Formulations, devices, and methods for alleviating 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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480016951.X (22) Application Date 2024.02.02 (30) Priority Data 63 / 443,082 2023.02.03 US (85) PCT International Application Entering National Phase Date 2025.09.04 (86) PCT International Application Application Data PCT / US2024 / 014354 2024.02.02 (87) PCT International Application Publication Data WO2024 / 163973 EN 2024.08.08 (71) Applicant: Vision Medical Co., Ltd. Address: USA (72) Inventors: Charles Siddoti, Tomarsh Strejewski, James Stefair, Olivier Kagan, Samir Sabir, Caitlin Lee, Danielle Brukato, Joseph Allen (74) Patent Agency: Beijing J&J Intellectual Property Agency Co., Ltd. 11227 Patent Attorneys: Zhang Fuyu, Chen Jiuzhou (51) Int.Cl. A61B 18 / 02 (2006.01) A61F 7 / 10 (2006.01) A61F 9 / 00 (2006.01) A61K 9 / 10 (2006.01) A61M 19 / 00 (2006.01) A61P 27 / 02 (2006.01) (54) Title of Invention: Formulations, Apparatus, and Methods for Relieving Symptoms of Ocular Surface Discomfort (57) Abstract: This document discloses cryopreservation formulations, apparatus, and methods for relieving symptoms of ocular surface discomfort. Cryopreservation formulations containing ice, a freezing temperature reducing agent, and optionally lipids are disclosed. Apparatus and methods for protecting the target ocular surface from contact with the cryopreservation formulation are disclosed for maintaining the target ocular surface at a temperature desired for relieving symptoms of ocular surface discomfort. A separate device configured to receive the cryopreservation formulation is disclosed for maintaining the target ocular surface at a temperature desired for relieving symptoms of ocular surface discomfort. Apparatus and methods for protecting the cornea and / or eyelids of a subject from the effects of a cryopreservation formulation applied directly or indirectly to or injected into the target ocular surface are disclosed. A kit containing multiple syringes for applying multiple doses of cryopreservation to the target ocular surface is disclosed. Claims 8 pages, Description 34 pages, Drawings 37 pages, CN 121127188 A 2025.12.12 CN 1 21 12 71 88 A 1. A cold plasma preparation for relieving symptoms of ocular surface discomfort, the cold plasma preparation comprising: water, and a freezing point depressant, wherein the cold plasma preparation is configured to be applied directly or indirectly to a 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.2. The cold paste formulation of claim 1, wherein the formulation further comprises lipids. 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 lipids 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 lipids is about 15% to 45% (v / v). 7. The formulation of any one of claims 1, 4, to 6, wherein the concentration of the freezing point depressant is about 10% to 25% (v / v). 8. 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, and ocular sensation in the eye is restored after the cryosol is applied to the target ocular surface. 9. The method of claim 8, wherein the cryosol preparation further comprises a lipid. 10. The method of claim 8, wherein the cryosol preparation is applied to the posterior portion of the limbus. 11. The method of any one of claims 8 to 10, wherein 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 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 soybean-phosphatidylcholine (soy-PC). 14. The method of any one of claims 9 to 12, wherein the lipid comprises a fatty acid selected from 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 paste formulation further comprises hyaluronic acid. 16. The method of any one of claims 8 to 15, wherein the cold paste formulation further comprises poloxamer. 17. The method of any one of claims 8 to 16, wherein ocular sensation in the eye recovers approximately 21 days after application of the cold paste formulation. 18. The method of any one of claims 8 to 17, wherein during application of the cold paste, the sclera of the patient's eye is cooled to a temperature of approximately -6°C to approximately 4°C. 19. The method of any one of claims 8 to 18, wherein the cold paste is applied for approximately 2 minutes to approximately 15 minutes. 20. The method of any one of claims 7 to 19, wherein an additional amount of the cold paste is applied again approximately 90 seconds after the first application.21. The method of any one of claims 8 to 20, wherein the application is performed on the surface. (Claims 1 / 8 page 2 CN 121127188 A) 22. The method of any one of claims 8 to 20, wherein the application is performed by injection. 23. A device for protecting the cornea on the ocular surface, 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 to form a vacuum within the internal cavity when the structure is activated. 24. The device of claim 23, wherein the adhesion of the structure to the ocular surface substantially seals the cornea within the opening surface of the sealing wall. 25. The device of any one of claims 23 to 24, wherein the structure includes a suction cup. 26. The device of any one of claims 23 to 25, wherein the enclosure wall comprises a non-porous material having low thermal conductivity, said non-porous material being selected from polymers, polyvinyl chloride (PVC), neoprene rubber, polyethylene (PE), polytetrafluoroethylene (PTFE), silicone, thermoplastic elastomers (TPU), thermoplastic polyurethanes (TPE), and combinations thereof. 27. The device of any one of claims 23 to 26, wherein said enclosure wall comprises a thermal insulation material, said thermal insulation material being selected from 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 said enclosure wall comprises an optically transparent or translucent material. 29. The device of any one of claims 23 to 28, wherein said enclosure wall comprises an optically opaque material. 30. The device of any one of claims 23 to 29, wherein said structure is activated by contracting the internal cavity and subsequently releasing the contraction of the internal cavity. 31. The device of any one of claims 23 to 30, wherein the structure is activated by compressing the sealing wall and subsequently releasing the sealing wall. 32. The device of any one of claims 23 to 31, wherein the vacuum is a partial vacuum. 33. A method 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 cornea of ​​the object; 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.34. The method of claim 33, further comprising applying a cold plasma preparation to the surface of the eye. 35. The method of claim 34, wherein the corneal protection device is configured to protect the cornea physically and thermally from the effects of the cold plasma preparation. 36. The method of any one of claims 33 to 35, wherein creating a vacuum within the internal 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 eyelid 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 surface and the second surface are configured to be reversibly connected to each other to create an opening between the first surface and the second surface, and wherein, upon insertion into the eye, the device prevents the upper eyelid and the lower eyelid from closing and protects the eyelid from the ocular surface or substances deposited on the ocular surface by physically and thermally separating the eyelid. 39. The device of claim 38, further comprising channels in one or more of the first surface and the second surface, wherein the channels are configured to allow fluid to escape from the ocular surface when the device is inserted into the 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 being 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 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. 42. The device of any one of claims 38 to 41, wherein the first surface and the second surface are curved. 43. The device of any one of claims 38 to 42, wherein one or more of the first surface and the second surface are arcuate. 44. The device of any one of claims 38 to 43, wherein the dimensions of the first surface and the second surface are 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, which can be assembled to form the device. 47. The device of any one of claims 38 to 46, wherein one of the first surface and the second surface...48. The device of any one of claims 38 to 47, wherein a segment or more of the distance spanning the opening between the first surface and the second surface can be adjusted to accommodate eyelids and eyes of various shapes and sizes. 49. The device of any one of claims 38 to 48, wherein the device comprises one or more types of plastic. 50. The device of any one of claims 38 to 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 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 to 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 PVA, open-cell foam materials, and combinations thereof. 54. The device of any one of claims 38 to 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: 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 an internal cavity, wherein the opening surface is configured to contact and surround the periphery of the cornea, and to form a vacuum within the internal cavity when the structure is activated. 56. The device of any one of claims 54 to 55, wherein the receiving structure is located in the opening of the device such that when the device is inserted into the eye, the receiving structure is substantially on the cornea. 57. The device of any one of claims 54 to 56, wherein the receiving structure comprises a substantially circular shape and is connected to the first surface and the second surface. 58. The device of any one of claims 54 to 57, wherein the device is configured to protect both the eyelid and the cornea. 59. The device of claims 38 to 58, further comprising one or more structures configured to function as a speculum to keep the eyelid open when the device is inserted into the eye. 60. A method for protecting the upper and lower eyelids of an object, the method comprising: inserting an eyelid protection device into the eye of the object; 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;The first surface and the second surface are configured to be connected to each other to create an opening between the first surface and the second surface, 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. 61. The method of claim 60, further comprising applying a cold-slurry preparation to the ocular surface. 62. The method of claim 61, wherein the cold-slurry preparation comprises water and a freezing point depressant. 63. The method of claim 62, wherein the cold-slurry preparation further comprises lipids. 64. A kit comprising: one or more syringes containing a cold-slurry preparation; and a package enclosing the plurality of syringes, wherein the package is configured to store, seal, and provide thermal and moisture protection to the one or more syringes. 65. The kit of claim 64, wherein the kit comprises at least two syringes containing the cold-slurry preparation. 66. The kit of any one of claims 64 to 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 to 66, wherein one or more of the syringes containing the cold plasma formulation contains about 1 to 20 ml of the cold plasma formulation. 68. The kit of any one of claims 64 to 67, wherein the packaging comprises a phase change material, a thermal insulation material, a reflective barrier, or a combination thereof. 69. The kit of any one of claims 64 to 68, wherein the packaging 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 to 69, wherein the cold plasma formulation comprises water and a freezing point depressant. 71. The kit of any one of claims 64 to 70, wherein the cold plasma formulation further comprises lipids. Claims 4 / 8, page 5, CN 121127188 A 72. A kit comprising: one or more syringes; a first package enclosing the one or more syringes; a container containing a cold plasma 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 plasma formulation comprises water and a freezing point depressant. 74. The kit of claim 73, wherein the cold plasma formulation further comprises lipids. 75. A separate cooling device for cooling a target tissue 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 cold plasma formulation;A removable cap configured to fit over and seal the opening of the formulation chamber; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target tissue surface, and the second surface is configured to form or contact the closed end of the formulation chamber. 76. The independent cooling device of claim 75, further comprising a movable plate disposed within the formulation chamber, wherein, as the movable plate advances within the formulation chamber toward the closed end of the formulation chamber, the liquid phase of the cold slurry formulation shifts away from the closed end of the formulation chamber and is replaced by a substantially non-liquid phase of the cold slurry formulation, and wherein the movable plate is disposed within the formulation chamber and has a smaller dimension than the opening of the formulation chamber. 77. The independent 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 operatively connected to the movable plate and the second end is operatively connected to the removable cover; and one or more side pins operatively connected to the hollow chamber; wherein the 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 advance toward a closed end of the formulation chamber within the formulation chamber. 78. The independent cooling device of any one of claims 74 to 77, wherein 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. 79. The independent cooling device of any one of claims 74 to 78, wherein the formulation chamber is configured to receive a cold plasma formulation according to any one of claims 1 to 6. 80. The independent cooling device of any one of claims 74 to 79, wherein the target surface interface is structurally integrated with the formulation chamber. 81. The independent 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 independent cooling device of any one of claims 78 to 81, wherein 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 contacts the ocular surface. 83. The independent cooling device of any one of claims 74 to 82, wherein the target surface interface is configured to allow heat energy to transfer from the target surface interface to the formulation chamber. 84. The independent cooling device of any one of claims 74 to 83, wherein the target surface interface is configured to promote uniform cooling of the target tissue surface when the formulation chamber is filled with the cold plasma formulation. 85. The independent cooling device of any one of claims 82 to 84, wherein the opening in the target surface interface is...86. The independent cooling device of claim 85, wherein the corneal protection device is the device of any one of claims 23 to 32. 87. The independent cooling device of any one of claims 85 to 86, wherein 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 contacts the ocular surface. 88. The independent cooling device of any one of claims 77 to 87, wherein the force spring is a tension spring, a torsion spring, or a combination thereof. 89. The independent cooling device of any one of claims 74 to 88, wherein the target surface interface comprises a thermally conductive material selected from Al, Cu, stainless steel, metal alloys, and combinations thereof. 90. The independent cooling device of any one of claims 74 to 89, wherein the target surface interface comprises one or more encapsulated phase change materials (PCMs), shape-stabilized PCMs, or combinations thereof. 91. The independent device of any one of claims 74 to 90, wherein the first surface of the target surface interface comprises a non-stick coating. 92. The independent device of claim 91, wherein the non-stick coating is PTFE. 93. The independent cooling device of any one of claims 74 to 92, wherein the first surface of the target surface interface comprises a hydrophobic coating. 94. The independent cooling device of any one of claims 74 to 93, wherein the first surface of the target surface interface comprises a surface coating that protects the target tissue from adhering to the target surface interface. 95. The independent cooling device of any one of claims 74 to 94, wherein 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. 96. The independent cooling device of claim 95, wherein the geometric design feature comprises one or more of hierarchical microstructures, hierarchical nanostructures, bio-inspired surface patterns, or combinations thereof. 97. The independent cooling device of any one of claims 74 to 96, wherein the first surface of the target surface interface comprises a hydrophilic surface coating. 98. The independent cooling device of any one of claims 74 to 97, wherein the first surface of the target surface interface comprises a low surface energy material. 99. The independent cooling device of any one of claims 74 to 98, wherein the target surface interface comprises an embedded thermoelectric Peltier cooler. 100. The independent cooling device of any one of claims 74 to 99, wherein the target surface interface comprises a thin film of material. 101. A method for relieving symptoms of ocular surface discomfort, 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 claims 6 / 8, page 7.CN 121127188 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 eye 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 lipids. 104. The method of any one of claims 101 to 103, wherein the independent cooling device further comprises 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 liquid phase of the cold slurry formulation is displaced away from the closed end of the formulation chamber and replaced by a substantially non-liquid phase of the cold 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. 105. The method of claim 104, further comprising a movable plate disposed within the formulation chamber that advances the independent cooling device toward the closed end of the formulation chamber. 106. The method of any one of claims 104 to 105, wherein the independent cooling device further comprises: 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 the removable cover; and one or more side pins operatively connected to the hollow chamber; wherein the one or more side pins are configured to, upon being pressed, cause the first end of the force spring to extend beyond its original length to allow the movable plate to advance within the formulation chamber toward the closed end of the formulation chamber. 107. The method of claim 106, further comprising 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 to cause the movable plate to advance within the formulation chamber toward the closed end of the formulation chamber. 108. A separate cooling device 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 ​​a subject; 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. 109. The separate cooling device of claim 108, wherein the cold environment is a standard cryostat. 110. The separate cooling device of claim 108, wherein the formulation comprises water and a freezing point depressant.111. The independent cooling device of claim 110, wherein the concentration of the freezing point depressant is about 20% (w / w). 112. The independent cooling device of claim 111, wherein the freezing point depressant is glycerol. 113. The independent cooling device of claim 108, wherein the first surface is configured to adhere to the target tissue surface upon contact. 114. The independent cooling device of claim 108, wherein the target surface comprises the sclera. 115. The independent cooling device of claim 114, wherein the sclera is adjacent to the limbus. 116. The independent cooling device of claim 108, wherein the sub-zero temperature is about -20°C to about 0°C. 117. The independent cooling device of claim 108, wherein the target surface interface comprises copper. 118. The independent cooling device of any one of claims 108 to 117, wherein the independent cooling device is configured to receive an accessory. 119. The independent cooling device of claim 118, wherein the accessory is a trocar. 120. The independent cooling device of claim 118, wherein the accessory is configured to keep the subject's eye open during surgery. 121. The independent cooling device of any one of claims 118 to 120, wherein the accessory is configured to protect the subject's eyelids from sub-zero temperatures during surgery. 122. The independent cooling device of claim 121, wherein the accessory comprises silicone. 123. The independent cooling device of any one of claims 108 to 122, wherein the independent 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 surgery. 124. A method for relieving symptoms of ocular surface discomfort, 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; 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. 125. The method of claim 124, wherein the independent 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 eye closure in the subject. 126. The method of claim 125, wherein the accessory is configured to protect the eyelids of the subject from sub-zero temperatures during surgery. 127. The method of claim 124, wherein the target surface comprises the sclera.128. The method of claim 127, wherein the sclera is adjacent to the 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 sub-zero temperature is from 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 to 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 from about 2 minutes to about 10 minutes. 136. The method of claims 133 to 135, further comprising rinsing the target tissue surface with a liquid formulation before removing the target surface interface from the target tissue surface. 137. The method of claim 136, wherein the liquid formulation comprises saline. Claims 8 / 8 Page 9 CN 121127188 A Formulations, apparatus, and methods for relieving symptoms of ocular surface discomfort Technical Field

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

[0002] The present invention generally relates to apparatuses, systems, and methods for producing and applying biological materials such as cold slurry. More particularly, the present invention relates to apparatuses, 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 Art

[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, so as to refract light when it enters.

[0004] The innervation of the cornea begins in the brainstem, where the large sensory roots branch from the pons and attach to the trigeminal nucleus caudalis, located in the lateral part of the medulla. From the trigeminal nucleus caudalis, the trigeminal nerve branchesIt branches into three branches, one of which is the ocular branch. The root then branches into three more 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. The two types of branches from this nerve are called the short ciliary nerve and the long ciliary nerve. 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, T. T., & Gallar, J. (2011), CHAPTER 16 - Sensory Innervation of the Eye, Adler's Physiology of the Eye (11th edition, pp. 363-384), Elsevier Inc.

[0005] The perchoroidal space is located between the sclera (the outermost layer of the eyeball) and the choroid (a vascularized layer responsible for supplying nutrients to the structures of the eye). Approximately 8 to 10 short ciliary nerves pierce the sclera, but once they enter the perichoroidal space, they branch into about 15 to 20 branches. Regarding the long ciliary nerves, more than 50 branches pierce the sclera and further divide within the perichoroidal space. At the limbus, the junction of the sclera and cornea, the nerve loses its myelin sheath and continues as a free nerve ending. The nerve collects sensory signals from the cornea and transmits 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 innervation are fully understood, and they can vary from patient to patient. Other nerve fibers or some normal anatomical variations in the innervation pathways may contribute to this understanding.

[0006] Free nerve endings are located beneath the corneal epithelium (the anterior layer that protects the corneal structure) and often cause painful eye sensations. When a patient is 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. One important 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 dry eye syndromes, Journal of Optometry, 10, 5-13 (2017). Importantly, some patients continue to experience ocular surface pain even after their ocular surface has returned to a clinically normal appearance. This condition presents a clinical challenge because its cause is believed to be a persistent somatosensory dysfunction of corneal innervation following the initial damage to the stimulating nerves.

[0008] Other causes of corneal discomfort may include postoperative pain potentially following optical refractive corneal ablation. Optical refractive keratotomy is a procedure used to treat refractive errors that requires the removal of corneal epithelium before the application of 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, which are 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.” tearing). Levitt, AE, et al., Chronic dry eye symptoms after LASIK:Parallels and lessons to be learned from other persistent post-operative pain disorders, Molecular Pain, 11:21 (2015). The last 10 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 about 0.3 degrees per second, thereby 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 clinical syndromes of OSD, notably with signs and characteristics of ocular irritation such as dryness, burning, or discomfort. Even after the initial damage to this mechanism has been addressed and 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 of hypersensitivity or abnormal pain. In fact, the references state 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 ocular pain are limited, have short-term value, or are associated with adverse side effects.The eye pain mentioned includes eye pain associated with 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, which are 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 cause of dry eye and can also lead to increased debris accumulation under the eyelids. Shen Lee, B., et al., Managing dry eye disease and facilitating realistic patient expectations: A review and appraisal of current therapies, Clinical Ophthalmology, 14 119–126 (January 2020).

[0012] Regarding postoperative pain management for optical refractive corneal ablation 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 involved in inflammation that are produced in the event of corneal tissue damage). Pathak, A. K., & Karacal, H., (2019), Pain reduction 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 melting (which can lead to vision loss). For soft bandage-type contact lenses, this method can stimulate epithelial cell regeneration and serve as a delivery system for antibiotics or surface NSAIDs. However, bandage-type contact lenses can promote bacterial growth and are generally ineffective in relieving pain. (Shetty, R., et al., Pain management after photorefractive keratectomy, Journal of Cataract Refract Surgery)45(7):972-976 (2019).

[0013] Acute ocular pain can also be treated with topical anesthetic eye drops, such as proparacaine hydrochloride and tetracaine hydrochloride. These aqueous solutions are given as short-term treatment for pain, or when measuring intraocular pressure, removing foreign bodies, relieving 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. In cases of such short-term pain relief, patients need to continue application, but long-term use can eventually lead to corneal toxicity. The toxic effects on the cornea include damage to stromal corneal cells, which are cells that play an important role in healing corneal trauma. If epithelial cells cannot migrate across the cornea, the epithelium will eventually begin to shed and lead to long-term non-healing of the corneal epithelium.

[0014] However, maintaining some perception 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 after controlled thermal coagulation of the trigeminal ganglion in rabbits. This denervation was found to significantly affect epithelial proliferative activity and reduce mitosis.

[0015] As mentioned above, the cornea is extremely sensitive to pain or disturbance. There are many clinical conditions in people who experience 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 eye pain result in complete anesthesia of the eye's sensation, which can be very problematic in the long term due to the risk of developing neurokeratopathy. Moreover, as stated on page 3 / 34 of the instruction manual (CN 121127188 A), corneal somatosensory dysfunction becomes a major feature of pain syndromes in eyes with chronic inflammation and pain. In conclusion, there are many patients...Patients suffer from debilitating ocular surface discomfort that may be associated with active corneal disease or may persist for a long time after the original injury without detectable persistent lesions. Clearly, there is a significant unmet clinical need for developing a long-acting, safe corneal anesthesia that partially blocks corneal sensation and significantly reduces patient discomfort. Summary of the Invention

[0016] The following embodiments record a non-limiting arrangement of the feature combinations described in the invention. 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 preparation for relieving symptoms of ocular surface discomfort, the cold plasma preparation comprising: water, and a freezing point depressant, wherein the cold plasma preparation 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 preparation also comprises lipids. In some embodiments, the formulation comprises a freezing point depressant at a concentration of about 10% to 40% (v / v). In some embodiments, the formulation comprises lipids at a concentration of 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 at a concentration of about 10% to 20%, 20% to 30%, or 30% to 40% (v / v). In some embodiments, the formulation comprises lipids at a concentration of 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 cold slurry preparation to a surface adjacent to the limbus of a patient's eye, wherein the cold slurry preparation comprises water and a freezing point depressant, wherein the application of the cold slurry preparation is configured to cause a degree of numbness in the cornea of ​​the eye for a period of time, and during that period...After a period of time, ocular sensation is restored. In some embodiments, the cold plasma preparation also comprises lipids. In other embodiments, a method is provided in which the cold plasma preparation is applied to the posterior portion of the limbus. In other embodiments, a method is provided in which the cold plasma remains on the surface of the eye for more than about 4 hours if the cold plasma preparation is not applied again on any day after the first day of application. In some embodiments, a method is provided in which the cold plasma preparation comprises a freezing point depressant, wherein the freezing point depressant is glycerol. In other embodiments, a method is provided in which the cold plasma 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 excipients. 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, during application of the cold plasma, the sclera of the patient's eye is cooled to a temperature of approximately -6°C to approximately 4°C. 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 plasma is applied approximately 90 seconds after the first application. In other embodiments, a method is provided in which the application of the cold plasma preparation is by surface application. In other embodiments, a method is provided in which the application of the cold plasma preparation is 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, 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 a certainIn some embodiments, the structure includes a suction cup to ensure proper alignment and retention on the eye. In some embodiments, the enclosure wall comprises a non-porous material with low thermal conductivity, selected from polymers, polyvinyl chloride (PVC), neoprene, 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), expanded polystyrene (EPS), 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 of the internal cavity. In some embodiments, the structure is activated by compressing the enclosure wall and subsequently releasing the enclosure wall. 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 placing 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 an upper eyelid; and a second surface configured to contact a 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 separating 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 when the device is inserted into the eye...Fluid may escape from the ocular surface. In some embodiments, the device further includes 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 includes a first end and a second end, and the second surface includes 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 other 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 segments 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, the one or more porous materials comprise a thermal insulation 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 a thermal insulation 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 further comprises 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 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, wherein the inner surface forms an internal cavity, and 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 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 eyelid and the cornea. In some embodiments, the device...It 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 eye of the object; 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 separating the eyelids. In some embodiments, the method further includes applying a cold paste formulation to the ocular surface. In other embodiments, the cold paste formulation 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 one or more syringes; a container containing a cryo-slurry formulation; and a second package enclosing 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 cryo-slurry formulation comprises water, a freezing point lowering agent, 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 having 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; and a removable cap configured to fit into the formulation chamber.The independent cooling device includes: an open end of the formulation chamber and a sealed opening end; and a target surface interface comprising a first surface and a second surface, wherein the first surface is configured to contact the target tissue surface, and the second surface is configured to form or contact the closed end of the formulation chamber. In some embodiments, the independent 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, the liquid-phase cold slurry formulation is displaced away from the closed end of the formulation chamber and replaced by a substantially non-liquid-phase cold 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 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, so as to allow the movable plate to be advanced within the formulation chamber toward the closed end of the formulation chamber. In some embodiments, the target surface interface is configured to contact the ocular surface, and a separate 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 cryosol 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 heat energy to transfer from the target surface interface to the formulation chamber. In some embodiments, the target surface interface is configured to promote uniform cooling of the target tissue surface when the formulation chamber is filled with a cryosol formulation. In some embodiments, the opening in the target surface interface is configured to receive a corneal protection device. In some embodiments, the corneal protection device is a corneal protection device according to the present disclosure. In some embodiments, the corneal protection device is 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 contacts 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 includes 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 includes a geometric design feature that protects the target tissue from adhering to the target surface interface. In other embodiments, the geometric design feature includes 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 includes a hydrophilic surface coating. In some embodiments, the first surface of the target surface interface includes a low surface energy material. In some embodiments, the target surface interface includes an embedded thermoelectric Peltier cooler. In some embodiments, the target surface interface includes 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 cold plasma 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. In some embodiments, the cold plasma formulation comprises water, a freezing point depressant, and optionally a lipid. In some embodiments, the independent 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 cold slurry formulation shifts away from the closed end of the formulation chamber and is replaced by a substantially non-liquid-phase cold 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 method further includes advancing the movable plate of the independent cooling device disposed within the formulation chamber 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, so as to allow the movable plate to be advanced within the formulation chamber toward the closed end of the formulation chamber. In some embodiments, the method further includes pressing one or more side pins of the independent device operably connected to the hollow chamber to cause a first end of the force spring to extend beyond its original length, thereby causing a movable plate to advance within the formulation chamber toward the closed end of the formulation chamber.

[0027] In some aspects, an independent cooling device is provided for cooling the surface of a target tissue, said independent cooling deviceThe 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 cold environment; an aperture, wherein the aperture is configured to allow a clinician to visualize the cornea of ​​a subject; and a target surface interface including 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 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, a separate cooling device is configured to receive an accessory. In some embodiments, the accessory is a trocar. In some embodiments, the attachment is configured to keep the subject's eye open during surgery. In some embodiments, the attachment is configured to protect the subject's eyelids from sub-zero temperatures during surgery. In some embodiments, the attachment comprises silicone. In some embodiments, the attachment comprises thermoplastic elastomer (TPU) or thermoplastic polyurethane (TPE).

[0029] In some aspects, the independent cooling device is also configured to receive a 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 an 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; a target surface interface including 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, the independent cooling device is configured to receive an accessory, and 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 eyes.The instruction manual, page 8 / 34, 17 CN 121127188 A, exempts the eyelid from contact with the contact surface interface. In some embodiments, the attachment is configured to provide an aperture for visualization of the cornea. In some embodiments, the attachment is configured to facilitate positioning of the device. In some embodiments, the attachment 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 interface 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 before use.

[0034] The following figures illustrate some exemplary embodiments of the invention.

[0035] Figure 1 depicts the freezing point depression of liquid water, a solution containing 10% glycerol (volume by volume, v / v), and a solution containing 20% ​​glycerol (v / v).

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

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

[0038] Figures 4A and 4B show diagrams of the human eye, showing different regions of the eye (4A) and degrees for anatomical reference (4B).

[0039] Figure 5 is a graph showing real-time scleral temperature monitoring in rabbits after application of a cold slurry to the eye surface (solid line) and injection of a cold slurry (dashed line).

[0040] Figure 6 is a graph showing the decrease in sensory perception in rabbit eyes over time after application of injected cold gel (diamond), surface application of cold gel (triangle), and surface application of gel at room temperature (square) with corneal exposure.

[0041] Figure 7 is a graph showing the decrease in sensory perception in rabbit eyes over time after application of surface application of cold gel to the eye without corneal exposure.

[0042] Figures 8A and 8B 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 surface application of cold gel (8B).

[0043] Figure 9 shows the eyes of 6 rabbits after a combined treatment in which surface application of cold gel was followed by injection of cold gel.A graph showing the decrease in sensation over time. In three rabbits (shown as rhombuses, squares, and triangles), the injected paste did not contain liposomes, while in another three rabbits (shown as "X", stars, and circles), the injected paste contained liposomes.

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

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

[0046] Figure 12 is a perspective view of an exemplary corneal protection device according to some 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] Figures 13A and 13B illustrate exemplary corneal protection devices as described herein. Figure 13A is a perspective view of an exemplary corneal protection device and Figure 13B illustrates an exemplary corneal protection device placed on the ocular surface to enclose and seal the periphery of the cornea. Specification 9 / 34 pages 18 CN 121127188 A

[0048] Figures 14A and 14B are perspective views of exemplary eyelid protector devices according to certain embodiments described herein.

[0049] Figures 15A and 15B illustrate exemplary eyelid protector devices combined with exemplary corneal protection devices according to certain embodiments described herein.

[0050] Figure 16 illustrates an exemplary kit comprising multiple syringes containing cooling plasma according to certain embodiments described herein.

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

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

[0053] Figure 19 illustrates an exemplary treatment protocol using an exemplary independent eye cooling device 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] Figures 21A through 21E show exemplary independent eye cooling devices from multiple angles according to certain embodiments described herein.

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

[0057] Figures 23A through 23D show devices used with independent eye cooling devices according to certain embodiments described herein.Multiple views of the accessory (e.g., speculum).

[0058] FIG24 is a graph plotting the treatment time in seconds relative to the removal time in seconds for treatment with an independent eye cooling device according to some embodiments described herein.

[0059] FIG25 is a diagram depicting an exemplary treatment area 2500 on a drawing of the eye.

[0060] FIG26 is a graph showing a representative temperature curve comparing the temperature (°C) of the surface of a pig eye relative to the time (seconds) following contact with an independent cooling device according to some embodiments described herein.

[0061] FIG27 is a drawing showing temperature measurement locations 1 and 2 on a drawing of the eye and the treatment area 2500 (located below the contact surface of the independent cooling device according to the present disclosure).

[0062] FIG28 is a graph showing the temperature (°C) relative to the time (seconds) for obtaining the temperature at measurement locations 1 and 2 and from the tissue below the treatment area 2500.

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

[0064] This disclosure relates to devices, apparatus, systems, and methods for treating ocular surface discomfort using biological materials (e.g., cold paste) or cooling devices. In some embodiments, the biological material is a cold paste (e.g., ice paste) 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 preventive or therapeutic purposes to alleviate ocular discomfort. The systems and methods disclosed herein provide unexpectedly long-term hypoesthesia (also known as hypoesthesia, page 10 / 34 of the specification, CN 121127188 A hypoesthesia). Hypopnea can cause prolonged corneal numbness, followed by restoration of eye sensation over days or weeks after the application of cryotherapy 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 cryotherapy (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 0°C).Approximately 4°C) and maintained at this low temperature for a period sufficient to cause decreased sensation on the ocular surface. This treatment does not cause harmful side effects to the eye or damage to tissues in or around the eye.

[0066] In some embodiments, the cold paste may be applied directly or indirectly to the surface of the eye to achieve the desired therapeutic effect, such as improving or treating ocular surface discomfort through 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 paste or cooling treatment to the subject's eye may be varied to cause greater or milder sensory reduction. In some embodiments, the temperature of the paste or cooling treatment, applied directly or indirectly to the surface of the eye or injected into the subject's eye, is varied to induce a greater or milder reduction in sensation. In some embodiments, the reduction in sensation induced after treatment decreases to an imperceptible point over time. In other embodiments, a greater reduction in sensation may be induced to cause more nerve numbness in the subject's eye where the eye may be particularly sensitive.

[0068] In some embodiments, a container (e.g., vial, syringe, independent cooling device) containing biological material is received at a clinical point of care. The biological material may be received in a crystalline (or partially crystalline) state. In some embodiments, the final product to be applied to a human patient or subject (e.g., a person who is not a patient or a non-human animal) by surface application or injection is a cold paste consisting of sterile ice pellets 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 can 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, or greater than about 60% by weight. In some embodiments, the size of the ice particles is controlled to allow the slurry to flow 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 particles to allow the slurry to flow through containers of various sizes. In some embodiments,Most ice pellets are smaller than about half the inner diameter of the cavity or container used for application or injection. For example, in some embodiments, the diameter of the ice pellets may be about 1.5 mm or smaller 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 paste formulations and methods for their preparation have previously been disclosed, for example, in the following: 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 to page 11 / 34 of the specification, 20 CN 121127188 A.

[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 a 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 the cold paste (e.g., lower the freezing point), alter the ice percentage of the cold paste, alter the viscosity of the cold paste, 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, increase the thermal conductivity of the fluid phase, and / or improve the overall preventative, therapeutic, or aesthetic efficacy of the cold paste.

[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 a desired and effective percentage of ice particles. Suitable freezing point depressants include, but are not limited to, salts (e.g., sodium chloride, betadex sulfobutyl ether sodium), ions, lactated Ringer's solution, and sugars (e.g., glucose, oxalic acid).Rhizobutyrol, 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 depressants 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 depressant 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 depression 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] where is the freezing point depression (as defined), is the cryoscopic constant, is the molality, and 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] Referring to Figure 1, which shows the freezing point depression graphs for 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 are 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 mixture of water and glycerol 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, which begins immediately after pure water T1 passes its supercooling point of approximately -6°C. For pure solvents, an equilibrium window for crystallization (i.e., the "flat line" portion of pure water T1 in Figure 1) is typical. For the 10% glycerol solution T2, cooling causes the solution to begin crystallizing at its initial freezing point of approximately -3°C after approximately 2.2 hours, and continues to crystallize 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 its supercooling point of approximately -8°C (this can vary depending on the sample, e.g., the supercooling point is approximately -15°C to approximately -3°C), which is shown in the instructions after approximately 2.2 hours.Page 12 / 34 21 CN 121127188 A. For solutions (i.e., impure mixtures), a 10% glycerol solution T2 typically has a declining crystallization temperature window. Similarly, for a 20% glycerol solution T3, cooling causes the solution to begin crystallizing at an initial freezing point of about -7°C after about 3.5 hours (after which the initial supercooling point may vary from sample to sample, for example, from about -25°C to about -5°C), and continues to crystallize after about 6 hours as the temperature of the solution further decreases to about -11°C, and continues to decrease after more than 6.5 hours thereafter. Initial crystallization occurs immediately after the 20% glycerol solution T3 passes through a supercooling point of about -14°C, which is shown at about 3.5 hours. Similar to the trace of the 10% glycerol solution T2, the declining crystallization temperature window of the 20% glycerol solution T3 is typical for solutions.

[0076] Referring to FIG2, the graph illustrates the components of an exemplary biomaterial that can form a cold slurry. The chart shows that the ice percentage of an 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] Referring to FIG3, different slurry compositions (batches) were characterized according to their temperature spectra and ice content. Different slurry batches were placed on a copper plate heated to 40°C 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 (traces AC, BC, and CC) and in the middle of the copper plate exposed outside the plate (traces AM, BM, and CM). The temperature traces show three separately produced slurry batches: a slurry composition with 15% glycerol (with a temperature setpoint of -8.1°C) represented by traces AC and AM, and two different slurry batches, both with 10% glycerol (with a temperature setpoint of -5.5°C) represented by traces BC and BM, and traces CC and CM. When the slurry batches were first introduced into the copper plate, the thermocouples embedded inside the plate...The thermocouples (traces AC, BC, and CC) initially measure the warm temperature of the heated plate (e.g., trace AC at time point 0 is 31°C), and subsequently reach equilibrium at a lower temperature due to the cooling effect of the introduced paste (e.g., trace AC at approximately 2 minutes). On the other hand, for thermocouples located in the middle of the plate, when the paste is first introduced into the copper plate, the paste immediately contacts the thermocouples because the lines are exposed. This results in an initial negative temperature reading at the middle location due to the contact of the crystalline paste with the lines (e.g., trace AM at time point 0 is -5°C), which then reaches equilibrium at a warmer temperature as the paste begins to melt on the heated plate (e.g., trace AM at approximately 4 minutes). Thermocouples exposed outside the plate (traces AM, BM, and CM) can be used to detect phase transitions during the initial melting of the crystalline paste. The figure shows that the two slurry compositions with 10% glycerol reached their phase transitions at similar time points (trace BM at approximately 4 minutes and trace CM at approximately 2.7 minutes), which differs from the phase transition of the 15% glycerol slurry (trace AM's phase transition occurred at approximately 0.2 minutes). The figure also shows that, depending on the thermocouple position (middle / bottom), two slurry batches with the same composition (10% glycerol: traces BC and BM, and traces CC and CM) reached equilibrium at 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 thermocouple position (middle / bottom), the slurry with different compositions (15% glycerol: traces AC and AM) exhibited a different temperature spectrum than the other two slurries, reaching equilibrium more quickly at temperatures ranging from approximately 19°C to 22°C. Therefore, Figure 3 shows that slurries with different compositions have different temperature spectra, and batch-to-batch consistency exists among slurries with the same composition (e.g., slurries represented by BC and BM, and slurries represented by CC and CM, have similar temperature spectra, which are different from those represented by AC and AM).

[0078] Referring to Figure 4A, a diagram of the eye is shown, depicting the scleral region 2, scleral region 3, cornea 1, and limbus (the dashed line between cornea 1 and scleral region 2). Figure 4A is reproduced 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 is obtained. Figure 4B shows a diagram of an eye with an overlay goniometer, which shows the angle relative to the eye in degrees (°). In this diagram, 90° represents the highest position of the eye.

[0079] In some embodiments, the cold paste described herein may be applied directly or indirectly to the surface of the eye, or alternatively, injected, to achieve long-term hypoesthesia to relieve discomfort on the ocular surface. Hypesthesia, also known as hypoesthesia, refers to a reduction in discomfort or pain without complete blockage of sensation, which in this disclosure specifically relates to sensation on the ocular surface or ocular structures. Thus, hypoesthesia differs from anesthesia, which is characterized by a deeper blockage of ocular sensation. Hypesthesia of the ocular surface may include corneal numbness that leads 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 cold plasma or device described herein may be configured to induce complete loss of corneal sensation, i.e., anesthesia. This may be advantageous for surgical procedures or other ocular treatments.

[0081] In some embodiments, the cold plasma droplets are applied directly to the ocular surface. In some embodiments, the amount of plasma applied directly to the ocular surface may range from 1 to 100 ml by volume. In some embodiments, the amount of plasma applied directly to the ocular surface may be about 10 to 80 ml. In some embodiments, the formulation may be applied directly to the ocular surface. In some alternative embodiments, the cornea may be scraped first, and then the droplets may be applied directly to the ocular surface. In some embodiments, the surface-applied cold plasma has a free-flowing paste consistency and may be applied surface-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.The surface, for example, the area marked as scleral region 2 in Figure 4A.

[0083] In some embodiments, sensitive ocular structures are protected from contact with the cold plasma 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. Potential adverse effects on the cornea can be minimized by selectively applying the plasma directly or indirectly to the ocular surface above the bulbar conjunctiva, posterior to the limbus (corresponding to the anterior anatomical region referred to as region 2, Figure 4A).

[0084] In some embodiments, a protective contact lens or other protective covering (such as those otherwise described herein) may be applied over the cornea to protect it from potential damage from the plasma. In some embodiments, the corneal covering completely prevents the cold plasma from directly contacting the corneal surface. In some embodiments, an eyelid protection device is used to keep the eyelids open during the surface application of the cold plasma. 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 can be used in eyelid protection devices to prevent the eyelids (internal and external) from contacting the gel and potentially freezing during cryopreservation treatment, which can lead to eyelid damage. In some embodiments, as described on pages 14 / 34 of CN 121127188 A, the eyelid protection device includes a speculum to help keep the eyelids open. In some embodiments, the cryopreservation 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 can be used to control the area exposed to the cryopreservation to be only the bulbar conjunctiva / sclera, so that the cryopreservation does not physically contact or freeze adjacent tissues unrelated to the desired clinical effect. In some embodiments, the cryopreservation 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 comes into contact with 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 cold plasma described herein is injected as a subconjunctival bolus. In some embodiments, the cold plasma is injected at approximately every 2 minutes. In some embodiments, each injection provides approximately 0.5 to 1.5 [units of fluid].ml of cryopreservative. 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 cryopreservative is injected at an axon more adjacent to 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 suit the injection of the slurry may be used. In some embodiments, the syringe may have a needle of approximately 18G to approximately 25G.

[0088] In some embodiments, real-time temperature sensing of the ocular surface is performed during treatment (e.g., cryopreservative injection, slurry surface application, or surface application using a separate cooling device). In some embodiments, a cold paste or independent 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 paste or independent 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 independent cooling device can be varied to alter the sensory loss experienced by the subject.

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

[0090] In some embodiments, 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 with the methods described herein, including those described above. Other specific embodiments of the cold plasma are described with reference to Figures 5 through 9. "ETX-4143" is a plasma 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 plasma). In some embodiments, ETX-4143 is applied to the eye (surface or by injection) at a temperature of about -18°C (the temperature of the plasma, for example, in the embodiments described below with reference to Figures 5 through 9). ETX-4143 is applied every about 90 seconds, with each application being about 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, ECT-1719 is applied to the eye (surface or by injection) at a temperature of about -11°C (the temperature of the slurry, for example, in the embodiments described below with reference to Figures 5 to 9). In some embodiments, as described on page 15 / 34 of CN 121127188 A, 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] Referring to Figure 5, real-time scleral temperature monitoring was performed in rabbits after the following administration to the eye: a surface application of a cold gel (ETX-4143, solid line) in one rabbit and an injection of a cold gel (ECT-1719, dashed line) in a second rabbit. Temperature monitoring was achieved by inserting a 25G needle with a temperature probe at its distal end into the subtenon space of the ocular fascia. As can be seen in Figure 5, the scleral temperature of the rabbits receiving the injected cold gel (ECT-1719) fluctuated between approximately 0°C and approximately 8°C throughout the procedure (from approximately 0 seconds after the injection to approximately 463 seconds after the injection). The sharp line at approximately 463 seconds in the figure indicates the end of the study after 7.5 minutes, and the temperature probe was removed from the ocular tissue. For most of the temperature recording period (from approximately 0 seconds to approximately 600 seconds after surface application), the scleral temperature of rabbits receiving surface-applied cooling plasma (ETX-4143) was lower than that of rabbits receiving injected cooling plasma, fluctuating between approximately -6°C and approximately 4°C. After surface application, the scleral temperature steadily decreased from approximately 4°C at application (approximately 0 seconds in Figure 5) to approximately 0°C after approximately 120 seconds. Following the initial cooling period of the sclera, 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, treatment ended and the temperature probe was removed, showing a sharp increase in the measured temperature, as shown in Figure 5.

[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 monofilament length of 6 cm and starting at 0.5 cm...The sensory reduction increments in cm, with the eye 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 (highest 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 long monofilament is used to probe the eye. If the rabbit again does not blink, the next 5 cm monofilament 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 reduction is when the rabbit does not blink when probed with the shortest monofilament length (e.g., 0.5 cm). Zero level of sensory reduction (no pain blockage / no numbness) is when the rabbit blinks when probed with the longest monofilament length (e.g., 6 cm). The monofilament length can be converted into pressure (g / mm2), such that a 6 cm monofilament produces a pressure of 0.4 g / mm2 (minimum pressure), while a 0.5 cm monofilament produces a pressure of 15.9 g / mm2 (maximum pressure). Therefore, the recorded pressure corresponds to the pressure of the shortest monofilament length in the absence of a blink response.

[0094] Referring to FIG6, sensory reduction (the degree of corneal numbness as measured herein using tactile stimulation) was measured over time after administration of injected cold paste (ECT-1719, 3 rabbits in this group, shown in diamond shape), surface-applied cold paste (ETX-4143, 3 rabbits in this group, shown in triangle shape), and surface-applied paste (ETX-4143, 1 rabbit in this group) to the eye with corneal exposure in rabbits. In Figure 6, the degree of sensory impairment is shown as a percentage of the recorded pressure (i.e., based on the shortest monofilament in which there is no blink response) relative to the highest possible pressure (i.e., using the shortest monofilament of 0.5 cm, corresponding to a pressure of 15.9 g / mm²). The degree of sensory impairment is shown on days 1, 7, 14, and 28 after application of the cold gel. For the injected cold gel (ECT-1719, shown in diamonds), the sensory impairment was approximately 20% on day 1 and continued to gradually decrease, reaching baseline levels by day 14 (error bars overlap with 0%). For the surface-applied cold gel (ETX-4143 applied at 18°C, shown in triangles), the sensory impairment was 100% on day 1 (measurable maximum corneal numbness), which then continued to decrease, gradually decreasing by day 28, during which time the pain response returned to baseline levels (error bars overlap with 0%). For slurries applied to surfaces at room temperature (ETX-4143, shown in squares), after treatment, see page 16 / 34 of the instruction manual, 25 CN 121127188 A.No sensory reduction was observed at any point in time. Therefore, Figure 6 illustrates the unexpectedly strong sensory reduction of surface-applied cold paste, which resulted in long-term sensory reduction (almost 1 month). Injected cold paste resulted in moderate sensory reduction, which also lasted longer than expected (e.g., about 1 to 2 weeks). Importantly, for both surface and injection methods, cold paste treatment produced long-term sensory reduction that normalized to baseline levels without causing any permanent numbness.

[0095] Figure 7 shows sensory reduction over time in rabbits similar to Figure 6 after surface-applied cold paste (6 rabbits, ETX-4143), except that the cornea was not exposed (protected by contact lenses). Sensory reduction was measured in the same manner as described above with respect to Figure 6. Sensory reduction is shown at days 1, 7, 14, 21, and 28 after treatment with surface-applied cold paste. 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 illustrates the unexpected moderate to strong sensory reduction from surface-applied cold gel (with corneal protection), which resulted in long-term sensory reduction (approximately 3 weeks) without causing permanent corneal numbness or any corneal damage.

[0096] Referring to Figure 8, representative images of rabbit corneas stained with fluorescein show corneal healing over time following an intentional 8 mm corneal abrasion (Figure 8A) in the control group with corneal and eyelid protection, and following surface-applied cold gel (Figure 8B) in the treatment group. Damage progression was determined by measuring the size of the lesion over time. As can be seen in Figure 8A, corneal healing in the control group (3 rabbits) occurred at an average healing rate of 1.31 mm² / hour in the first 24 hours after the corneal abrasion, and at an average healing rate of 0.62 mm² / hour from 24 to 60 hours after the corneal abrasion. Unexpectedly, as shown in Figure 8B, corneal healing was not impaired in rabbits receiving topical application of the cold serum (ETX-4143) compared to the control group. In this group (3 rabbits), corneal healing following the cold serum treatment occurred at an average healing rate of 1.09 mm² / hour in the first 24 hours after treatment and at an average healing rate of 0.63 mm² / hour from 24 to 60 hours after treatment.

[0097] Referring to Figure 9, this figure illustrates the sensory reduction over time following a combined treatment of topical application of the cold serum followed by injection of the cold serum in 6 rabbits. In 3 rabbits (shown as rhombuses, squares, and triangles), the topical application of the cold serum was ECT-1719 without liposomes, followed by injection of the same cold serum formulation (ECT-1719). In another 3 rabbits (shown as "X", stars, and circles), the topical application of the cold serum was still ECT-1719 (without liposomes), followed by injection of liposome-containing ECT-1719.Cold plasma (ETX-4143). Sensory hyposensitivity is shown in rabbits at maximum pressure that does not produce blinking (as described herein with reference to Figures 6 and 7). As shown in Figure 9, regardless of the combination of treatments (liposome or non-liposome injection), sensory hyposensitivity continues to increase after treatment, likely peaking sometime between day 4 and day 11. Sensory hyposensitivity gradually diminishes, returning to baseline levels by approximately day 17. Surprisingly, a second, less pronounced period of sensory hyposensitivity spontaneously occurs around day 22, gradually diminishing back to baseline levels by day 26.

[0098] Cold plasma formulations containing one or more lipids

[0099] In some embodiments, it is desirable to increase the ice fraction in the plasma, as it translates into a greater amount of heat energy being carried away from the ocular surface. However, adding more ice to a cold plasma generally makes the plasma less fluid, making it difficult to inject or surface apply to the target site. As further described herein, certain embodiments of the invention relate to cold plasma formulations described herein that also contain one or more lipids that enhance plasma fluidity. In some embodiments, one or more lipids enhance the fluidity and flow properties of the slurry while also allowing for a desired proportion of ice in the slurry. In some embodiments, the enhanced fluidity results in improved properties of the slurry, thereby better allowing application by means of 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 result in the formation of an emulsion with the ice and / or ice-freezing point depressant mixture in the slurry, preventing or reducing the aggregation of ice particles into larger crystal sizes that reduce the fluidity of the slurry. In some embodiments, the slurry contains one or more lipids that prevent smaller ice crystals from agglomerating into larger crystals or reduce the amount of smaller ice crystals agglomerating into larger crystals by encapsulating ice and / or ice-freezing point depressant crystals when their size is 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...In the application regimen, the slurry contains about 0% to 45% (v / v) of lipids and / or about 0% to 45% (v / v) of a freezing point depressant (e.g., glycerol).

[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, etc.). In some embodiments, such an emulsified slurry may be stored in a standard freezer and will retain its fluidity when removed from the freezer for use (e.g., in a treatment 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 slurry are prepared by rapidly freezing one or more syringes containing slurry. In some embodiments, one or more syringes containing slurry are prepared by cooling syringes containing slurry in a -20°C freezer, a -80°C freezer, an ultra-low temperature (“ULT”) freezer, or by rapid freezing (e.g., using liquid nitrogen) that causes emulsification of the slurry. In some embodiments, one or more syringes containing 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 degradation characteristics, resulting in long-term stability of the slurry mixture. In some embodiments, the slurry contains one or more lipids containing soy-phosphatidylcholine (soy-PC). In some embodiments, the slurry contains one or more lipids containing one or more fatty acids. In some embodiments, 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] Referring to FIG10, a graph is shown showing 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 clumps together. When the cold slurry contains ice, the injectability of the slurry is significantly reduced.When the amounts of glycerol and lipids in the slurry are in the range of approximately 10% to 25% (v / v) and approximately 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 slurry from flowing freely from a suitably sized syringe. When the amounts of glycerol and lipids in the cold slurry are in the range of approximately 40% to 50% (v / v) and approximately 0% to 45% (v / v), respectively, there is no ice in the slurry because the lowering of the freezing point of water makes any water present in the slurry liquid, thus rendering the cold slurry unsuitable for cold slurry application. When the amounts of glycerol and lipids in the cold plasma are in the range of about 25% to 40% (v / v) and about 0% to 45% (v / v), respectively, the cold plasma 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 plasma is still low, making it less effective at removing heat than is required in cold plasma application. When the amounts of glycerol and lipids in the cold plasma are in the range of about 10% to 25% (v / v) and about 15% to 45% (v / v), respectively, the cold plasma is fluid and both injectable and an effective heat carrier. Within this performance range, the heat carrying capacity of the cold plasma can be maximized depending on the desired degree of injectability. In some embodiments, the lipids used in Figure 10 are soybean-PC.

[0106] Generally, cold plasmas 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 depressants (such as glycerol) and lipids to the slurry is expected to improve the slurry's flowability, but it reduces the amount of ice, thereby reducing the slurry's heat-carrying capacity. When the amount of glycerol in the cold slurry 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 slurry, small ice crystals will begin to form and then begin to aggregate into larger crystals, which further coalesce to result in large blocks of ice. Such large blocks of ice cause the slurry to become non-flowable, making the cold slurry mixture unsuitable for injection or direct surface application to the eye, but non-flowable cold slurries can be used in combination with stand-alone cooling devices for cold therapy on the ocular surface. When the amounts of glycerol and lipids in the slurry are in the range of about 10% to 25% and 0% to 15% (v / v), respectively, the cold slurry still lacks the flowability required for injection or surface application purposes. When the amounts of glycerol and lipids in the slurry are in the range of approximately 25% to 40% and 0% to 40% (v / v), respectively, the cold slurry contains sufficient glycerol to lower the freezing point of ice to the desired level while still exhibiting flow properties that allow for a certain degree of injectability. For example, within this range, even when the cold slurry does not contain lipids, it can still exhibit a lowered freezing point and a certain degree of fluidity, which allows it to be used for cold slurry therapy. When the glycerol in the slurry...When the amounts of glycerol and lipid are in the ranges of approximately 25% to 40% and 15% to 45% (v / v), respectively, the increased amount of lipid 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). Since cold serum 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 differences experienced during treatment) to maintain the low temperature of the ocular surface for an extended period, this range is not suitable for cold serum treatment. Optimized cold serums consist of amounts of glycerol and lipid varying between approximately 25% to 40% and 15% to 45% (v / v), respectively. Such a cold paste will maximize the heat-carrying capacity of the cold paste without compromising its fluidity, and therefore without compromising the injectability required for paste application (e.g., the desired injectability depending on syringe size, treatment temperature, etc.).

[0107] In some embodiments, the present invention relates to a cold paste formulation comprising water, one or more freezing point depressants, and one or more lipids. In some embodiments, the paste formulation is configured to maintain a desired temperature on the ocular surface for a prolonged period of time. In some embodiments, the paste 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 paste 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 adjacent to the patient's eye via a surface treatment, 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 paste 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 paste formulation by gently stirring water, one or more freezing point depressants, and one or more lipids in a desired proportion. In some embodiments, the paste 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, as described on pages 19 / 34 of document 28 (CN 121127188 A), the slurry formulation contains approximately 15% to 45% (v / v) lipids. In some embodiments, the lipids are 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 water components into tiny and / or millimeter-sized droplets encapsulated by one or more lipids. In some embodiments, such a method for preparing a slurry formulation results in the formation of water and freezing point depressant components into tiny and / or millimeter-sized droplets encapsulated by one or more lipids.

[0110] Device for Corneal Protection

[0111] In some embodiments, some aspects of the invention relate to a device for corneal protection. In some embodiments, the device for corneal protection described herein can be used when the slurry described herein is applied to the eye of an object. In some embodiments, contacting certain parts of the eye (e.g., the cornea) with 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 subject's eye is contacted with the paste described herein, it is desirable to provide physical and thermal protection / isolation of the cornea to protect it 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, wherein the corneal protection device is used in conjunction with the application of a paste to the surface of the eye, the member providing suction provides a seal around the periphery of the cornea to prevent deposited (i.e., surface-applied or injected) paste from direct contact with the cornea. The diameter of the suction-providing component (e.g., suction cup) of the corneal protection device can be of various sizes to accommodate corneal sizes, thereby allowing the device to be used on different objects of different ages and sizes (e.g., children, adults, etc.), including animals and humans. For example, the diameter of the opening of the suction-providing component (e.g., suction cup) can be 11 to 14 mm.

[0113] Referring to FIG11, in some embodiments, the suction-providing component of the corneal protection device 10 includes a suction cup 100, which includes one or more curved circular walls 110, wherein the diameter of the walls gradually decreases until it reaches the 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 one or more curved walls 110 is released, resulting in 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 a thermal insulating material to further protect the cornea from lateral heat diffusion from the surrounding environment, including if a cooling gel has been applied to the sclera adjacent to the cornea. In some embodiments, the partially or completely vacuum-emptied internal cavity 130 may provide additional thermal protection to the enclosed cornea 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 comprises 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), elastomer materials, silicone, thermoplastic elastomer (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 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 corneal protection device provides suction (e.g., suction cup) and / or one or more components.Multiple curved walls 110 provide high thermal resistance to slow the rate of heat transfer from the surrounding cold plasma to the cornea. In some embodiments, the suction cup and / or one or more walls of the corneal protector contain optically clear or translucent materials, such as optically clear silicone. In some embodiments, the suction cup and / or one or more walls of the corneal protector contain optically opaque materials, such as silicone and stained elastomer materials.

[0116] In some embodiments, the suction-providing component (e.g., the suction cup) includes design parameters such as suction area / diameter, wall thickness, vertical height, etc.

[0117] In some embodiments, when the suction-providing component (e.g., the 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 from the surrounding environment, including deposited cold plasma that may contact the outer wall of the corneal protector.

[0118] Referring to FIG12, in some embodiments, the corneal protection device includes an upper portion 212 for activating and deactivating suction. Suction can be activated by squeezing and releasing the 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 suction-providing member (e.g., a suction cup) 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, the suction-providing member (e.g., a suction cup) is used to protect the cornea from its surrounding environment (including any cold plasma applied to the ocular surface) by first pinching or squeezing the top element 212 of the device to activate the suction-providing member (e.g., a suction cup), then positioning the bottom element 214 on the ocular surface such that the edge of the device contacting the eye surrounds the outer edge or periphery of the cornea, and subsequently releasing the top element 212 to activate suction so that the suction-providing member adheres to the ocular surface. Suction ensures 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 embodiments, the 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, by first positioning the bottom element 214 on the ocular surface such that the edge of the device contacting 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] Referring to Figures 13A and 13B, a corneal protection device 300 and its application in forming a seal around the periphery of the cornea are shown. The corneal protection device 300 includes one or more walls 310, an open 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 held 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. As shown in Figure 13B, the bottom element 314 includes an open surface 330 positioned on 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 creating a suction (i.e., vacuum) force within the cavity that holds the corneal protection device in place on the target surface (e.g., the region above the cornea as shown in Figure 13B).

[0121] Contact Lens for Corneal Protection

[0122] In some embodiments, aspects of the invention relate to the use of a contact lens to protect the cornea both physically and thermally during cryo-plasma treatment. A contact lens may be placed on the cornea before the cryo-plasma is applied to the eye. The contact lens can act as both a physical barrier and a thermal barrier between the cornea and the surrounding cryo-plasma. Potential advantages of using a contact lens for corneal protection during cryo-plasma treatment include ease of use and patient familiarity with the product, which helps reduce anxiety during treatment. However, there may be some challenges with the use of a contact lens: 1) the contact lens may shift during treatment, exposing the cornea to the plasma; 2) the plasma 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 plasma 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-plasma provided by the contact lens.

[0123] In some embodiments, contact lenses comprising materials having low thermal conductivity but still allowing sufficient suction may be used, such as polymethyl methacrylate (PMMA), silicone, hydrogels, etc.

[0124] Devices for Protecting Eyelids

[0125] If the eyelids of an object 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 to the eyelids. Eyelid protection devices are described herein, which may 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, eyelid protection devices also serve asA speculum is used to keep the eye open during treatment.

[0126] Referring to Figures 14A and 14B, in 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 the eye. In some embodiments, one or more of the surfaces 410, 510 and 420, 520 of the eyelid protection device include members (e.g., platforms) 470, 570 to assist the practitioner in handling and manipulating the device, for example, for insertion into and removal from the eye. In some embodiments, one or more of the 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 or around 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 can be adjusted to provide a means of accommodating 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 into which the eyelid protection device is inserted under the eyelid is 2.54 to 5.85 mm. In some embodiments, the eyelid protection device comprises one or more types of plastic, extruded plastic, etc.Plastic), 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 protection device is configured to allow molten (i.e., liquid or lower viscosity) paste to drain from the eye surface. For example, in some embodiments, the eyelid protection device includes gaps or channels 440, 540 in one or more of surfaces 410, 510 and 420, 520, which allow molten paste to drain from the eye surface. In some embodiments, it is advantageous to remove hotter, molten paste from the eye surface because it allows a new batch of cold paste to be supplied to the eye surface while the eyelid protector remains in place. In some embodiments, it is desirable to remove such molten paste during treatment to ensure that the ocular surface remains in contact with the ice-crystal-containing paste at the desired temperature (rather than being covered by a hotter molten paste), thereby improving the efficiency and effectiveness of the treatment. In some embodiments, the eyelid protection device includes a wicking structure and / or wicking material that facilitates the removal of molten paste from the ocular surface. Some examples of wicking materials and structures that can be incorporated into the eyelid protection device include, but are not limited to, PVA, open-cell foam materials, etc.

[0129] Referring to FIG14B, in some embodiments, the eyelid protection device includes a structure for receiving and retaining a corneal protection device, such as feature 550, which is described herein and, for example, the corneal protection device shown in FIGS. 11 to 13. Such an eyelid protection device combined with a corneal protection device can be used to protect both the eyelids and the cornea, for example, when the cold paste described herein is applied to the ocular surface. FIGS. 15A and 15B show some examples of eyelid protection devices and corneal protection devices used in combination.

[0130] Kit

[0131] For more effective cold plasma treatment, the ocular surface should be maintained at a sub-zero temperature throughout the treatment duration. In some cases, the surface-applied cold plasma may heat up above a critical temperature and melt on the ocular surface before the treatment is completed, thus requiring the application of additional doses to maintain the desired sub-zero ocular surface temperature. Therefore, a kit for providing multiple doses of cold plasma is described herein, which allows for treatments including multiple applications of the plasma to maintain the ocular surface at a sub-zero temperature throughout the treatment. Referring to FIG16, in some embodiments, kit 600 includes multiple syringes 610 pre-filled with plasma. In some embodiments, kit includes an outer package 620 containing multiple syringes 610. In some embodiments, outer package 620 is configured to store, seal, and provide thermal and moisture protection to the multiple syringes 610. In some embodimentsIn this protocol, kit 600 contains at least two syringes pre-filled with slurry. In some embodiments, kit 600 contains 2 to 20, 2 to 15, 2 to 10, or 2 to 5 syringes pre-filled with slurry. In some embodiments, kit 600 contains only one 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). The kit can be stored in a cryostat before and during the cryoslurry procedure to ensure that the cryoslurry in each syringe is initiated and substantially maintained at the desired temperature (e.g., sub-zero temperatures) during the procedure. Such kits can also help facilitate the proper use and effectiveness of cryoslurry therapy, as clinicians have a better understanding of how much dose to administer to the treatment area and at what intervals new doses should be administered.

[0132] In some embodiments, kit 600 includes a heat pack configured to maintain the cold slurry at a sub-zero temperature for the desired duration after the kit is 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 procedure, such as in remote, underdeveloped areas. In some embodiments, the heat pack of the kit includes a phase change material, insulation, a reflective barrier, reflective foil, polystyrene foam, or a combination thereof.

[0133] In some embodiments, the kit includes one or more empty syringes and a separate container containing the 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, the slurry can be drawn into one or more empty syringes under ambient temperature conditions, under which the liquid slurry can be readily drawn by the syringes. In such embodiments, the filled syringes can be returned to the kit and placed and / or stored in the 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 degree of protection against, for example, potential contamination, temperature changes, 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), all of 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, all of 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 Device

[0137] In some embodiments, aspects of the invention relate to an independent cooling device that allows the transfer of heat energy from a target surface (e.g., the ocular surface) using cryo-slurry treatment. In some embodiments, the independent cooling device is used for cryoneurolysis purposes. In some embodiments, such an independent 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 an independent cooling device comprising a container containing a thermal mass (e.g., a liquid, solid, or cryo-slurry preparation) with a freezing point lower than that of water. In some embodiments, such devices can be transported and stored in sterile packaging at ambient temperature or in a standard freezer. In some embodiments, such packaging is frozen before 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 in a container such that its...It must not directly contact the surface of the target eye or surrounding tissues and body parts (e.g., cornea, eyelids, skin) and thus cause any damage to the surface of the target eye or surrounding tissues and body parts (e.g., cornea, eyelids, skin).

[0139] In some embodiments, the independent cooling device comprises a thermophysical mass (e.g., a liquid, solid, or cryopreservative formulation). In some embodiments, the thermophysical mass is contained within a heat exchanger. In some embodiments, the thermophysical mass comprises a formulation of about 20% by weight / weight glycerol in water (e.g., pure water). Specification 24 / 34 pages 33 CN 121127188 A

[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 a package after sterilization. In some embodiments, the independent cooling device is sterilized after being placed in a package. 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 transport 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 on the subject's eye when the subject is in a supine position.

[0142] In some embodiments, some aspects of the invention relate to an independent cooling device capable of maintaining the ocular surface at sub-zero temperatures. Referring to FIG17, in some embodiments, the 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 act as an effective thermal interface that efficiently transfers heat energy from the ocular surface to a thermoplastic mass, 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 paste, solid ice, or liquid formulation. Some advantages of such a stand-alone cooling device are that the biocompatibility or flowability of the thermoplastic mass (e.g., cold paste, 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 stand-alone cooling device includes a container for holding the thermoplastic mass (e.g., liquid or paste formulation).The formulation chamber or reservoir 720 of the thermoplasm may 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 an integral part of the reservoir or chamber 720 or attached to the underside 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 conform to the contours of the ocular surface. In some embodiments, the ocular surface interface 710 has an opening or aperture (e.g., a circular, rectangular, elliptical, or 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 the chamber 720 utilizes the latent heat of a phase change (e.g., a solid-liquid phase transition) to maintain a sub-zero temperature on the target ocular surface for a predetermined duration (i.e., a volume-controlled amount of heat transfer).

[0146] In some embodiments, the ocular surface (i.e., the 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 comprises geometric design features (e.g., hierarchical micro / nanostructures and surfaces, bio-inspired hydrophobic surface patterns) that protect the ocular surface.Ocular surface interface 710 is free from adhesion to freezing. 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 that circulate coolant (or cold air) through the ocular surface interface 710. In some embodiments, the independent cooling device comprises one or more mechanical systems that deliver coolant to the ocular surface interface 710. In some embodiments, the independent cooling device comprises one or more mechanical systems that facilitate manual application of coolant to the ocular surface interface.

[0148] To ensure that the target surface remains at the desired sub-zero temperature during treatment, the ocular surface interface 710 should remain in partial contact with the formulation (e.g., a frozen or slurry formulation) at the desired temperature within the chamber or storage container 720. In some embodiments, as heat is transferred from the ocular surface to the ocular surface interface 710 and subsequently to the formulation within the chamber or reservoir 720, portions of the slurry or frozen formulation in contact with the ocular surface interface 710 will begin to melt as they heat up. 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 reduction in the 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 downwardly pushing a frozen portion of the formulation within the chamber or reservoir 720 to maintain contact between a colder (e.g., ice or frozen) portion of the formulation and an ocular surface interface 710 in contact with the bottom of the chamber or reservoir 720. This is achieved by downwardly pushing the formulation 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, and allowing a 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, the mechanism for downwardly pushing the formulation within the chamber or reservoir 720 to maintain contact between the colder (e.g., ice or frozen) portion of the formulation and the ocular surface interface includes one or more side pins 734 that can be pushed in or pushed out from the bottom of the chamber or reservoir 720 in contact with the ocular surface interface 710.A hollow chamber 732 above or forming the upper part 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 part 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 is slidable up and down within the formulation chamber or reservoir 720 while maintaining contact or close proximity to the interior of the vertical wall 722 of the formulation chamber or reservoir 720. In some embodiments, the sliding plate includes one or more holes to allow molten liquid to pass through the sliding plate as it 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, its spring 736 is released, causing the movable plate 738 to translate downward within the formulation chamber or reservoir 720, thereby forcing 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., melted 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 device description 26 / 34 pages 35 CN 121127188 A or structures, such as the eyelid protection device and / or corneal protection device described herein. In some embodiments, such a stand-alone cooling device also includes an eyelid protection device and a corneal protection device. Such a stand-alone cooling device can simplify the cold plasma treatment described herein by reducing the number of devices and related steps that clinicians must assemble / handle and use during the procedure.

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

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

[0153] In some embodiments, when the stand-alone cooling device 800 is mounted above the ocular surface to allow contact with the ocular surface interface 810...When the desired portion of the ocular surface is exposed, the corneal protector device 850 contacts the cornea in a manner that protects the cornea from physical or thermal contact with any foreign substance (e.g., cryopreservation). 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 allows the ocular surface interface 810 to remain in contact with the cold cryopreservation and allows the liquid slurry to be pushed away from the ocular surface interface 810).

[0154] In some embodiments, a method for treating ocular surface discomfort using a separate cooling device is provided. An exemplary method according to certain embodiments of this disclosure is shown in Figure 19. 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 the speculum is placed, a separate cooling device is placed. Optionally, the speculum includes a guide configured to ensure proper placement of the separate cooling device. The independent cooling device may include an orifice configured to allow a clinician to visualize the subject's cornea and maintain proper device positioning. Once the independent cooling device contacts the subject's eye, it is allowed to remain in contact with the eye for a sustained treatment time (e.g., from about 2 minutes to about 10 minutes). After the treatment time, the eye is flushed (e.g., with saline) to prevent adhesion between the eye and the independent cooling device after treatment. After flushing, the device and speculum are removed. Figure 24 provides a graph illustrating treatment time relative to removal time after treatment using the method according to this disclosure.

[0155] In some embodiments, the independent cooling device achieves cooling of the target surface via conduction. In some embodiments, the independent cooling device first contacts the target surface, e.g., the sclera, and conducts heat from the target surface into the device, e.g., to the target surface interface and into a heat exchanger, and ultimately from the heat exchanger to 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 treatment temperature to be maintained.

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

[0157] In some aspects, a separate cooling device is placed in a cold environment before use. In some embodiments, the cold environment is a standard freezer, a -20°C freezer, a -80°C freezer, an ultra-low temperature (“ULT”) freezer, 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 method provided herein. In some embodiments, the predetermined temperature is a sub-zero temperature. In some embodiments, the predetermined temperature is about -20°C to about 0°C. In some implementations, 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 approximately -20°C to approximately -18°C, approximately -19°C to approximately -17°C, approximately -18°C to approximately -16°C, approximately -17°C to approximately -15°C, approximately -16°C to approximately -14°C, approximately -15°C to approximately -13°C, approximately -14°C to approximately -12°C, approximately -13°C to approximately -11°C, approximately -12°C to approximately -10°C, approximately -11°C to approximately -9°C, approximately -10°C to approximately -8°C, approximately -9°C to approximately -7°C, approximately -8°C to approximately -7°C, approximately -6°C to approximately -4°C, approximately -5°C to approximately -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 aspects, 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 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 embodiments, the treatment temperature is about -20°C to about -18°C, about -19°C to about -17°C, about -18°C to about -16°C, about -17°C to about -15°C, about -16°C to about -14°C, about -15°C to about -13°C, about -14°C to about -12°C, about -13°C to about -11°C, about -12°C to about -10°C, about -11°C to about -9°C, about -10°C to about -8°C, about -9°C to about -7°C, about -8°C 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 about 30 seconds. In some implementations, the sclera is positioned at 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, and 260 seconds. Approximately 270 seconds, approximately 280 seconds, approximately 290 seconds, approximately 300 seconds, approximately 310 seconds, approximately 320 seconds, approximately 330 seconds, approximately 340 seconds, approximately 350 seconds, approximately 360 seconds, approximately 370 seconds, approximately 380 seconds, approximately 390 seconds, approximately 400 seconds, approximately 410 seconds, approximately 420 seconds, approximately 430 seconds, approximately 440 seconds, approximately 450 secondsThe treatment temperature (e.g., below 0°C) is reached after approximately 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 device includes an insulating feature. In some embodiments, the insulating feature is a gap between the housing of the cooling device 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 device provides advantages by minimizing condensation on the independent cooling device, maintaining the desired temperature of the independent cooling device (including one or more contact surfaces), and / or by maintaining the volume of the thermomass (e.g., within the heat exchanger).

[0162] In some aspects, the independent cooling device is configured to be balanced. A balanced independent cooling device can be advantageous because it allows for easy positioning by the clinician during use.

[0163] Referring to Figures 20A and 20B, an exploded view of an independent cooling device according to this disclosure is provided. In some embodiments, the independent cooling device 900 includes a housing 910 that houses 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 independent 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 thermomaterial (e.g., a liquid, solid, or partially solid cryogenic preparation). In some embodiments, the thermomaterial is contained within the heat exchanger 920. In some embodiments, the thermomaterial is frozen in a standard freezer. 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 thermomaterial is sealed within the heat exchanger 920, for example, by using an adhesive to join the top and bottom components after the thermomaterial 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 for independent cooling devices by promoting…Heat exchange between the ocular surface and the heat exchanger 920 causes the ocular surface to reach a cold temperature very quickly. 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 cryothermal mass. 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] Referring to Figures 21A through 21E, several 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, drawings are provided of the independent cooling device and its appendices according to the present disclosure provided in Figures 20A, 20B, and 21A through 21E. In some embodiments, the independent cooling device includes a housing 910, a gripping interface 1020, an aperture 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 the procedure and to assist in the proper placement of an independent cooling device. In other embodiments, the accessory isolates the eyelid from the ocular surface interface 940. In some embodiments, the accessory comprises a flexible insulating material (e.g., silicone). Drawings of accessories according to certain embodiments of this disclosure are provided in Figures 23A to 23D. In some embodiments, the accessory includes an aperture 1230 configured to allow a clinician to visualize the subject's cornea. In some embodiments, the accessory includes one or more guiding features 1235 (e.g., cutouts) configured to assist the clinician in placing an independent cooling device during the procedure. In some embodiments, the accessory includes one or more surfaces 1260, which...Surface 1260 is configured to fit under the eyelid of the subject to keep the eyelid open during surgery. In some embodiments, the accessory includes one or more features 1270 configured to push the patient's eyelashes away from the independent cooling device. In some embodiments, the accessory also includes an accessory gripping interface 1220. In some embodiments, the accessory gripping interface 1220 is configured to assist the clinician in properly placing the accessory.

[0166] In some embodiments, the independent cooling device is reusable. In some embodiments, the independent device is disposable.

[0167] Referring now to FIG25, an exemplary treatment area 2500 is shown 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, the clinician may place the ocular (i.e., target) surface interface 940 of the independent cooling device through the guide feature 1235. The clinician may then visualize the patient's eye (e.g., including the cornea) through the aperture 1030 / 1230 to maintain the correct device position before using the ocular surface interface 940 to contact the eye. Upon contact, the ocular surface interface 940 may adhere to the eye and remain in contact with the eye 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, after treatment, the eye is removed by, for example, using an electric heating element or system, removing the thermoplastic body, or using a fluid (and optionally...The independent cooling device is warmed by flushing the interior of the device with a warm fluid or by a chemical (exothermic) reaction. In some embodiments, the ocular surface interface 940 or its attachment includes one or more channels configured to facilitate flushing.

[0169] Mechanism of Action

[0170] Without being bound by any theory, the basic premise is that the application of sub-zero temperatures (e.g., about -20°C to about 0°C) terminates the signaling of painful stimuli by causing degeneration of the myelin sheath on the nerve. Myelin is a lipid-rich fatty substance that allows electrical stimulation to travel down the nerve axon in a rapid and efficient manner. When cold plasma or other cold treatments (e.g., using an independent cooling device according to this disclosure) are applied to both the free nerve endings and the myelinated portion of the nerve, the cold temperature will freeze or crystallize the lipid components of the adipocytes, induce apoptosis, and cause myelin degeneration, a process known as Wallerian degeneration. This process will significantly reduce 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 that induce Wallerian degeneration include radiofrequency ablation (see page 30 / 34 of CN 121127188 A) and cryo-neurolysis (freezing at temperatures close to -80°C), but these procedures carry the risk of damaging surrounding tissues and structures. Additionally, inactive carriers containing ice crystals will not harm other parts of the eye, making them reasonably applicable 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 cryopreserved fluid to distribute around the free nerve endings of the ciliary nerve. Furthermore, surface application of a slurry 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 with 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. Injection of a cold slurry and / or the cold temperature from a surface-applied cold slurry and / or an independent cooling device diffuses downstream to the site of myelination of the ciliary nerve axons. As the cold slurry and / or the cold temperature from a surface-applied cold slurry and / or an 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 slurry and / or the cold temperature from a surface-applied cold slurry and / or an independent cooling device can cause Wallerian degeneration of the nerve, similarly preventing pain signals from being transmitted.Delivered to the brain. Alternatively, the cold plasma and / or the cold temperature from surface-applied cold plasma and / or a separate cooling device can target the free nerve endings of the ciliary nerve.

[0172] Surface-applied and / or injected cold plasma, or a separate 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 a separate cooling device as a long-term and safe treatment for corneal numbness, which causes sensory reduction without permanent corneal numbness or damage.

[0174] Example 1 - In vivo testing of cold plasma treatment for corneal numbness

[0175] The results of the studies described in this example can be seen in Figures 5 through 9. Preclinical testing in animals was conducted to determine the efficacy of the treatment, including exploring the optimal manner of delivery of the treatment, the duration of the therapeutic effect, and any potential side effects. For ophthalmic research, the New Zealand white rabbit is an ideal model because its cornea and corneal nerve innervation system are very similar to those of humans, and it is the standard and 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). The 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 under study. Animals were given inhalation anesthesia (1.5% to 2% isoflurane) and O2 was supplemented.

[0178] Study Procedure

[0179] Animals were prepared and draped in a routine aseptic manner, including instilling povidone-iodine drops onto the ocular surface. A speculum was placed, and the paste was injected superficially or subconjunctivally.

[0180] Injection Administration

[0181] To evaluate the sensory reduction potential of ECT-1719, approximately 0.7 mL of the cold paste was injected into the subconjunctival space around the limbus. The injected cold paste was evenly distributed 360 degrees around the limbus, partly due to pressure from the cornea and injection force. (Instructions for Use, pages 31 / 34, 40 CN)121127188 A and the existing natural potential space. The injection procedure was repeated every 120 seconds for a total of 10 minutes.

[0182] Control animals were treated with sterile saline (control) or with 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 washed with sterile saline. There was also an additional control group in which routine anesthetic drops were applied to the cornea. All procedures were performed only on the left eye (for control purposes) and lasted for about 10 minutes.

[0183] The above-described procedures are usually performed in humans, with a variety of different agents (e.g., steroids, antibiotics, etc.) injected as appropriate.

[0184] Surface application

[0185] To evaluate the sensory reduction potential of ETX-4143, the slurry was applied to the ocular surface (posterior part of the limbus). The cornea was protected with a contact lens and the eyelids were protected with a plastic speculum. Approximately 2 mL of cold paste was applied to the surface every 30 seconds for the first 4 minutes, and then applied approximately every minute 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-procedure for surviving animals

[0187] Neomycin / polymyxin / bacitracin ophthalmic ointment was applied to the operated eye, and a few drops of prednisone acetate were applied postoperatively. The animal was removed from the operating table and placed on a heating pad. The animal's vital signs (e.g., heart rate, respiration, SpO2) were monitored while awaiting recovery. The animal was monitored until muscle control was restored. The animal was returned to its original cage.

[0188] Postoperative animal monitoring

[0189] The animal underwent a full eye examination one day after the operation and thereafter weekly, including measurements of corneal sensation. Intraocular pressure measurements were also performed, as a beneficial reduction in intraocular pressure could be observed in animals that had already received this treatment. In addition, 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 confinement cage for several seconds while eye drops were instilled.

[0190] Effects of Application

[0191] The effects of cold ointment application were examined using a variety of techniques.

[0192] The numbing effect of cold ointment was tested using a tactile meter. A monofilament with a certain stiffness was extended from the device. Animals treated with cold ointment were able to tolerate greater forces from the tactile meter than animals in the control group. This was demonstrated by whether the animal withdrew 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 ointment on the healing capacity of the eye was also examined. Epithelial defects were created on the cornea using a trephine and corneal brush. The damage was verified with fluorescein staining and recorded by photography. The progression of the damage was measured using fluorescein staining and by measuring the size of the damage.The cold plasma does 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 results of the study described in this example can be seen in Figures 26, 27, and 28. Preclinical animal studies were conducted to determine the thermal effect of the stand-alone cooling device according to this disclosure.

[0196] Referring to Figure 26, in this example, a pig eye surface was used to generate a representative temperature profile of the temperature taken from the pig eye surface. The pig eye was brought into contact with the ocular surface interface of the stand-alone cooling device according to this disclosure. In this example, the ocular surface interface is a copper ocular surface interface connected to a heat exchanger to form a piece, and the stand-alone cooling device contains a thermoplastic mass containing 20% ​​by weight of glycerol in purified water. The temperature of the pig eye was measured over time and is presented in Figure 26. As shown in Figure 26, the temperature reached 0°C after 29 seconds. The lowest temperature recorded was -3.5°C. Finally, after 536 seconds (8 minutes and 56 seconds, pages 32 / 34 of the specification, CN 121127188 A), the temperature rose above 0°C again.

[0197] As shown in FIG27 and as described below, the temperature of the pig eye was also measured at three locations. The pig eye was partially immersed in a water bath to heat the eye to a representative surface temperature of approximately 33°C. As shown in FIG27, the 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] The pig eye was brought into contact with the independent cooling device described above with respect to FIG26, and the measurements were recorded over time. As shown in FIG28, the temperature below the treatment area 2500 reached 0°C after 29 seconds and rose above 0°C again after 536 seconds (8 minutes and 58 seconds). The representative temperature curve below treatment area 2500 depicted in Figure 26 is also shown in Figure 28. Temperatures were also recorded at location 1 (located at 0° relative to the horizontal and 1.5 mm from treatment area 2500) and location 2 (located at 45° relative to the horizontal and 1.5 mm from treatment area 2500). The results showed that location 1 reached a cooler temperature compared to location 2.

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

[0200] The results of the study described in this example can be seen in Figure 29. Preclinical testing was conducted in animals 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, New Zealand white rabbits are an ideal model for ophthalmic investigation because their cornea and corneal nerve innervation system are very similar to those of humans, and they areThe standard, accepted model used in the literature for corneal research.

[0201] Independent Cooling Device

[0202] The independent cooling device is designed to allow for the treatment of rabbit eyes, which is similar to the treatment of human eyes. The independent cooling device contains a thermocouple embedded in the eye contact surface to measure the temperature of the eye surface during surgery. The device is designed to contact and treat the rabbit eye at 200 degrees (220° total - 20° gap), specifically targeting the sclera portion just outside the cornea. Previous studies have shown that it is difficult to treat all areas around the cornea 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, place the device in a cryostat set at -20°C and allow it to stand for at least 12 hours, or alternatively, stand at -27°C for 2 hours, then stand at -20°C for 2 hours (refreeze after 4 hours).

[0203] Independent Cooling Device Procedure

[0204] Before anesthesia, a corneal sensation test is performed. The subject is anesthetized in accordance with the standard procedures of the approved IACUC protocol. Topical promethazine is applied to both the treatment eye and the control eye. Using a speculum, the subject's eyelids are opened to expose the cornea and as much of the sclera as possible. If necessary, the corneal protector device (contact lens adsorption device) is placed onto the cornea by 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 around the cornea, carefully ensuring that the device is minimally obstructed by the subject's eyelids. The device is kept in contact with the eye 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] The overall health status of the subjects was monitored for one week after surgery. Subjects also underwent a comprehensive eye examination one week after surgery and subsequently weekly (+ / - 3 days), including corneal sensation testing and intraocular pressure (IOP) measurement using a tactile meter.

[0207] Effect of Independent Cooling Device Procedure

[0208] Rabbits showed a significant reduction in sensation compared to their corresponding untreated eyes, with an average reduction of approximately 75% in the first week and approximately 63% in the second week. See 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. Figure 1 (Page 1 / 37, 44 CN)Figure 2 of 121127188 A, Appendix 2 / 37, Page 45, CN; Figure 3 of 121127188 A, Appendix 3 / 37, Page 46, CN; Figure 4A of 121127188 A, Appendix 4 / 37, Page 47, CN; Figure 4B of 121127188 A, Appendix 5 / 37, Page 48, CN; Figure 5 of 121127188 A, Appendix 6 / 37, Page 49, CN; Figure 6 of 121127188 A, Appendix 7 / 37, Page 50, CN; Figure 7 of 121127188 A, Appendix 8 / 37, Page 51, CN; Figure 8A of 121127188 A, Appendix 9 / 37, Page 52, CN; Figure 8B of 121127188 A, Appendix 10 / 37, Page 53, CN; Figure 9 of 121127188 A, Appendix 11 / 37, Page 54, CN Figure 10 of the instruction manual, page 12 / 37, CN 121127188 A; Figure 11 of the instruction manual, page 13 / 37, CN 121127188 A; Figure 12 of the instruction manual, page 14 / 37, CN 121127188 A; Figure 13A of the instruction manual, page 15 / 37, CN 121127188 A; Figure 13B of the instruction manual, page 16 / 37, CN 121127188 A; Figure 14A of the instruction manual, page 17 / 37, CN 121127188 A; Figure 14B of the instruction manual, page 18 / 37, CN 121127188 A; Figure 15A of the instruction manual, page 19 / 37, CN 121127188 A; Figure 15B of the instruction manual, page 20 / 37, CN 121127188 A 121127188 A Figure 16, Instruction Manual Drawings, Page 21 / 37, 64 CN 121127188 A Figure 17A-17B, Instruction Manual Drawings, Page 22 / 37, 65 CN 121127188 A Figure 18A-18B, Instruction Manual Drawings, Page 23 / 37, 66 CN 121127188 A Figure 19, Instruction Manual Drawings, Page 24 / 37, 67 CN 121127188 A Figure 19 (Continued), Instruction Manual Drawings, Page 25 / 37, 68 CN 121127188 A Figure 20A-20B, Instruction Manual Drawings, Page 26 / 37Page 69 CN 121127188 A Figure 21A Figure 21B Instruction Manual Drawings 27 / 37 Page 70 CN 121127188 A Figure 21C Figure 21D Figure 21E Instruction Manual Drawings 28 / 37 Page 71 CN 121127188 A Figure 22A-22B Instruction Manual Drawings 29 / 37 Page 72 CN 121127188 A Figure 23A Figure 23B Instruction Manual Drawings 30 / 37 Page 73 CN 121127188 A Figure 23C Figure 23D Instruction Manual Drawings 31 / 37 Page 74 CN 121127188 A Figure 24 Instruction Manual Drawings 32 / 37 Page 75 CN 121127188 A Figure 25 Instruction Manual Drawings 33 / 37 Page 76 CN 121127188 A Figure 26 Instruction Manual Drawings 34 / 37 Page 77 CN 121127188 A Figure 27 Instruction Manual Drawings, Page 35 / 37, 78 CN 121127188 A Figure 28 Instruction Manual Drawings, Page 36 / 37, 79 CN 121127188 A Figure 29 Instruction Manual Drawings, Page 37 / 37, 80 CN 121127188 A

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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