ECT-1719, dashed line) into the eye in a second rabbit. Temperature monitoring was achieved by inserting a 25G needle with a temperature probe at its distal end into the subtenonic space of the eye. Figure 5 As can be seen, the scleral temperature of rabbits receiving the injected cryosol (ECT-1719) fluctuated between approximately 0°C and approximately 8°C throughout the entire surgical period (from approximately 0 seconds after injection to approximately 463 seconds after injection). The sharp line at approximately 463 seconds in the figure indicates the end of the study and removal of the temperature probe from the ocular tissue after 7.5 minutes. For most of the temperature recording period (from approximately 0 seconds after surface application to approximately 600 seconds after surface application), the scleral temperature of rabbits receiving surface-applied cryosol (ETX-4143) was lower than that of rabbits receiving injected cryosol, fluctuating between approximately -6°C and approximately 4°C. After surface application, the scleral temperature decreased from the time of application (…). Figure 5The temperature dropped from approximately 4°C (around 0 seconds) to approximately 0°C after about 120 seconds. Following the initial cooling period, the temperature remained relatively stable between approximately 0°C and -5°C from approximately 120 seconds to approximately 520 seconds after surface application. Additionally, for the duration from approximately 220 seconds to approximately 520 seconds after surface application, the scleral temperature showed very little variability, remaining stable between approximately -2°C and approximately -3°C. Approximately 620 seconds after surface application, the treatment ended and the temperature probe was removed, showing a sharp increase in the measured temperature. Figure 5 As shown.

[0093] Sensory reduction following cold therapy (whether by injection, application of a cold paste, or application of a separate cooling device) can be measured as a response to tactile stimulation of the eye. Starting with a 6 cm monofilament length and decreasing in 0.5 cm increments, the eye is probed three times at each length until a blink response is elicited. The monofilament becomes stiffer as it shortens, allowing for greater pressure to be applied to the eye when the probe enters. Sensory reduction at each time point is based on the given length of the monofilament. At each time point, the specific monofilament length recorded is the shortest length (maximum pressure) at which no blink response is observed. For example, starting with the longest 6 cm monofilament, if the rabbit does not blink during the probe, the next 5.5 cm length is used to probe the eye. If the rabbit again does not blink, the next 5 cm length is used. Now, if the rabbit blinks, the previous 5.5 cm length is recorded, as this is the shortest length at which no blink response is observed (reflecting a degree of sensory reduction). The deepest level of sensory impairment is when the rabbit does not blink when probed with the shortest monofilament length (e.g., 0.5 cm). Zero sensory impairment (no pain blockage / no numbness) is when the rabbit blinks when probed with the longest monofilament length (e.g., 6 cm). Monofilament length can be converted to pressure (g / mm). 2 This results in a 0.4 g / mm² production rate for a 6 cm monofilament. 2 Pressure (minimum pressure), while a 0.5 cm monofilament produces 15.9 g / mm. 2 Pressure (maximum pressure). Therefore, the recorded pressure corresponds to the shortest monofilament length in the absence of a blink response.

[0094] Reference Figure 6 In rabbits, sensory attenuation (as measured using tactile stimulation as described herein) was measured over time following administration of an intraocular cryotherapy gel (ECT-1719, 3 rabbits in this group, shown as a rhombus) with corneal exposure, a surface-applied cryotherapy gel (ETX-4143, 3 rabbits in this group, shown as a triangle), and a surface-applied gel at room temperature (ETX-4143, 1 rabbit in this group, shown as a square). Figure 6In this study, the degree of sensory impairment was defined as the recorded pressure (i.e., based on the shortest monofilament in which no blinking response occurred) relative to the highest possible pressure (i.e., using the shortest monofilament at 0.5 cm, corresponding to 15.9 g / mm²). 2 The percentage of sensory reduction (pressure) is shown. The degree of sensory reduction on days 1, 7, 14, and 28 after application of the cold gel is shown. For injected cold gel (ECT-1719, shown as a diamond), the sensory reduction was approximately 20% on day 1 and gradually decreased, reaching baseline levels by day 14 (error bars overlap with 0%). For surface-applied cold gel (ETX-4143 applied at 18°C, shown as a triangle), the sensory reduction was 100% (measurable maximum corneal numbness) on day 1, which then gradually decreased, gradually decreasing by day 28, during which time the pain response returned to baseline levels (error bars overlap with 0%). For surface-applied gel at room temperature (ETX-4143, shown as a square), no sensory reduction was observed at any time point after treatment. Therefore, Figure 6 This study demonstrated an unexpectedly strong sensory reduction effect from surface-applied cold paste, resulting in prolonged sensory loss (almost one month). Injected cold paste caused moderate sensory loss, which also lasted longer than expected (e.g., approximately one to two weeks). Importantly, for both surface and injection methods, cold paste treatment produced prolonged sensory loss that normalized to baseline levels without causing any permanent numbness.

[0095] Figure 7 The results showed similarities in rabbits except that the cornea was not exposed (protected by a contact lens). Figure 6 The sensory reduction over time following the application of a surface-applied cooling paste (ETX-4143) to the eye. This is consistent with the above description. Figure 6 Sensory reduction was measured in the same manner as described above. Sensory reduction is shown on days 1, 7, 14, 21, and 28 after surface-applied cold slurry treatment. The sensory reduction on day 1 was approximately 50% and gradually decreased, reaching baseline levels by day 21 (error bars overlap with 0%). Therefore, Figure 7 This study demonstrated an unexpected moderate to strong reduction in sensation from surface-applied cold gel (with corneal protection), resulting in long-term sensory reduction (approximately 3 weeks) without causing permanent corneal numbness or any corneal damage.

[0096] Referring to Figure 8, a representative image of a rabbit cornea stained with fluorescein shows an intentional 8 mm corneal abrasion applied to a control group while protecting the cornea and eyelids. Figure 8A After that, and after applying cold slurry to the surface in the treatment group ( Figure 8B The cornea then heals over time. The progression of the damage is determined by measuring the size of the lesion over time. For example, in... Figure 8A As can be seen from the data, corneal healing in the control group (3 rabbits) occurred at a rate of 1.31 mm / min within the first 24 hours after corneal abrasion. 2 The average healing rate occurred at 0.62 mm / hour, and continued for 24 to 60 hours after corneal abrasion. 2 An average healing rate of / hour occurred. Unexpectedly, as... Figure 8B As shown, corneal healing was not impaired in rabbits receiving topical application of cold gel (ETX-4143) compared to the control group. In this group (3 rabbits), corneal healing after cold gel treatment increased by 1.09 mm in the first 24 hours following treatment. 2 The average healing rate occurred at 0.63 mm / hour, and increased at 0.63 mm / hour from 24 to 60 hours after cold slurry treatment. 2 An average healing rate of / hour occurs.

[0097] Reference Figure 9 This figure illustrates sensory impairment over time following a combined treatment of topical application of a cold paste followed by injection of a cold paste in six rabbits. In three rabbits (shown as rhombuses, squares, and triangles), the topical application of the cold paste was ECT-1719 without liposomes, followed by injection of the same cold paste formulation (ECT-1719). In another three rabbits (shown as “X”, stars, and circles), the topical application of the cold paste was again ECT-1719 (without liposomes), followed by injection of a cold paste containing liposomes (ETX-4143). Sensory impairment is shown at the maximum pressure at which the rabbits do not blink (as described herein). Figure 6 and Figure 7 As mentioned above. Figure 9 As shown, regardless of the combination of treatments (liposomal or non-liposomal injections), sensory decline continued to increase after treatment, likely peaking sometime between day 4 and day 11. Sensory decline gradually diminished, returning to baseline levels around day 17. Surprisingly, a second, less pronounced period of sensory decline spontaneously occurred around day 22, gradually diminishing back to baseline levels by day 26.

[0098] Cold paste formulations containing one or more lipids

[0099] In some embodiments, it is desirable to increase the ice fraction in the slurry because it translates into a greater amount of heat energy being carried away from the ocular surface. However, adding more ice to a cold slurry typically makes the slurry less flowable, making it difficult to inject or surface apply to the target site. As further described herein, some embodiments of the invention relate to cold slurry formulations described herein that also contain one or more lipids that enhance the flowability of the slurry. In some embodiments, one or more lipids enhance the flowability and flow properties of the slurry while also allowing for a desired ice fraction in the slurry. In some embodiments, the enhanced flowability results in improved properties of the slurry, thereby better allowing application via devices of various sizes (e.g., syringes) for injection and / or surface application of the slurry.

[0100] In some embodiments, the slurry contains one or more lipids that cause 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 slurry's flowability. In some embodiments, the slurry contains one or more lipids that prevent smaller ice crystals from agglomerating into larger crystals or reduce the amount of smaller ice crystals agglomerating into larger crystals when the ice and / or ice-freezing-point depressant crystals are small.

[0101] In some embodiments, the amount of lipids contained in the slurry varies between about 0% and 45% (v / v). In some embodiments, the amount of lipids contained in the slurry varies between about 0% and 10%, about 10% and 20%, about 20% and 30%, or about 30% and 45%. In some embodiments, the amount of freezing point depressant contained in the slurry varies between about 0% and 10%, about 10% and 40%, about 10% and 30%, about 10% and 20%, or about 40% and 50% (v / v). In some embodiments, the amounts of lipids and freezing point depressants (e.g., glycerol) contained in the slurry vary between about 15% and 45% (v / v) and 10% and 25% (v / v), respectively. In some embodiments, the amount of lipids contained in the slurry is about 0% to 45% (v / v) and / or the amount of freezing point depressant (e.g., glycerol) contained is about 0% to 45% (v / v).

[0102] In some embodiments, a slurry containing water, one or more freezing point depressants, and / or one or more lipids is prepared by rapid freezing. In some embodiments, a slurry containing water, one or more freezing point depressants, and / or one or more lipids is prepared by freezing the slurry in a -20°C freezer, a -80°C freezer, an ultra-low temperature (“ULT”) freezer, or by rapid freezing to produce an emulsified slurry (e.g., using liquid nitrogen). In some embodiments, such an emulsified slurry can be stored in a standard freezer and will retain its fluidity when removed from the freezer for use (e.g., in a therapeutic procedure).

[0103] In some embodiments, a slurry containing water, one or more freezing point depressants, and / or one or more lipids may be contained in one or more syringes. In some embodiments, one or more syringes containing the slurry are prepared by rapidly freezing the syringes containing the slurry. In some embodiments, one or more syringes containing the slurry are prepared by cooling the syringes containing the slurry in a -20°C freezer, a -80°C freezer, an ultra-low temperature (“ULT”) freezer, or by rapid freezing that causes emulsification of the slurry (e.g., using liquid nitrogen). In some embodiments, one or more syringes containing the slurry can be conveniently stored in a standard freezer without experiencing any significant loss of flowability characteristics.

[0104] In some embodiments, the slurry contains one or more lipids with low degradability characteristics, resulting in long-term stability of the slurry mixture. In some embodiments, the slurry contains one or more lipids comprising soy-phosphatidylcholine (soy-PC). In some embodiments, the slurry contains one or more lipids comprising one or more fatty acids. In some embodiments, the one or more fatty acids are selected from stearic acid, palmitic acid, lauric acid, and myristic acid. In some embodiments, the slurry contains one or more lipids derived from non-animal sources, including soy-based and synthetic alternatives. In some embodiments, the slurry contains non-lipids, including hyaluronic acid, polysorbate, and other hygroscopic molecules.

[0105] Reference Figure 10The diagram illustrates the injectability of an exemplary cold slurry containing ice, glycerol, and lipids as a function of the volume fractions of glycerol and lipids. When the amounts of glycerol and lipids in the cold slurry are in the ranges of about 0% to 10% (v / v) and about 0% to 45% (v / v), respectively, the slurry is non-flowable or non-injectable because the ice in the cold slurry aggregates into large clumps. When the amounts of glycerol and lipids in the cold slurry are in the ranges of about 10% to 25% (v / v) and about 0% to 15% (v / v), respectively, the slurry remains non-flowable and non-injectable because the ice in the cold slurry aggregates into sufficiently large crystals to prevent the cold slurry from flowing freely from a suitably sized syringe. When the amounts of glycerol and lipids in the cold slurry are in the ranges of about 40% to 50% (v / v) and about 0% to 45% (v / v), respectively, there is no ice in the slurry because the lower freezing point of water makes any water present in the slurry liquid, rendering the cold slurry unusable for cold slurry application. When the amounts of glycerol and lipids in the cold paste are in the ranges of about 25% to 40% (v / v) and about 0% to 45% (v / v), respectively, the cold paste is more fluid and injectable because the ice crystals are small enough to allow them to flow freely; however, the amount of ice in the cold paste is still low, making it less effective at removing heat than is required in cold paste application. When the amounts of glycerol and lipids in the cold paste are in the ranges of about 10% to 25% (v / v) and about 15% to 45% (v / v), respectively, the cold paste is fluid and both injectable and an effective heat carrier. Within this performance range, the heat carrying capacity of the cold paste can be maximized depending on the desired degree of injectability. In some embodiments, Figure 10 The lipid used is soybean-PC.

[0106] Generally, cold serums containing a higher amount of ice will remove more heat from the ocular surface, but will be less fluid due to the presence of ice particles. On the other hand, adding freezing point lowering agents (such as glycerol) and lipids to the serum is expected to improve its fluidity, but will reduce the amount of ice, thus reducing the serum's heat-carrying capacity. When the amount of glycerol in the cold serum is in the range of about 0% to 10% (v / v), the amount of glycerol is insufficient to lower the freezing temperature sufficiently to prevent adequate water freezing. Regardless of the amount of lipids added to the serum, small ice crystals will begin to form and then begin to aggregate into larger crystals, which further coalesce to result in large chunks of ice. Such large chunks of ice cause the serum to become non-flowable, making the cold serum mixture unsuitable for injection or direct surface application to the eye, but non-flowable cold serums can be used in combination with stand-alone cooling devices to apply cold therapy to the ocular surface. When the amounts of glycerol and lipids in the serum are in the range of about 10% to 25% and 0% to 15% (v / v), respectively, the cold serum still lacks the fluidity required for injection or surface application. When the amounts of glycerol and lipids in the serum are in the ranges of approximately 25% to 40% and 0% to 40% (v / v), respectively, the cold serum contains sufficient glycerol to lower the freezing point of ice to the desired level while still exhibiting flow properties that allow for a degree of injectability. For example, within this range, even when the cold serum is lipid-free, it can still exhibit a lower freezing point and some fluidity, which allows it to be used for cold serum therapy. When the amounts of glycerol and lipids in the serum are in the ranges of approximately 25% to 40% and 15% to 45% (v / v), respectively, the increased amount of lipids improves the fluidity of the serum; however, this also leads to a decrease in the amount of ice, thereby reducing the heat-carrying capacity of the cold serum. When the amount of glycerol in the serum exceeds approximately 40% v / v, the aqueous component of the serum will remain liquid at the target temperatures required to be maintained on the ocular surface (i.e., approximately -6°C and 4°C). Because cryosol treatment relies on the latent heat of ice (rather than the sensible heat of liquid water, which results in a significantly lower heat-carrying capacity under the temperature difference experienced during treatment) to maintain the low temperature of the ocular surface for an extended period, this range is unsuitable for cryosol treatment. Optimized cryosols consist of amounts of glycerol and lipids varying between approximately 25% to 40% and 15% to 45% (v / v), respectively. Such cryosols will maximize the heat-carrying capacity of the cryosol without compromising its fluidity, and therefore without compromising the injectability required for sol application (e.g., the desired injectability depending on syringe size, treatment temperature, etc.).

[0107] In some embodiments, the present invention relates to a cold plasma formulation comprising water, one or more freezing point depressants, and one or more lipids. In some embodiments, the plasma formulation is configured to maintain a desired temperature on the ocular surface for an extended period of time. In some embodiments, the plasma formulation comprises about 25% to 40% (v / v) of a freezing point depressant. In some embodiments, the freezing point depressant is glycerol. In some embodiments, the plasma formulation comprises about 15% to 45% (v / v) of lipids. In some embodiments, the lipid is soybean-phosphatidylcholine (soybean-PC).

[0108] In some embodiments, the present invention relates to a method for relieving symptoms of ocular surface discomfort, the method comprising: applying a cold paste to the limbus of the cornea adjacent to the patient's eye, wherein the cold paste comprises water, a freezing point depressant, and one or more lipids, wherein the surface application of the cold paste is configured to induce a degree of numbness in the cornea of ​​the eye for a period of time, and wherein ocular sensation is restored after that period of time.

[0109] In some embodiments, the present invention relates to a method for preparing a cold slurry formulation, the method comprising mixing water, one or more freezing point depressants, and one or more lipids in a desired proportion at a mixing rate 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 water, one or more freezing point depressants, and one or more lipids in a desired proportion. In some embodiments, the slurry formulation comprises about 25% to 40% (v / v) of a 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 lipids. In some embodiments, the lipid is soybean-phosphatidylcholine (soybean-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 an emulsion of water and a freezing point depressant component with one or more lipids. In some embodiments, such a method for preparing a slurry formulation provides a stable dispersion of one or more lipid particles in water or in water and a freezing point depressant component. In some embodiments, such a method for preparing a slurry formulation results in the formation of tiny and / or millimeter-sized droplets of the aqueous component encapsulated by one or more lipids. In some embodiments, such a method for preparing a slurry formulation results in the formation of tiny and / or millimeter-sized droplets of the water and freezing point depressant components encapsulated by one or more lipids.

[0110] Device for protecting the cornea

[0111] In some embodiments, aspects of the invention relate to devices for protecting the cornea. In some embodiments, the devices for protecting the cornea described herein can be used when the paste described herein is applied to the eye of a subject. In some embodiments, contact between certain parts of the eye (e.g., the cornea) and the cold paste described herein could pose a risk of damage to that area (e.g., the cornea), for example: 1) the sub-zero temperature of the cold paste could cause the cornea to freeze, and / or 2) chemicals used in the paste could be harmful to the cornea (e.g., irritate the cornea). Therefore, in some embodiments where the eye of a subject is in contact with the paste described herein, it is desirable to provide physical and thermal protection / isolation of the cornea from the effects of the cold paste.

[0112] In some embodiments, as described herein, the device for protecting the cornea includes a member that provides suction, such as a suction cup. In some embodiments, the member providing suction is placed over the cornea, covering it and held in place by suction. In some embodiments, the member providing suction of the corneal protection device forms a seal around the periphery of the cornea. In some embodiments, where the corneal protection device is used in conjunction with the application of a paste to the ocular surface, the member providing suction provides a seal around the periphery of the cornea, preventing the deposited (i.e., surface-applied or injected) paste from direct contact with the cornea. The diameter of the member providing suction (e.g., a suction cup) of the corneal protection device can be of various sizes to accommodate different corneal sizes, thus allowing the device to be used on different subjects of different ages and sizes (e.g., children, adults, etc.), including animals and humans. For example, the diameter of the opening of the member providing suction (e.g., a suction cup) can be 11 to 14 mm.

[0113] Reference Figure 11In some embodiments, the suction-providing component of the corneal protection device 10 includes a suction cup 100 comprising one or more curved circular walls 110, wherein the diameter of the walls gradually decreases until they reach a tip 140, and wherein the suction cup 100 includes an opening surface 120 configured to contact the ocular surface and surround the periphery of the cornea. In some embodiments, the corneal protection device includes an internal cavity 130 and is configured such that when one or more curved walls 110 are squeezed or pinched, air is expelled from the internal cavity 130, and after the opening surface of the suction cup 120 is placed on the ocular surface, the pinching or squeezing force on the one or more curved walls 110 is released, resulting in the formation of a vacuum or partial vacuum within the internal cavity 130, which allows the suction cup to adhere to the ocular surface and seal the cornea surrounded by the opening surface 120 of the suction cup. In some embodiments, one or more curved walls 110 and / or the entire corneal protection device 10 includes thermal insulation material to further protect the cornea from lateral heat diffusion from the surrounding environment, including if a cooling plasma has been applied to the sclera adjacent to the cornea. In some embodiments, an internal cavity 130 that may be partially or completely evacuated provides additional thermal protection to the enclosed cornea from the influence of the surrounding environment by delaying 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 includes a non-porous material with low thermal conductivity, such as polymers, polyvinyl chloride (PVC), neoprene rubber, polyethylene (PE), polytetrafluoroethylene (PTFE), silicone, ethylene propylene diene monomer rubber (EPDM), elastomers, silicone, thermoplastic elastomers (TPE), thermoplastic polyurethane (TPU), etc.

[0114] In some embodiments, one or more curved walls 110 and / or the entire corneal protection device 10 comprises one or more layers of a low thermal conductivity material. In some embodiments, the thermally conductive material is selected from polyurethane (PU) foam, polyisocyanurate foam, extruded polystyrene foam (XPS), expanded polystyrene foam (EPS), aerogel, silicone, EPDM, elastomer materials, etc.

[0115] In some embodiments, the suction-providing components (e.g., suction cups) and / or one or more curved walls 110 of the corneal protection device provide high thermal resistance to slow the rate of heat transfer from the surrounding cold plasma to the cornea. In some embodiments, the suction cups and / or one or more walls of the corneal protection device comprise optically clear or translucent materials, such as optically clear silicone. In some embodiments, the suction cups and / or one or more walls of the corneal protection device comprise optically opaque materials, such as silicone and stained elastomeric materials.

[0116] In some implementations, the component that provides suction (e.g., a suction cup) includes the following design parameters: suction area / diameter, wall thickness, vertical height, etc.

[0117] In some embodiments, when the suction-providing component (e.g., a suction cup) of the corneal protector is held in place by suction, a vacuum or partial vacuum is formed between one or more walls 110 of the internal cavity 130 of the corneal protector. This vacuum or partial vacuum provides thermal protection to the cornea against the effects of the surrounding environment, including deposited cold slurry that may contact the outer wall of the corneal protector.

[0118] Reference Figure 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 a wall of the corneal protection device in the region of the upper portion 212. In some embodiments, the corneal protection device includes a bottom element 214 that forms a member (e.g., a suction cup) providing suction, having an opening positioned on the ocular surface to cover the cornea, and creating a barrier between the periphery of the cornea and the sclera when held in place by suction.

[0119] In some embodiments, a suction-providing component (e.g., a suction cup) is used to protect the cornea from its surrounding environment, including any cold plaque applied to the ocular surface. This is achieved by first pinching or squeezing the top element 212 of the device to activate the suction-providing component (e.g., the suction cup), then positioning the bottom element 214 on the ocular surface such that the edge of the device contacts the eye around the outer edge or periphery of the cornea, and subsequently releasing the top element 212 to activate the suction, causing the suction-providing component to adhere to the ocular surface. The suction ensures that the device remains in position covering and protecting 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 implementations, a suction component (e.g., a suction cup) is used to protect the cornea from its surrounding environment (including any cold paste applied to the surface of the eye) by first positioning the bottom element 214 on the surface of the eye such that the edge of the device that contacts the eye surrounds the outer edge or periphery of the cornea, and then pinching / squeezing and releasing the top element 212 of the device to expel air from the component (e.g., the suction cup) and create a low-level vacuum within the component, thereby holding the component in place.

[0120] Reference Figure 13A and Figure 13B This illustrates a corneal protection device 300 and its application in forming a seal around the periphery of the cornea. The corneal protection device 300 includes one or more walls 310, an opening surface 330 that contacts a target surface (e.g., the ocular surface) and surrounds the periphery of a region on the target surface (e.g., the cornea), and an internal cavity maintained under vacuum or partial vacuum when the suction of the device is activated. In some embodiments, one or more walls 310 include a top element 312 and a bottom element 314 shaped as a cup. Figure 13B As shown, the bottom element 314 includes an open surface 330 positioned at the periphery of the target region (e.g., the cornea), and the top element 312 is squeezed or pinched to expel air from the internal cavity, thereby generating a suction (i.e., vacuum) force within the cavity that holds the corneal protection device in place on the target surface (e.g., as shown). Figure 13B (The area above the cornea shown).

[0121] Contact lenses used to protect the cornea

[0122] In some embodiments, aspects of the invention relate to the use of contact lenses to protect the cornea both physically and thermally during cryo-liquid therapy. A contact lens may be placed on the cornea before the cryo-liquid is applied to the eye. The contact lens can act as both a physical and thermal barrier between the cornea and the surrounding cryo-liquid. Potential advantages of using contact lenses for corneal protection during cryo-liquid therapy include ease of use and patient familiarity with the product, which helps reduce anxiety during treatment. However, there are some challenges associated with using contact lenses: 1) the contact lens may shift during treatment, exposing the cornea to the liquid; 2) the liquid may still spread laterally, i.e., the corner of the lens may enter from the sclera and into the cornea; 3) typical contact lenses are porous, potentially allowing surrounding liquid to enter the cornea; and 4) the contact lens needs to be very thin to be placed on the corneal surface, thus limiting the thermal resistance to the surrounding cryo-liquid provided by the contact lens.

[0123] In some implementations, contact lenses containing materials that have low thermal conductivity but still allow for sufficient suction can be used, such as polymethyl methacrylate (PMMA), silicone, hydrogels, etc.

[0124] Device for protecting eyelids

[0125] If the eyelids of the patient come into contact with the paste described herein, the sub-zero temperature of the cold paste and the duration of its contact with the eyelids may potentially cause inflammation and / or physical damage. Eyelid protection devices are described herein, which can be used alone or in combination with cold paste treatment to physically and thermally separate the eyelids from materials (e.g., cold paste) already applied to the ocular surface. Eyelid protection devices are typically shaped to fit between the patient's upper and lower eyelids and act as a physical and thermal barrier between the eyelids and the materials deposited on the ocular surface (e.g., cold paste). In some embodiments, the eyelid protection device also functions as a speculum to keep the eye open during treatment.

[0126] Reference Figure 14A and Figure 14BIn some embodiments, eyelid protection devices 400, 500 include surfaces 410, 510 that contact the upper eyelid and surfaces 420, 520 that contact the lower eyelid. In some embodiments, one or both of surfaces 410, 510 and 420, 520 are curved (e.g., convex) in shape 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 a 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 function as a speculum to keep the eyelid open when the device is inserted into the eye. In some embodiments, the eyelid protection device includes an opening located between or surrounded by surfaces 410, 510 and 420, 520, which adapts to the surface of the eye. The size of the opening may vary depending on the size of the subject's eye. In some embodiments, the eyelid protection device includes a single continuous component comprising both surfaces 410, 510 and surfaces 420, 520. In some embodiments, the eyelid protection device includes more than one component, wherein surfaces 410, 510 and 420, 520 are individual 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 segments of curvilinear links that are movable relative to each other to adjust the size of the opening in the device to accommodate eyelids of various shapes and sizes. In some embodiments, the distance between the openings 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.

[0127] The dimensions of each aspect of the eyelid protection device are adjustable to provide a device that adapts to eyelids and eyes of various shapes and sizes. In some embodiments, the eyelid protection device includes dimensions that allow the eyelid to open in the range of 0 to 20.83 mm or 17.25 to 20.83 mm. In some embodiments, the depth of the protrusion under the eyelid of the eyelid protection device is 2.54 to 5.85 mm. In some embodiments, the eyelid protection device comprises one or more types of plastics, extruded plastics, silicone, EPDM, etc. In some embodiments, the eyelid protection device comprises one or more low thermal conductivity materials, such as silicone and EPDM. In some embodiments, the eyelid protection device comprises one or more porous materials, such as open-cell foam, PVA, etc., which are both thermal insulators and wicking materials.

[0128] In some embodiments, the eyelid protector is configured to allow molten (i.e., liquid or lower viscosity) slurry to drain from the ocular surface. For example, in some embodiments, the eyelid protector 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 ocular surface. In some embodiments, it is advantageous to remove hotter, molten slurry from the ocular surface because it allows a new batch of cold slurry to be supplied to the ocular surface while the eyelid protector remains in place. In some embodiments, it is desirable to remove such molten slurry during treatment to ensure that the ocular surface remains in contact with the ice-crystal-containing slurry at the desired temperature (rather than being covered by hotter molten slurry), thereby improving the efficiency and effectiveness of treatment. In some embodiments, the eyelid protector includes a wicking structure and / or wicking material that facilitates the removal of molten slurry from the ocular surface. Some examples of wicking materials and structures that can be incorporated into the eyelid protector include, but are not limited to, PVA, open-cell foam materials, etc.

[0129] Reference Figure 14B In some embodiments, the eyelid protection device includes structures for receiving and retaining a corneal protection device, such as feature 550, which is described herein and, for example, in... Figures 11 to 1 The corneal protection device shown in Figure 3. Such an eyelid protection device combined with the corneal protection device can be used to protect both the eyelids and the cornea, for example, when the cold gel described herein is applied to the surface of the eye. Figure 15A and Figure 15B Examples of eyelid protection devices and corneal protection devices used in combination are shown.

[0130] kit

[0131] For more effective cold plasma treatment, the ocular surface should be maintained at sub-zero temperatures throughout the treatment duration. In some cases, the surface-applied cold plasma may heat above a critical temperature and melt on the ocular surface before the treatment is complete, necessitating the application of additional doses to maintain the desired sub-zero ocular surface temperature. Therefore, kits for providing multiple doses of cold plasma are described herein, allowing for treatments that include multiple applications of the plasma to maintain the ocular surface at sub-zero temperatures throughout the entire treatment process. (See reference...) Figure 16 In some embodiments, kit 600 includes a plurality of syringes 610 pre-filled with slurry. In some embodiments, the kit includes an outer package 620 containing the plurality of syringes 610. In some embodiments, the outer package 620 is configured to store, seal, and provide thermal and moisture protection to the plurality of syringes 610. In some embodiments, kit 600 includes at least two syringes pre-filled with slurry. In some embodiments, kit 600 includes 2 to 20, 2 to 15, 2 to 10, or 2 to 5 syringes pre-filled with slurry. In some embodiments, kit 600 includes a single syringe pre-filled with slurry. The number of syringes in the kit can vary depending on a variety of factors, including the planned duration of treatment, the size of the eye, and the ability to store kits of different sizes (e.g., the size of the available cryostat). The amount of slurry in each syringe can also vary depending on the same type of factors listed above that relate to the details of the desired treatment and storage resources (e.g., 1 to 20 ml). Before and during the use of cold plasma procedures, the kit can be stored in a cryostat to ensure that the cold plasma in each syringe is started and substantially maintained at the desired temperature (e.g., sub-zero) during the procedure. Such a kit can also help facilitate the proper use and effectiveness of cold plasma therapy, as clinicians have a better understanding of how much to administer to the treatment area and at what intervals new doses should be administered.

[0132] In some embodiments, kit 600 includes a thermal pack configured to maintain the cold slurry at a sub-zero temperature for the desired duration after the kit has been removed from the freezer and placed under ambient temperature conditions (e.g., during transport or before short-term use). This is particularly useful in situations where a freezer is not available during the cold slurry process, such as in remote, underdeveloped areas. In some embodiments, the thermal pack of the kit comprises a phase change material, insulation, a reflective barrier, reflective foil, polystyrene foam, or a combination thereof.

[0133] In some embodiments, the kit comprises one or more empty syringes and a separate container containing slurry. Prior to the procedure, one or more empty syringes can be filled with cold slurry by drawing slurry from the container. In some embodiments, slurry can be drawn into one or more empty syringes at ambient temperature conditions, under which conditions the liquid slurry can be readily drawn from the syringes. In such embodiments, the filled syringes can be returned to the kit and placed and / or stored in a freezer before use.

[0134] In some embodiments, the kit includes an outer packaging made of an air and / or moisture barrier, such as a metallized polymer film, a thin metal film, a polymer film, expanded polystyrene foam, etc., to impart a long shelf life to the slurry. In some embodiments, the outer packaging seals the kit to provide a level of protection against, for example, potential contamination, temperature variations, and / or other environmental conditions.

[0135] Methods for preparing and transporting cold slurry formulations have been previously described, for example, in: U.S. Patent No. 11,241,330; U.S. Patent No. 11,564,830; U.S. Patent No. 11,471,401; U.S. Patent Application Serial 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 herein by reference in their entirety. In some embodiments, the kit includes a pre-filled syringe 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 previously described manufacturing systems and methods, such as those described in: U.S. Patent Nos. 11,241,330 and 11,564,830, which are incorporated herein by reference in their entirety. In some embodiments, the kit includes at least one pre-filled syringe, wherein the kit is transportable, the contents of the syringe are convertible into a slurry, and the slurry is applicable according to the disclosure of Patent No. 11,471,401, which is incorporated herein by reference in its entirety.

[0136] Independent cooling unit

[0137] In some embodiments, aspects of the invention relate to a separate cooling device that allows the transfer of heat energy from a target surface (e.g., the ocular surface) during cryotherapy. In some embodiments, the separate cooling device is used for cryoneurolysis purposes. In some embodiments, such a separate cooling device is configured to protect the cornea, eyelids, and potentially other sensitive structures (e.g., tissues, skin) from the sub-zero temperatures required during cryoneurolysis procedures and from any physical damage that may occur during the application of treatment.

[0138] In some embodiments, aspects of the invention relate to a stand-alone cooling device comprising a container containing a thermal mass (e.g., a liquid, solid, or cryopreservation preparation) with a freezing point lower than that of water. In some embodiments, such a device may be transported and stored in sterile packaging at ambient temperature or in a standard freezer. In some embodiments, such packaging is frozen prior to use. In some embodiments, when ready for use, the device is removed from the freezer and its packaging (e.g., a sterile barrier) and applied to the target eye surface to achieve cryo-neurolysis. In some embodiments, the device is discarded after use. In some embodiments, the liquid or cryopreservation preparation is sealed within the container such that it cannot directly contact the target eye surface or surrounding tissues and body parts (e.g., cornea, eyelids, skin) and thus cause any damage to the target eye surface or surrounding tissues and body parts (e.g., cornea, eyelids, skin).

[0139] In some embodiments, the independent cooling device comprises a thermomaser (e.g., a liquid, solid, or cryopreservative formulation). In some embodiments, the thermomaser is contained within a heat exchanger. In some embodiments, the thermomaser comprises a formulation containing about 20% by weight of glycerol in water (e.g., pure water).

[0140] In some aspects, the independent cooling device according to this disclosure may be sterilized. In some embodiments, the independent cooling device is placed in packaging after sterilization. In some embodiments, the independent cooling device is sterilized after being placed in packaging. In some embodiments, the independent cooling device is sterilized before transportation. In some embodiments, the independent cooling device and optional packaging are sterilized, transported, received at the point of care, placed in a freezer, and subsequently opened for use, thereby maintaining sterility throughout the preparation and transportation process prior to surgery.

[0141] In some embodiments, the independent cooling device is configured to perform a cryo-neurolysis procedure to provide long-term relief of ocular pain. In some embodiments, such an independent 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 independent cooling device is used in combination with an eyelid protection device to protect the subject's eyelids from damage during the cooling treatment. In some embodiments, the independent cooling device is configured to maintain balance over the subject's eye when the subject is in a supine position.

[0142] In some embodiments, aspects of the invention relate to a stand-alone cooling device capable of maintaining the ocular surface at sub-zero temperatures. Referring to FIG17, in some embodiments, a stand-alone device 700 includes a target (e.g., eye) surface interface 710 configured to contact a desired portion of the target (e.g., eye) surface and acting as an effective thermal interface that efficiently transfers heat energy from the ocular surface to a thermoplastic mass, thereby enabling the ocular surface to be cooled and maintained at a desired sub-zero temperature for long-term sensory reduction. In some embodiments, where the thermoplastic mass is used to remove heat energy from the ocular surface, the ocular surface interface 710 of the device acts as a physical barrier between the ocular surface and the thermoplastic mass. In some embodiments, the thermoplastic mass comprises a cold plasma, solid ice, or a liquid formulation. Some advantages of such a stand-alone cooling device are that the biocompatibility or flowability of the thermoplastic mass (e.g., cold plasma, liquid formulation) is not an issue because the thermoplastic mass does not have direct physical contact with the ocular surface, which can lead to a more streamlined and simpler procedure.

[0143] In some embodiments, the independent cooling device includes a formulation chamber or reservoir 720 for containing a thermophysical mass (e.g., a liquid or slurry formulation) that can be frozen at a temperature lower than that of water, such as the cold slurry described herein. In some 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 or a portion of the reservoir or chamber 720 containing the formulation within a standard freezer. As shown in Figures 17A and 17B, the ocular surface interface 710 may be part of or attached to the bottom of the reservoir or chamber 720. In such a configuration, heat energy from the ocular surface is dissipated through the ocular surface interface 710 and enters the formulation within the chamber or reservoir 720.

[0144] In some embodiments, the ocular surface (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 aperture (e.g., circular, rectangular, elliptical, irregularly sized opening) 712, which is configured to be aligned above the target region of the eye (e.g., the cornea) to prevent the cornea from being directly cooled via the ocular surface interface 710 and through the cold plasma in the chamber 720.

[0145] In some embodiments, the formulation within chamber 720 utilizes the latent heat of a phase change (e.g., a solid-liquid phase transition) to maintain the sub-zero temperature on the target eye surface for a predetermined duration (i.e., a volume-controlled amount of heat transfer).

[0146] In some embodiments, the ocular surface (i.e., target surface) interface 710 comprises one or more highly thermally conductive materials, such as Al, Cu, Au, Ni, stainless steel, metal alloys, thermally conductive plastics comprising metal impregnated polyimide, or combinations thereof. In some embodiments, the ocular surface interface 710 comprises one or more encapsulated phase change materials (PCMs), shape-stable PCMs, or combinations thereof. In some embodiments, the surface of the ocular surface interface 710 in contact with the ocular surface comprises a non-stick coating, such as PTFE, a hard coating, an anodized coating, or a diamond-like coating (DLC). In some embodiments, the surface of the ocular surface interface 710 in contact with the ocular surface comprises a hydrophobic surface coating, which comprises a nanocoating and a composite material. In some embodiments, the surface of the ocular surface interface 710 in contact with the ocular surface comprises a surface coating that protects the ocular surface from adhesion to the frozen ocular surface interface 710, such as a hard coating, anodized coating, DLC, a nanocoating, a composite material, PTFE, etc. In some embodiments, the surface of the ocular surface interface 710 in contact with the ocular surface includes geometrically designed features (e.g., hierarchical micro / nanostructures and surfaces, bio-inspired hydrophobic surface patterns) that protect the ocular surface from adhesion to the frozen ocular surface interface 710. In some embodiments, the ocular surface interface 710 in contact with the ocular surface comprises a thin film of material.

[0147] In some embodiments, the surface of the ocular surface interface 710 in contact with the ocular surface comprises a hydrophilic surface coating. In some embodiments, the surface of the ocular surface interface 710 in contact with 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 independent cooling device comprises one or more electromechanical systems for circulating coolant (or cold air) through the ocular surface interface 710. In some embodiments, the independent cooling device comprises one or more mechanical systems for delivering coolant to the ocular surface interface 710. In some embodiments, the independent cooling device comprises one or more mechanical systems facilitating the manual application of coolant to the ocular surface interface.

[0148] To ensure the target surface remains at the desired sub-zero temperature during treatment, the ocular surface interface 710 should maintain partial contact with the formulation (e.g., a frozen or slurry formulation) 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 will begin to melt as it heats up, due to heat transfer from the ocular surface to the ocular surface interface 710 and subsequently to the formulation within the chamber or reservoir 720. For example, in embodiments where the formulation contains water, because liquid water is denser than ice, the melting (i.e., liquid, thawed) portion of the formulation will tend to sink to the bottom of the chamber or reservoir 720 in contact with the ocular surface interface 710, while the more solid portion of the formulation (e.g., the ice portion) will tend to float to the top of the chamber or reservoir 720 and lose contact with the ocular surface interface 710, resulting in a reduced heat-carrying capacity of the formulation in contact with the ocular surface interface 710.

[0149] In some embodiments, the independent cooling device includes a mechanism 730 for pushing the frozen portion of the formulation within the chamber or reservoir 720 downward 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. This is achieved by pushing the formulation downward and forcing the colder (e.g., ice or frozen) portion of the formulation toward the bottom of the chamber or reservoir 720 in contact with the ocular surface interface 710, while allowing the hotter portion of the formulation (e.g., melted or thawed liquid) with a lower heat carrying capacity than the colder portion of the formulation to flow from the bottom of the chamber or reservoir 720 in contact with the ocular surface interface 710 to the top of the chamber or reservoir 720. In some embodiments, a mechanism for pushing the formulation downward 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 includes: one or more side pins 734 that can be pushed in or out of a hollow chamber 732 located above or forming the upper portion of the formulation chamber or reservoir 720; a tension spring 736, the ends of which are operatively connected to or physically attached to a removable cover 733 and a movable plate 738 located in or forming the upper portion of the formulation chamber or reservoir 720; and a movable plate 738 fitted within an opening 724 at the top of the formulation chamber or reservoir 720 and contacting or closely approaching the 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 internal contact or close proximity to the vertical wall 722 of the formulation chamber or reservoir 720. In some embodiments, the sliding plate includes one or more holes to allow molten liquid to pass through it as the sliding plate moves up and down within the chamber or reservoir 720. In some embodiments, when the side pin 734 is pushed into or pulled out of the hollow chamber 732, it releases the spring 736, causing the movable plate 738 to translate downward within the formulation chamber or reservoir 720. This forces the colder (e.g., ice or frozen) portion of the formulation towards the bottom of the formulation chamber or reservoir 720 to contact the ocular surface interface 710 of the device, while the warmer (e.g., molten or thawed) portion of the formulation is pushed towards the upper part of the formulation chamber or reservoir 720. In some embodiments, the mechanism for maintaining contact between the colder (e.g., ice or frozen) portion of the formulation and the ocular surface interface 710 relies on vacuum, gravity, capillary force, magnetism, or a combination thereof.

[0150] In some embodiments, the independent cooling device 700 may also include a structure 740 for receiving additional devices or structures, such as the eyelid protection device and / or corneal protection device described herein. In some embodiments, such an independent cooling device also includes an eyelid protection device and a corneal protection device. Such an independent cooling device can simplify the cryosurgery described herein by reducing the number of devices and related steps that clinicians must assemble / handle and use during surgery.

[0151] In some implementations, the independent cooling device includes features (e.g., adsorption, physical positioning features) to prevent the independent device mounted on the ocular surface from shifting during treatment.

[0152] Referring to Figures 18A and 18B, in some embodiments, the independent cooling device 800 includes a corneal protection device 850 integrated with the structure 840 of the independent cooling device 800. Such an independent cooling device combined with a corneal protection device can be used to protect both the cornea and the target surface from direct contact with the cooling plasma, for example, while relying on the cooling plasma described herein to affect the cooling of the target surface.

[0153] In some embodiments, when the independent cooling device 800 is mounted above the ocular surface to allow the ocular surface interface 810 to contact the desired portion of the ocular surface, the corneal protector device 850 contacts the cornea in a manner that protects it from physical or thermal contact with any foreign substance (e.g., cold plasma). In some embodiments, the corneal protector device 840 maintains its position above the cornea when the side pin 834 is pressed against the hollow chamber 832 to activate the mechanism 830, which enables the ocular surface interface 810 to remain in contact with the cold, frozen plasma and allows the liquid plasma to be pushed away from the ocular surface interface 810.

[0154] In some implementations, a method for treating ocular surface discomfort using a separate cooling device is provided. Figure 19 Exemplary methods according to certain embodiments of this disclosure are provided. First, an anesthetic may be applied to the subject's eye. Next, an accessory (e.g., a speculum) may be placed to keep the eye open. After placing the speculum, a separate cooling device is placed. Optionally, the speculum includes a guide configured to ensure proper placement of the separate cooling device. The separate cooling device may include an orifice configured to allow a clinician to visualize the subject's cornea and maintain correct device positioning. Once the separate cooling device contacts the subject's eye, it is allowed to remain in contact with the eye for a certain treatment time (e.g., from about 2 minutes to about 10 minutes). After the treatment time, the eye is rinsed (e.g., with saline) to prevent adhesion between the eye and the separate cooling device after treatment. After rinsing, the device and speculum are removed. Figure 24A graph is provided showing the treatment time relative to the removal time after treatment using the method according to this disclosure.

[0155] In some embodiments, the independent cooling device cools the target surface via conduction. In some embodiments, the independent cooling device first contacts the target surface, such as the sclera, and conducts heat from the target surface into the device, such as to the target surface interface and into a heat exchanger, and ultimately from the heat exchanger into a thermomass (e.g., a liquid, solid, or partially solid cryopreservation formulation), where the latent heat of fusion (e.g., a solid-liquid phase transition) allows the therapeutic temperature to be maintained.

[0156] In some aspects, an independent cooling device is allowed to maintain continuous contact with the eye for a certain 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 exceeds 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 more than about 60 minutes. In some embodiments, the treatment time is about 1 to 2 minutes, about 2 to 3 minutes, about 3 to 4 minutes, about 4 to 5 minutes, about 5 to 6 minutes, about 6 to 7 minutes, about 7 to 8 minutes, about 8 to 9 minutes, about 9 to 10 minutes, about 2 to 4 minutes, about 3 to 5 minutes, about 4 to 6 minutes, about 5 to 7 minutes, about 6 to 8 minutes, about 7 to 9 minutes, about 8 to 10 minutes, about 2 to 5 minutes, about 3 to 6 minutes, about 4 to 7 minutes, about 5 to 8 minutes, about 6 to 9 minutes, about 7 to 10 minutes, or about 2 to 10 minutes. In some embodiments, the treatment time is about 10 to 15 minutes, about 15 to 20 minutes, about 20 to 25 minutes, about 25 to 30 minutes, about 30 to 35 minutes, about 35 to 40 minutes, about 40 to 45 minutes, about 45 to 50 minutes, about 50 to 55 minutes, or about 55 to 60 minutes.

[0157] In some aspects, the independent cooling device is placed in a cold environment prior to 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, achieved by rapid freezing (e.g., using liquid nitrogen), or any other suitable cold environment. In some embodiments, the independent cooling device is placed in a standard freezer for at least about 12 hours prior to the method of treating ocular surface discomfort using the independent cooling device provided herein. In some embodiments, the independent 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 prior to the method of treating ocular surface discomfort using the independent cooling device provided herein.

[0158] In some aspects, the independent cooling device is at a predetermined temperature prior to use in the methods provided herein. In some embodiments, the predetermined temperature is a sub-zero temperature. In some embodiments, the predetermined temperature is from 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 some embodiments, 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 to 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.

[0159] In some embodiments, the eye reaches the treatment temperature once the independent cooling device comes into contact with the subject's eye. In some embodiments, the treatment temperature is below zero. In some embodiments, the treatment temperature is from about -6°C to about 4°C. In some embodiments, the treatment temperature is about -6°C. In some embodiments, the treatment temperature is about 4°C. In some embodiments, the treatment 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 some implementations, 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 to 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.

[0160] In some aspects, the methods and apparatus provided herein achieve rapid cooling after the eye comes into contact with a separate cooling device according to this disclosure. In some embodiments, the eye (i.e., target) surface interface of the separate cooling device contacts the sclera of the eye, wherein the sclera reaches a therapeutic temperature (e.g., below 0°C) after approximately 30 seconds. In some implementations, the sclera is stained for approximately 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds, 110 seconds, 120 seconds, 130 seconds, 140 seconds, 150 seconds, 160 seconds, 170 seconds, 180 seconds, 190 seconds, 200 seconds, 210 seconds, 220 seconds, 230 seconds, 240 seconds, 250 seconds, 260 seconds, 270 seconds, 280 seconds, and 290 seconds. The treatment temperature (e.g., below 0°C) is reached after approximately 300 seconds, 310 seconds, 320 seconds, 330 seconds, 340 seconds, 350 seconds, 360 seconds, 370 seconds, 380 seconds, 390 seconds, 400 seconds, 410 seconds, 420 seconds, 430 seconds, 440 seconds, 450 seconds, 460 seconds, 470 seconds, 480 seconds, 490 seconds, 500 seconds, 510 seconds, 520 seconds, 530 seconds, 540 seconds, 550 seconds, 560 seconds, 570 seconds, 580 seconds, 590 seconds, or 600 seconds.

[0161] In some aspects, the independent cooling unit includes an insulating feature. In some embodiments, the insulating feature is a gap between the housing of the independent cooling unit and the heat exchanger. In some embodiments, the gap is an air gap. In some embodiments, the gap is filled with an insulating material. Insulating the independent cooling unit provides advantages by minimizing condensation on the independent cooling unit, maintaining the desired temperature of the independent cooling unit (including one or more contact surfaces), and / or by maintaining the volume of the thermomass (e.g., within the heat exchanger).

[0162] In some respects, the independent cooling unit is configured to be balanced. A balanced independent cooling unit can be advantageous because it allows clinicians easy access during use.

[0163] Referring to Figures 20A and 20B, an exploded view of a stand-alone cooling device according to this disclosure is provided. In some embodiments, the stand-alone cooling device 900 includes a housing 910 housing a heat exchanger 920. In some embodiments, the housing 910 includes multiple components, such as a top component and a bottom component. In some embodiments, the housing 910 includes one or more polycarbonate components. In some embodiments, the stand-alone cooling device includes a gap between the housing 910 and the heat exchanger 920. In some embodiments, the gap provides insulation for the heat exchanger 920, such as an air gap. 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 including metal-impregnated polyimide, or combinations thereof. In some embodiments, the heat exchanger 920 includes a cavity containing a thermomass (e.g., a liquid, solid, or partially solid cryogenic preparation). In some embodiments, the thermomass is contained within the heat exchanger 920. In some embodiments, the thermomass is frozen in a standard cryostat. In some embodiments, the heat exchanger 920 includes a bottom component and a top component, which may be separate components that can be joined together. In some embodiments, the thermomass is sealed within the heat exchanger 920, for example, by using an adhesive to join the top and bottom components after the thermomass has been placed inside the heat exchanger 920 chamber. In some embodiments, the heat exchanger 920 is formed from a single piece of metal, for example, by being machined from copper. This allows the independent cooling device to bring the ocular surface to a cold temperature very quickly by facilitating heat exchange between the ocular surface and the heat exchanger 920. In some embodiments, the heat exchanger 920 also includes a conductive structure 930 (e.g., fins or walls) to conduct heat from the ocular surface to the frozen thermomass. In some embodiments, the independent cooling device includes an ocular surface (i.e., target surface) interface 940 configured to freeze to the sclera of the eye upon contact. In some embodiments, the independent cooling device includes an ocular surface (i.e., target surface) interface 940 configured not to freeze to the sclera of the eye upon contact. In some embodiments, the independent cooling device includes a cap 950 configured to prevent condensation on the ocular surface (i.e., target surface) interface prior to use.

[0164] Reference Figures 21A to 21ESeveral external views of the independent cooling device depicted in Figures 20A and 20B are provided. In some embodiments, the independent cooling device includes a housing 910. In some embodiments, the housing 910 includes a gripping interface 1020. In some embodiments, the gripping interface 1020 is configured to assist clinicians in holding the device, for example, by indicating the correct finger placement or making the device easier to hold. In some embodiments, the independent cooling device includes an aperture 1030 configured to provide corneal visibility during surgery. In some embodiments, the independent cooling device includes an ocular surface (i.e., target surface) interface 940 configured to freeze to the sclera of the eye upon contact.

[0165] Referring to Figures 22A and 22B, Figures 20A, 20B, and... Figures 21A to 21E The drawings show the independent cooling device provided in this disclosure and its accessories. In some embodiments, the independent cooling device includes a housing 910, a gripping interface 1020, an orifice 1030, and an ocular surface (i.e., target surface) interface 940 configured to freeze to the sclera of the eye upon contact. In some embodiments, an accessory 1150 (e.g., a speculum) is provided, wherein the accessory is configured to help keep the subject's eye open during operation and to help the independent cooling device be properly positioned. In other embodiments, the accessory isolates the eyelid from the ocular surface interface 940. In some embodiments, the accessory comprises a flexible thermal insulation material (e.g., silicone). Figures 23A to 23D Drawings of attachments according to certain embodiments of this disclosure are provided. In some embodiments, the attachment includes an aperture 1230 configured to allow a clinician to visualize the subject's cornea. In some embodiments, the attachment includes one or more guide features 1235 (e.g., cutouts) configured to assist the clinician in placing an independent cooling device during surgery. In some embodiments, the attachment includes one or more surfaces 1260 configured to adapt to the lower eyelid of the subject to keep the eyelid open during surgery. In some embodiments, the attachment includes one or more features 1270 configured to push the patient's eyelashes away from the independent cooling device. In some embodiments, the attachment also includes an attachment gripping interface 1220. In some embodiments, the attachment gripping interface 1220 is configured to assist the clinician in correctly placing the attachment.

[0166] In some implementations, the independent cooling unit is reusable. In other implementations, the independent unit is disposable.

[0167] Now refer to Figure 25The figure illustrates an exemplary treatment area 2500 on a diagram of the eye. In some embodiments, an ocular surface (i.e., target surface) interface 940 is configured to contact the treatment area 2500.

[0168] In some aspects, the independent cooling device may be used in combination with the methods provided herein for treating ocular surface discomfort. In some embodiments, as described herein, the independent cooling device is placed in a cold environment (e.g., a standard cryostat) prior to use. In some embodiments, the independent cooling device is placed in a standard cryostat for at least 12 hours prior to use. In some embodiments, the independent cooling device is configured for use in combination with an accessory. For example, an accessory (e.g., a speculum) may be placed to keep the subject's eye open. A clinician may place the accessory into the subject's eye, for example, by squeezing the accessory while holding the accessory gripping interface 1220 so that the surface 1260 is positioned below the subject's eyelid to keep the eye open. After placing the speculum, the independent cooling device is placed. Optionally, feature 1270 may push the patient's eyelashes away from the independent cooling device during use. In some embodiments, the accessory (e.g., a speculum) includes a guide feature 1235 configured to ensure proper placement of the independent cooling device; for example, a clinician may place the ocular (i.e., target) surface interface 940 of the independent cooling device through the guide feature 1235. Next, the clinician can visualize the patient's eye (e.g., including the cornea) through orifices 1030 / 1230 to maintain the correct device position before using the ocular surface interface 940 to contact the eye. After contact, the ocular surface interface 940 may adhere to the eye and remain in contact for a certain treatment time (e.g., about 2 minutes to about 10 minutes). After the treatment time, steps may be taken to prevent adhesion between the eye and the ocular surface interface 940 of the independent cooling device 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 ocular surface interface 940 of the independent cooling device after treatment. After rinsing, the independent cooling device and accessories are removed from the eye. In some embodiments, the independent cooling device is warmed after treatment by, for example, using an electric heating element or system, removing the thermoplastic body, rinsing the interior of the device with a fluid (and optionally warm fluid), or a chemical (exothermic) reaction. In some implementations, the ocular surface interface 940 or accessory includes one or more channels configured to facilitate rinsing.

[0169] Mechanism of action

[0170] Unbound by any particular theory, the basic premise is that the application of sub-zero temperatures (e.g., from approximately -20°C to approximately 0°C) halts the transmission of painful stimuli by inducing degeneration of the myelin sheath in nerves. Myelin, a lipid-rich fatty substance, allows electrical stimulation to travel rapidly and effectively down the nerve axon. When cold plasma or other cryotherapy (e.g., using a separate cooling device according to this disclosure) is applied to both the free nerve endings and the myelinated portion of the nerve, the cold temperature freezes or crystallizes the lipid components of the adipocytes, inducing apoptosis and myelin degeneration—a process known as Wallerian degeneration. This process significantly reduces the transmission of painful stimuli from the cornea to the brainstem by the ciliary nerve. Due to the large volume of distal nerve endings on the ocular surface, not all peripheral nerves are affected, and therefore not all sensation from the ocular surface is eliminated, thus inducing relative sensory reduction rather than complete anesthesia. Furthermore, this effect subsides after approximately 4 to 8 weeks, at which point ocular sensation is fully restored. Other options for causing Waller's degeneration include radiofrequency ablation and cryo-neurolysis (freezing at temperatures close to -80°C), but these procedures carry the risk of damaging surrounding tissues and structures. Furthermore, inactive carriers containing ice crystals will not harm other parts of the eye, making them a reasonable option for treating nerves causing ocular surface pain. This approach preserves vision and normal ocular surface function.

[0171] Unbound by any particular theory, injection into the subconjunctival space around the limbus allows the cold paste to distribute around the free nerve endings of the ciliary nerve. Furthermore, surface application of the paste or cold application (e.g., using the independent cooling device provided herein) can be used to target the ciliary nerve and its free nerve endings using cold temperatures. There are two main ciliary nerves with free nerve endings branching into the cornea of ​​each eye. Each ciliary nerve is myelinated along its axon located downstream of its free nerve ending in the cornea. The injection of the cold paste, and / or the cold temperature from surface-applied cold paste and / or the independent cooling device, diffuses downstream to the site of myelination of the ciliary nerve axons. As the cold paste and / or the cold temperature from surface-applied cold paste and / or the independent cooling device diffuses to the axons of the ciliary nerve, it causes myelin crystallization and apoptosis, thereby demyelinating the ciliary nerve. Demyelination prevents the nerve from transmitting pain signals to the brain. Alternatively, the cold temperature from the surface-applied cold paste and / or the independent cooling device can induce Wallerian degeneration of the nerve and similarly prevent pain signals from being transmitted to the brain. Alternatively, the cold temperature from the surface-applied cold paste and / or the independent cooling device can target the free nerve endings of the ciliary nerve.

[0172] Topical application and / or injection of cold gel, or a stand-alone cooling device, is superior to other application methods because it does not damage the corneal surface.

[0173] The scope of the systems and methods disclosed herein is not limited to the specific embodiments described herein. In fact, various modifications to the devices, systems, and methods other than those described will become apparent to those skilled in the art from the foregoing description. The data described herein support the application of cold plasma (surface and injection) and independent cooling devices as a long-term and safe treatment for corneal numbness, causing hypoesthesia without permanent corneal numbness or damage.

[0174] Example 1 - In vivo testing of cryosurgery for corneal numbness

[0175] The results of the study described in this embodiment can be Figures 5 to 9 This was observed. Preclinical animal studies were conducted to determine the efficacy of the treatment, including exploring the optimal method of delivery, the duration of therapeutic effect, and any potential side effects. For ophthalmic research, the New Zealand white rabbit is an ideal model because its cornea and corneal innervation system are very similar to those of humans, and it is the standard, recognized model used in the literature for corneal research.

[0176] Procedural preparation

[0177] Animals were given a prophylactic anesthetic (rabbit xylazine 1.1 mg / kg IM, buprenorphine HCl 0.01 to 0.05 mg / kg IM) and a preoperative antibiotic (cefazoline 25 to 50 mg / kg IM). The animals were then anesthetized (rabbit ketamine 33 mg / kg IM). Animals were placed on a heating pad and their vital signs were monitored. Two drops of 0.5% proparacaine HCl and 0.5% phenylephrine / 0.5% tropicamide (expanding drops) were administered to the eye of study. Inhalation anesthesia (1.5% to 2% isoflurane) was administered and oxygen was supplemented.

[0178] Research Procedures

[0179] Prepare and drape the animal using standard aseptic techniques, including instilling povidone-iodine drops onto the ocular surface. Place a speculum and administer a topical or subconjunctival injection of the slurry.

[0180] Injection

[0181] To evaluate the sensory reduction potential of ECT-1719, approximately 0.7 mL of cryo-surgery was injected into the subconjunctival space around the limbus. The injected cryo-surgery was evenly distributed 360 degrees around the limbus, partly due to pressure from the cornea, injection force, and the presence of the natural potential space. The injection procedure was repeated every 120 seconds for a total of 10 minutes.

[0182] Control animals received either sterile saline (control) or a loading control (uncooled slurry). At the end of the procedure, the eye was carefully examined, the speculum was removed, the covering was removed, and the eye was rinsed with sterile saline. There was also a separate control group that received routine anesthetic drops to the cornea. All procedures were performed only on the left eye (for control purposes) and lasted approximately 10 minutes.

[0183] The above-mentioned surgical procedures are usually performed on a person, and various different drugs (such as steroids, antibiotics, etc.) are injected depending on the situation.

[0184] Surface application

[0185] To evaluate the sensory reduction potential of ETX-4143, the gel was applied topically to the ocular surface (posterior to the limbus). The cornea was protected with a contact lens, and the eyelids were protected with a plastic speculum. Approximately 2 mL of the cold gel was applied topically every 30 seconds for the first 4 minutes, and then approximately every minute thereafter, until a total treatment time of 10 minutes was reached. At the end of the procedure, the eye was carefully examined, the speculum was removed, the covering was removed, and the eye was rinsed with sterile saline.

[0186] Post-processing for surviving animals

[0187] Apply neomycin / polymyxin / bacitracin ointment to the operated eye, and apply a few drops of prednisone acetate postoperatively. Remove the animal from the operating table and place it on a heating pad. Monitor the animal's vital signs (e.g., heart rate, respiration, SpO2) while awaiting recovery. Continue monitoring the animal until muscle control is restored. Return the animal to its original cage.

[0188] Postoperative animal monitoring

[0189] Animals underwent a comprehensive eye examination one day post-surgery and thereafter weekly, including measurements of corneal sensation. Intraocular pressure measurements were also performed, as a beneficial reduction in intraocular pressure was observed in animals that had already received this treatment. Additionally, slit-lamp examination with fluorescein staining and dilated fundus examination (i.e., dilation of the eye with 5% phenylephrine and 0.5% tropicamide) were performed. Animals were placed in a restraining cage for several seconds while eye drops were instilled.

[0190] The effect of application

[0191] The effects of applying cold slurry were examined using a variety of techniques.

[0192] The numbing effect of the cold paste was tested using a tactile meter. A monofilament with a certain stiffness extended from the device. Animals treated with the cold paste were able to tolerate greater forces from the tactile meter than animals in the control group. This was demonstrated by whether the animals recoiled when the tactile meter monofilament was inserted into the eye. This test was performed multiple times during the study to determine the length of the numbing effect.

[0193] The effect of cold plasma on the eye's healing ability was also examined. Epithelial defects were induced on the cornea using a trephine and corneal brush. The lesions were verified using fluorescein staining and documented by photography. The progression of the lesions was measured using fluorescein staining and lesion size measurement. Cold plasma did not affect the eye's healing ability.

[0194] Example 2 - In vitro testing of a stand-alone cooling device for the treatment of corneal numbness

[0195] The research results described in this embodiment can be found in Figure 26 , Figure 27 and Figure 28 As can be seen from this. Preclinical animal studies were conducted to determine the thermal effects of the independent cooling device according to this disclosure.

[0196] Reference Figure 26 In this embodiment, the surface of a pig eye is used to generate a representative temperature profile of the temperature taken from the surface of the pig eye. The pig eye is brought into contact with the ocular surface interface of an independent cooling device according to this disclosure. In this embodiment, the ocular surface interface is a copper ocular surface interface connected to a heat exchanger to form a piece, and the independent cooling device includes a thermoplastic mass containing 20% ​​by weight of glycerol in purified water. The temperature of the pig eye is measured over time and presented as... Figure 26 In the middle. For example Figure 26 As shown, the temperature reached 0°C after 29 seconds. The lowest recorded temperature was -3.5°C. Finally, after 536 seconds (8 minutes and 56 seconds), the temperature rose back above 0°C.

[0197] like Figure 27 As shown and described below, temperature measurements were also taken at three locations on the pig's eye. The pig's eye was partially immersed in a water bath to heat it to a representative surface temperature of approximately 33°C. Figure 27 As shown, temperature was monitored at three locations: location 1 (located at 0° relative to the horizontal and 1.5 mm from the treatment area 2500); location 2 (located at 45° relative to the horizontal and 1.5 mm from the treatment area 2500); and below the treatment area 2500.

[0198] Make the pig's eyes and the above-mentioned Figure 26 The independent cooling device is in contact with the object and records measurements over time. For example... Figure 28 As shown, the temperature below the treatment area 2500 reached 0°C after 29 seconds, and rose back above 0°C after 536 seconds (8 minutes and 58 seconds). Figure 26 The representative temperature curve depicted in the treatment area below 2500 is also... Figure 28 The results are shown in the figure. Temperatures were also recorded at location 1 (located at 0° relative to the horizontal and 2500 1.5 mm from the treatment area) and location 2 (located at 45° relative to the horizontal and 2500 1.5 mm from the treatment area). The results indicate that location 1 reached a cooler temperature compared to location 2.

[0199] Example 3 - In vivo testing of a stand-alone cooling device for the treatment of corneal numbness

[0200] The results of the study described in this embodiment can be Figure 29 As can be seen from the results. Preclinical animal studies were conducted to determine the efficacy of the treatment using the independent cooling device, including studying the ability to cool the eye, evaluating the effect on corneal surface numbness / anesthesia, the duration of the treatment effect, and any potential side effects. As noted in Example 1, the New Zealand white rabbit is an ideal model for ophthalmic research because its cornea and corneal innervation system are very similar to those of humans, and it is the standard and recognized model used in the literature for corneal research.

[0201] Independent cooling unit

[0202] An independent cooling device is designed to allow for the treatment of rabbit eyes, similar to treatment of human eyes. The independent cooling device contains thermocouples embedded in the ocular contact surface to measure the temperature of the ocular surface during surgery. The device is designed to contact and treat the rabbit eye at a 200° (220° to -20° gap) angle, specifically targeting the sclera portion just outside the cornea. Previous studies have shown that treating all areas around the cornea is difficult in this model. The contact surface (copper) is protected from the rabbit eyelids. The contact surface is configured to conduct heat directly to the chamber of the device, which is filled with ice with a reduced freezing point. In this embodiment, the ice is a mixture of purified water and glycerin (20% by weight). Before use, the device is placed in a freezer set at -20°C and allowed to stand for at least 12 hours, or alternatively, stood at -27°C for 2 hours, then at -20°C for 2 hours (4 hours refreezing).

[0203] Independent cooling device program

[0204] Prior to anesthesia, a corneal sensation test is performed. Subjects are anesthetized according to the standard procedures approved by the IACUC protocol. Topical promethazine is administered to both the treatment and control eyes. Using a speculum, the subject's eyelids are opened to expose the cornea and as much of the sclera as possible. If necessary, a corneal protector device (contact lens adsorption device) is placed onto the cornea via adsorption. When using the device, the cornea is centered between the two contact surfaces. The device is positioned such that it covers approximately 240 degrees of the scleral surface surrounding the cornea, carefully ensuring minimal obstruction from the subject's eyelids. Contact between the device and the eye is maintained for 10 minutes. At the end of the contact time, the eye and device are rinsed with warm water or saline, and the device is removed from the eye.

[0205] Postoperative monitoring

[0206] Following the surgery, the subject's overall health was monitored for one week. The subject also underwent a comprehensive eye examination one week after surgery, and subsequently weekly (+ / - 3 days), including corneal sensation tests and intraocular pressure (IOP) measurements using a tactile meter.

[0207] The function of independent cooling device program

[0208] Compared to their corresponding untreated eyes, rabbits exhibited a significant reduction in sensation, averaging approximately 75% in the first week and approximately 63% in the second week. See also Figure 29 The maximum reduction in sensation was measured approximately one week after treatment, with five out of eight rabbits showing a reduction of more than 85% compared to the control eye. No adverse effects were observed as a result of the treatment.

Claims

1. A cold serum formulation for reducing symptoms of ocular surface discomfort, the cold serum formulation comprising: water, and a freezing point depressant, wherein the cold serum formulation is configured to be applied directly or indirectly to a target ocular surface to cause numbing of the target ocular surface, and wherein ocular ocular sensation of the eye is restored after the cold serum is applied to the target ocular surface.

2. The cold serum formulation of claim 1, wherein the formulation further comprises a lipid.

3. The formulation of any one of claims 1 to 2, wherein the concentration of the freezing point depressant is about 10% to 40% (v / v).

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

5. The formulation of any one of claims 1 to 4, wherein the concentration of the freezing point depressant is about 10% to 20%, 20% to 30%, or 30% to 40% (v / v).

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

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

8. A method of reducing symptoms of ocular surface discomfort, the method comprising: applying a cold serum formulation on a surface of a patient's eye proximal to a limbus, wherein the cold serum formulation comprises water and a freezing point depressant, wherein the application of the cold serum formulation is configured to cause a degree of numbing of a cornea of the eye, and ocular ocular sensation of the eye is restored after the cold serum is applied to the target ocular surface.

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

10. The method of claim 8, wherein the cold serum formulation is applied to a posterior portion of the limbus.

11. The method of any one of claims 8 to 10, wherein the cold serum remains on the surface of the eye for more than about 4 hours without reapplication of the cold serum on any day following the first day of application.

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

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

14. 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 serum formulation further comprises hyaluronic acid.

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

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

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 the application of the cold serum.

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. The method of any one of claims 7 to 19, wherein an additional amount of the cold slurry is applied again about 90 seconds after the first application.

21. The method of any one of claims 8 to 20, wherein the applying is performed topically.

22. The method of any one of claims 8 to 20, wherein the applying is performed by injection.

23. A device for protecting a cornea on an ocular surface, the device comprising: a structure configured to adhere to the ocular surface by forming a vacuum, the structure comprising: an enclosing wall having an inner surface, an outer surface, and an open surface, the enclosing wall extending from a first end to a second end and the inner surface forming an interior cavity, wherein the open surface is configured to contact and surround a limbus of the cornea and form a vacuum within the interior cavity when the structure is activated.

24. The device of claim 23, wherein the adherence of the structure to the ocular surface substantially seals the cornea within the open surface of the enclosing wall.

25. The device of any one of claims 23 to 24, wherein the structure comprises a suction cup.

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

27. The device of any one of claims 23 to 26, wherein the enclosing wall comprises a thermal insulation material, the thermal insulation 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 enclosing wall comprises an optically transparent or translucent material.

29. The device of any one of claims 23 to 28, wherein the enclosing wall comprises an optically opaque material.

30. The device of any one of claims 23 to 29, wherein the structure is activated by constricting the interior cavity and subsequently releasing the constriction of the interior cavity.

31. The device of any one of claims 23 to 30, wherein the structure is activated by compressing the enclosing wall and subsequently releasing the enclosing wall.

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

33. A method for protecting a cornea on an ocular surface of a subject, the method comprising: a) positioning a cornea protection device comprising an interior cavity on a cornea of the subject; b) constricting and releasing a portion of the cornea protection device to form a vacuum within the interior cavity; and c) adhering the cornea protection device to the ocular surface. wherein the corneal protection device comprises an enclosing wall having an inner surface, an outer surface, and an open surface, the enclosing wall extending from a first end to a second end, wherein the inner surface forms the interior cavity.

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

35. The method of claim 34, wherein the corneal protection device is configured to protect the cornea from physical and thermal effects of 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 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, wherein the first surface and the second surface are configured to reversibly connect to each other so as to create an opening between the first surface and the second surface, and wherein upon insertion onto an eye, the device prevents the upper eyelid and the lower eyelid from closing and protects the eyelids from the ocular surface or a substance deposited on the ocular surface by physically and thermally spacing the eyelids.

39. The device of claim 38, further comprising a channel in one or more of the first surface and the second surface, wherein the channel is configured to allow fluid to escape from the ocular surface when the device is inserted on an eye.

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

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

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

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

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

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 opening.

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. The device of any one of claims 38-46, wherein one or more of the first surface and the second surface comprise curvilinearly connected segments that can be articulated relative to one another to adjust the size of the opening.

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

49. The device of any one of claims 38-48, wherein the device comprises one or more types of plastic.

50. The device of any one of claims 38-49, wherein the device comprises one or more porous materials.

51. The device of claim 50, wherein the one or more porous materials comprise a thermal insulation 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. The device of any one of claims 38-51, wherein one or more of the first surface and the second surface comprise a thermal insulation material and a wicking material.

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

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

55. The device of claim 54, wherein the corneal protection device comprises: a structure configured to adhere to the ocular surface by forming a vacuum, the structure comprising: an enclosing wall having an inner surface, an outer surface, and an opening surface, the enclosing wall extending from a first end to a second end, wherein the inner surface forms an interior cavity, wherein the opening surface is configured to contact and surround a perimeter of the cornea and form a vacuum within the interior cavity when the structure is activated.

56. The device of any one of claims 54-55, wherein the receiving structure is located in an opening of the device such that the receiving structure is substantially over the cornea when the device is inserted over the eye.

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

58. The device of any one of claims 54-57, wherein the device is configured to protect both the eyelids and the cornea.

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

60. A method for protecting the upper and lower eyelids of a subject, the method comprising: inserting an eyelid protection device over an eye of the subject; bringing a first surface of the eyelid protection device into contact around a contour of the upper eyelid; bringing a second surface of the eyelid protection device into contact around a contour of the lower eyelid; wherein the first surface and the second surface are configured to connect to each other so as to create an opening between the first surface and the second surface, and wherein, when inserted on an eye, the device prevents the upper and lower eyelids from closing and protects the eyelids from the ocular surface or substances deposited on the ocular surface by physically and thermally separating the eyelids.

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

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

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

64. A kit comprising: one or more syringes containing a cold slurry formulation; and a package enclosing the plurality of syringes, wherein the package is configured to store, seal, and provide thermal and moisture protection for the one or more syringes.

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

66. The kit of any one of claims 64-65, wherein the kit comprises 2 to 20, 2 to 15, 2 to 10, or 2 to 5 syringes.

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

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

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

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

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

72. A 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, wherein the second package is configured to store, seal, and provide thermal and moisture protection for the one or more syringes and the container.

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

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

75. A stand-alone cooling device for cooling a target tissue surface, the stand-alone cooling device comprising: 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 cap configured to fit over and seal the open end of the formulation chamber; and a handle coupled to the formulation chamber, wherein the handle is configured to be held by a user and to be moved by the user to dispense the cold slurry formulation from the formulation chamber. 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.

76. The stand-alone cooling device of claim 75, further comprising a movable plate disposed within the formulation chamber, wherein when the movable plate is advanced within the formulation chamber toward the closed end of the formulation chamber, the cold slush formulation in liquid phase is displaced away from the closed end of the formulation chamber and replaced by the cold slush formulation in substantially non-liquid phase, and wherein the movable plate is disposed within the formulation chamber and has a smaller dimension than the open end of the formulation chamber.

77. The stand-alone cooling device of any one of claims 74 to 76, further comprising: a force spring having a first end and a second end, wherein the first end is operably connected with the movable plate and the second end is operably connected with the removable cover; and one or more side pins operably connected to the hollow chamber; wherein the one or more side pins are configured to, when pressed, cause the first end of the force spring to extend beyond the original length so as to allow the movable plate to be advanced within the formulation chamber toward the closed end of the formulation chamber.

78. The stand-alone cooling device of any one of claims 74 to 77, wherein the target surface interface is configured to contact an ocular surface, and the stand-alone cooling device is configured to maintain the ocular surface at a temperature suitable for reducing ocular surface discomfort.

79. The stand-alone cooling device of any one of claims 74 to 78, wherein the formulation chamber is configured to receive the cold slush formulation of any one of claims 1 to 6.

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

81. The stand-alone cooling device of any one of claims 78 to 80, wherein the target surface interface is configured to contact the sclera of the ocular surface.

82. The stand-alone cooling device of any one of claims 78 to 81, wherein the target surface interface comprises an opening configured to fit over the cornea of the ocular surface to avoid contact between the target surface interface and the cornea when the target surface interface is in contact with the ocular surface.

83. The stand-alone cooling device of any one of claims 74 to 82, wherein the target surface interface is configured to allow heat energy to be transferred from the target surface interface to the formulation chamber.

84. The stand-alone cooling device of any one of claims 74 to 83, wherein the target surface interface is configured to facilitate uniform cooling of the target tissue surface when the formulation chamber is filled with the cold slush formulation.

85. The stand-alone 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 stand-alone cooling device of claim 85, wherein the corneal protection device is the device of any one of claims 23 to 32.

87. The stand-alone cooling device of any one of claims 85 to 86, wherein the corneal protection device is configured to be disposed within the opening of the ocular surface interface and physically and thermally protect the cornea when the ocular surface interface is in contact with the ocular surface.

88. The stand-alone cooling device of any one of claims 77-87, wherein the force spring is a tensile spring, a torsional spring, or a combination thereof.

89. The stand-alone cooling device of any one 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. The stand-alone cooling device of any one of claims 74-89, wherein the target surface interface comprises one or more encapsulated phase change materials (PCMs), shape-stable PCMs, or combinations thereof.

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

92. The stand-alone device of claim 91, wherein the non-stick coating is PTFE.

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

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

95. The stand-alone cooling device of any one of claims 74-94, wherein a first surface of the target surface interface comprises a geometric design feature that protects the target tissue from adhering to the target surface interface.

96. The stand-alone cooling device of claim 95, wherein the geometric design feature comprises one or more of a hierarchical microstructure, a hierarchical nanostructure, a biologically inspired surface pattern, or combinations thereof.

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

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

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

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

101. A method of reducing symptoms of ocular surface discomfort, the method comprising: positioning a stand-alone cooling device on a target ocular surface; wherein the stand-alone cooling device comprises: a formulation chamber comprising a hollow chamber having an open end and a closed end, wherein the formulation chamber is configured to receive and contain a cold slurry formulation; a removable cap 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 contact the closed end of the formulation chamber.

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

103. The method of claim 102, wherein the cold slurry formulation further comprises a lipid. ​ 104. The method of any one of claims 101 to 103, wherein the self-contained cooling device further comprises a movable plate disposed within the formulation chamber, wherein wherein when the movable plate is advanced within the formulation chamber toward the closed end of the formulation chamber, the cold slurry formulation in liquid phase is displaced away from the closed end of the formulation chamber and replaced by the cold slurry formulation in substantially non-liquid phase, and wherein the movable plate is disposed within the formulation chamber and has a smaller dimension than the open end of the formulation chamber.

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

106. The method of any one of claims 104 to 105, wherein the self-contained cooling device further comprises: a force spring having a first end and a second end, wherein the first end is operably connected with the movable plate and the second end is operably connected with the removable cover; and one or more side pins operably connected to the hollow chamber; wherein the one or more side pins are configured to, when pressed, cause the first end of the force spring to extend beyond the original length so as to allow the movable plate to be advanced within the formulation chamber toward the closed end of the formulation chamber.

107. The method of claim 106, further comprising pressing the one or more side pins of the self-contained device operably connected to the hollow chamber to cause the first end of the force spring to extend beyond the original length so as to cause the movable plate to be advanced within the formulation chamber toward the closed end of the formulation chamber.

108. A self-contained cooling device for cooling a target tissue 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, wherein the formulation is configured to be frozen to subzero temperatures in a cold environment; an aperture, wherein the aperture is configured to allow a clinician to visualize a cornea of a subject; 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.

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

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

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

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

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

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

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

116. The self-contained cooling device of claim 108, wherein the subzero temperatures are about -20 °C to about 0 °C.

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

118. The stand-alone cooling device of any one of claims 108-117, wherein the stand-alone cooling device is configured to receive an accessory.

119. The stand-alone cooling device of claim 118, wherein the accessory is a speculum.

120. The stand-alone cooling device of claim 118, wherein the accessory is configured to hold open an eye of a subject during a procedure.

121. The stand-alone cooling device of any one of claims 118-120, wherein the accessory is configured to protect an eyelid of a subject from subzero temperatures during a procedure.

122. The stand-alone cooling device of claim 121, wherein the accessory comprises silicone.

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

124. A method of reducing symptoms of ocular surface discomfort, the method comprising: positioning a stand-alone cooling device on a target ocular surface; wherein the stand-alone cooling device comprises: a housing; a heat exchanger, wherein the heat exchanger comprises a formulation chamber configured to receive and contain a formulation, wherein the formulation is configured to be frozen to a subzero temperature in a standard freezer; an aperture, wherein the aperture is configured to allow a clinician to visualize a cornea of a subject; 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.

125. The method of claim 124, wherein the stand-alone cooling device is configured to receive an accessory, and wherein the accessory is configured to be positioned adjacent to the target ocular surface and to prevent closure of an eye of a subject.

126. The method of claim 125, wherein the accessory is configured to protect an eyelid of a subject from subzero temperatures during a procedure.

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

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

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

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

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

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

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

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

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

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

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

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