Cryotherapy and cryoablation systems and methods for treatment of tissue

Abstract

To provide systems and methods for using cooling to trigger desirable effects of increased vasculature and / or development of new collagen in biological tissue.SOLUTION: The systems and methods provide a cooling treatment system configured to provide bulk or fractionated cooling at either ablative temperatures or intermediary remodeling temperatures to promote tissue remodeling by inducing increased vasculature and / or formation of new collagen.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 381,231, entitled "Cryotherapy and Cryoablation Systems and Methods for Treating Tissue," filed August 30, 2016, which is incorporated by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH Not applicable. [Background technology]

[0003] FIELD OF THE DISCLOSURE This disclosure relates generally to the therapeutic use of cooling, and more particularly to cryotherapy and cryoablation systems and methods for the treatment of tissue.

[0004] Controlled cooling and / or heating of biological tissues, such as skin tissue, can produce a variety of therapeutic effects. For example, heating has been shown to improve skin defects by application of electromagnetic radiation that induces thermal damage to the skin. Thermal damage results in a complex wound healing response of the skin, which can result in biological repair of damaged skin and can be accompanied by other desirable effects.

[0005] Cutaneous tissue cooling has been implemented in pigmentation reduction and tissue remodeling applications. Certain tissue cooling procedures and devices, such as conventional cryoprobes, can cause cryoinjury or wounding in tissue, resulting in cellular damage (i.e., cryoablation). Similar to thermal injury, cryoinjury can trigger a complex wound healing process that can lead to biological repair of the skin. Other tissue cooling techniques may implement temperatures that do not induce cryoinjury, but still promote a therapeutic effect as a result of exposure to cold (i.e., cryotherapy). Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides systems and methods for the use of cooling to induce desirable effects, such as increased vasculature and / or new collagen generation in biological tissue. In particular, the systems and methods provide cooling treatment systems configured to provide bulk or fractionated cooling at ablation temperatures or intermediate remodeling temperatures to promote tissue remodeling by inducing increased vasculature and / or new collagen formation.

[0007] In one aspect, the present disclosure provides a method for inducing angiogenesis in a subject. The method includes identifying treatment parameters for a desired tissue region of the subject to receive a treatment that includes cooling using a cooling device to a desired temperature provided by the cooling device. The treatment parameters are based in part on at least one of the desired treated tissue region or the treatment. The method further includes administering the treatment using the treatment parameters and inducing an angiogenic response of the desired treated tissue to the treatment.

[0008] In another aspect, the present disclosure provides a method for inducing collagen remodeling in a subject. The method includes identifying treatment parameters for a desired tissue region of the subject to receive a treatment that includes cooling using a cooling device to a desired temperature provided by the cooling device. The treatment parameters are based in part on at least one of the desired treated tissue region or the treatment. The method further includes administering the treatment using the treatment parameters and inducing a collagen remodeling response of the desired treated tissue to the treatment.

[0009] In yet another aspect, the present disclosure provides a method for inducing cryolipolysis in a subject, the method including identifying treatment parameters for a desired tissue region of the subject to receive a treatment that includes cooling using a cooling device to a desired temperature provided by the cooling device, the treatment parameters being based in part on at least one of the desired treated tissue region or the treatment, the desired temperature being between about minus 200° C. and about 30° C. The method further includes administering the treatment using the treatment parameters and inducing a cryolipolysis response of the desired treated tissue to the treatment.

[0010] In yet another aspect, the present invention provides a cooling therapy system for administering cold therapy to a desired tissue region of a patient, the cooling therapy system including a cooling device and a delivery device configured to be cooled by the cooling device and to expose the desired tissue region to a desired temperature provided by the cooling device, the desired temperature being between about minus 200°C and about 30°C.

[0011] [The present invention 1001] 1. A cooling therapy system for applying cooling therapy to a desired tissue region of a patient, comprising: A cooling device; a delivery device configured to be cooled by the cooling device and to expose a desired tissue region to a desired temperature provided by the cooling device; A cooling therapy system, wherein the desired temperature is between about minus 200 degrees Celsius and about 30 degrees Celsius. [The present invention 1002] The cooling treatment system of the present invention 1001, wherein the delivery device comprises one or more protrusions configured to engage the desired tissue region. [The present invention 1003] The cooling therapy system of claim 1002, wherein the one or more prongs comprise a needle conductively coupled to the cooling device. [The present invention 1004] The cooling treatment system of claim 1002, wherein the one or more prongs comprise a needle array conductively coupled to the cooling device. [The present invention 1005] each of the one or more prongs comprises a needle including an axially wrapped insulating material; A cooling therapy system according to the present invention 1002, wherein the tip of the needle is not insulated. [The present invention 1006] The cold therapy system of claim 1002, wherein the one or more protrusions comprise a needle configured to inject a slurry. [The present invention 1007] The cold treatment system of claim 1002, wherein the one or more protrusions comprise a needle array configured to inject a slurry. [The present invention 1008] each of the one or more projections comprises a needle including an inlet passage and an outlet passage disposed therein; The cooling therapy system of claim 1002, wherein the inlet and outlet passages are configured to receive a flow of fluid to actively cool the needle. [The present invention 1009] The cold treatment system of claim 1001, wherein the one or more protrusions comprise an array configured to locally apply a slurry. [The present invention 1010] The cooling therapy system of claim 1001, wherein the delivery device comprises an expandable needle including a balloon expandable between an expanded position and a contracted position. [The present invention 1011] The cooling therapy system of the present invention 1001 further comprises a heating device. [The present invention 1012] The cooling therapy system of the present invention 1011, wherein the warming device is coupled to a base of the delivery device adjacent a proximal end of the one or more prongs to heat a surface of the desired tissue region. [The present invention 1013] The cooling treatment system of the present invention 1011, wherein the heating device comprises at least one of a radiofrequency heating device and an infrared laser. [The present invention 1014] The cooling treatment system of the present invention 1001 further comprising a depth imaging device configured to monitor the depth of the delivery device within the desired tissue region. [The present invention 1015] The cooling therapy system of the present invention 1001 further comprising a thermal imaging device configured to monitor the temperature of the desired tissue region. [The present invention 1016] The cooling treatment system of the present invention 1001 further comprising one or more temperature sensors configured to monitor a temperature of the delivery device and / or the desired tissue region. [The present invention 1017] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 180 degrees Celsius and about 30 degrees Celsius. [The present invention 1018] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 160 degrees Celsius and about 30 degrees Celsius. [The present invention 1019] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 140 degrees Celsius and about 30 degrees Celsius. [The present invention 1020] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 120 degrees Celsius and about 30 degrees Celsius. [The present invention 1021] The cooling treatment system of the present invention 1026, wherein the desired temperature is between about minus 100 degrees Celsius and about 30 degrees Celsius. [The present invention 1022] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 80 degrees Celsius and about 30 degrees Celsius. [The present invention 1023] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 70 degrees Celsius and about 30 degrees Celsius. [The present invention 1024] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 60 degrees Celsius and about 30 degrees Celsius. [The present invention 1025] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 50 degrees Celsius and about 30 degrees Celsius. [The present invention 1026] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 40 degrees Celsius and about 30 degrees Celsius. [The present invention 1027] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 30 degrees Celsius and about 30 degrees Celsius. [The present invention 1028] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 20 degrees Celsius and about 30 degrees Celsius. [The present invention 1029] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 20 degrees Celsius and about 20 degrees Celsius. [The present invention 1030] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 20 degrees Celsius and about 20 degrees Celsius. [The present invention 1031] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 20 degrees Celsius and about 10 degrees Celsius. [The present invention 1032] The cooling treatment system of the present invention 1001, wherein the desired temperature is between about minus 20 degrees Celsius and about 5 degrees Celsius. [The present invention 1033] The cooling therapy system of claim 1001, wherein the delivery device further comprises a manifold configured to be removably coupled to one or more needles. [The present invention 1034] 1033. A cooling therapy system according to claim 1033, wherein said manifold comprises an inlet port configured to be removably coupled with a slurry injector. [The present invention 1035] The cooling therapy system of claim 1034, wherein the manifold is configured to provide fluid communication between the inlet port and the one or more needles coupled thereto. [The present invention 1036] The cooling therapy system of the present invention 1001 further configured to induce an angiogenic, cryolipolytic, or collagen remodeling response in the patient. [The present invention 1037] 1. A method for inducing angiogenesis in a subject, comprising: identifying treatment parameters for a desired tissue region of the subject to receive a treatment comprising cooling to a desired temperature using a cooling device provided by the cooling device, the treatment parameters being based in part on at least one of the desired treatment tissue region or the treatment; administering a treatment using the treatment parameters; and eliciting a desired angiogenic response of the treated tissue to said treatment. [The present invention 1038] The method of claim 1037, wherein the treatment comprises a fractionated cooling treatment. [The present invention 1039] The method of claim 1038, wherein the split cooling process is split slurry injection. [The present invention 1040] The method of claim 1038, wherein the split cooling process is conduction cooling via a split needle array. [The present invention 1041] The method of claim 1037, wherein said treatment comprises ablative cryotherapy. [The present invention 1042] The method of claim 1037, wherein the treatment comprises a bulk cooling treatment. [The present invention 1043] The method of claim 1037, wherein the desired tissue to be treated comprises an ischemic organ or tissue. [The present invention 1044] The method of the present invention 1043, wherein the ischemic organ or tissue comprises one of a burn scar, a scar, a keloid, aging skin, tissue affected by diabetic neuropathy, lipoma, cellulite, ischemic damaged tissue, chronic wound, tissue affected by male pattern baldness, the heart, the liver, or the kidney. [The present invention 1045] The method of claim 1037, wherein said treatment is part of a vaginal rejuvenation treatment, a skin rejuvenation treatment, or an onychomycosis treatment. [The present invention 1046] The method of claim 1037, further comprising the step of inducing collagen remodeling or a cryolipolytic response in said subject. [The present invention 1047] The method of claim 1037, wherein the cooling device comprises the system of claim 1001. [The present invention 1048] 1. A method for inducing collagen remodeling in a subject, comprising: identifying treatment parameters for a desired tissue region of the subject to receive a treatment comprising cooling to a desired temperature using a cooling device provided by the cooling device, the treatment parameters being based in part on at least one of the desired treatment tissue region or the treatment; administering a treatment using the treatment parameters; and inducing a collagen remodeling response of the desired treated tissue to the treatment. [The present invention 1049] The method of claim 1048, wherein the treatment comprises a fractionated cooling treatment. [The present invention 1050] The method of claim 1048, wherein the treatment comprises ablative cryotherapy. [The present invention 1051] The method of claim 1048, wherein the treatment comprises a bulk cooling treatment. [The present invention 1052] The method of claim 1048, wherein the desired treatment tissue comprises tissue undergoing relaxation. [The present invention 1053] The method of claim 1052, wherein the desired tissue to be treated comprises one of a burn scar, a scar, a keloid, aging skin, cellulite or a chronic wound. [The present invention 1054] The method of claim 1048, wherein the treatment is part of a vaginal rejuvenation treatment or a skin rejuvenation treatment. [The present invention 1055] The method of claim 1048, wherein the desired treatment tissue comprises soft tissue of the subject's airway. [The present invention 1056] The method of claim 1055, wherein said treatment is part of a treatment for ameliorating obstructive sleep apnea. [The present invention 1057] The method of claim 1048, further comprising the step of inducing an angiogenic or cryolipolytic response in said subject. [The present invention 1058] The method of claim 1048, wherein the cooling device comprises the system of claim 1001. [The present invention 1059] 1. A method for inducing low temperature lipolysis in a subject, comprising: identifying treatment parameters for a desired tissue region of the subject to receive a treatment that includes cooling to a desired temperature using a cooling device provided by the cooling device, the treatment parameters being based in part on at least one of the desired treatment tissue region or the treatment, the desired temperature being between about minus 200 degrees Celsius and about 30 degrees Celsius; administering a treatment using the treatment parameters; and inducing a cryolipolytic response of the desired treatment tissue to said treatment. [The present invention 1060] The method of claim 1059, wherein the treatment comprises a fractionated cooling treatment. [The present invention 1061] The method of claim 1059, wherein said treatment comprises ablative cryotherapy. [The present invention 1062] The method of claim 1059, wherein the treatment comprises a bulk cooling treatment. [The present invention 1063] The method of claim 1059, wherein the desired treatment tissue comprises one of the tongue or tissue within the respiratory tract of the subject. [The present invention 1064] The method of claim 1059, wherein said treatment is part of a treatment for ameliorating obstructive sleep apnea. [The present invention 1065] The method of claim 1059, further comprising the step of inducing an angiogenic or collagen remodeling response in said subject. [The present invention 1066] The method of claim 1059, wherein the cooling device comprises the system of claim 1001. The above and other aspects and advantages of the present invention will become apparent from the following description. In this description, reference is made to the accompanying drawings, which form a part hereof, in which there is shown by way of example preferred embodiments of the invention. Such embodiments do not necessarily represent the full scope of the invention, and reference is therefore made to the claims and this specification for interpreting the scope of the invention.

[0012] The present invention will be better understood, and further features, aspects and advantages will become apparent, when considered in light of the following detailed description, which refers to the following drawings, in which: [Brief description of the drawings]

[0013] [Figure 1] 1 illustrates a cooling therapy system according to one aspect of the present disclosure. [Diagram 2] FIG. 2 is a schematic diagram of the cold treatment system of FIG. 1. [Diagram 3] 2 illustrates the cooling therapy system of FIG. 1 including a warming unit, thermal imaging, and depth imaging according to another embodiment of the present disclosure. [Figure 4] FIG. 4 is a schematic diagram of the cold treatment system of FIG. [Diagram 5] 2 illustrates an interface and delivery device of the cooling therapy system of FIG. 1, where the delivery device includes a shorter prong, according to one embodiment of the present disclosure. [Figure 6] 2 illustrates an interface and delivery device of the cooling therapy system of FIG. 1, where the delivery device includes a longer protrusion, according to one embodiment of the present disclosure. [Figure 7] 2 illustrates an interface and delivery device of the cooling therapy system of FIG. 1, the delivery device defining a wider area and including shorter protrusions, according to one embodiment of the disclosure. [Figure 8]2 illustrates an interface and delivery device of the cooling therapy system of FIG. 1, where the delivery device defines a wider area and includes longer protrusions, according to one embodiment of the disclosure. [Figure 9] 2 illustrates an interface and delivery device of the cooling therapy system of FIG. 1 according to one embodiment of the disclosure, where the delivery device defines an arcuate shape. [Figure 10A] 2 illustrates a delivery device of the cooling therapy system of FIG. 1 according to one embodiment of the disclosure, where the delivery device defines a rod shape with protrusions extending from approximately half of the circumference of the rod. [Figure 10B] FIG. 10B is a top view of the delivery device of FIG. [Figure 11A] 2 illustrates a delivery device of the cooling therapy system of FIG. 1 according to one embodiment of the disclosure, where the delivery device defines a rod shape with protrusions extending circumferentially around the rod. [Figure 11B] FIG. 11B is a top view of the delivery device of FIG. [Figure 12] 2 illustrates a protrusion of the cooling treatment system of FIG. 1 configured to be cooled by conduction, according to one embodiment of the present disclosure. [Figure 13] 2 illustrates a protrusion of the cooling therapy system of FIG. 1 having an insulating jacket according to one embodiment of the present disclosure. [Figure 14] 2 illustrates a protrusion of the cooling therapy system of FIG. 1 configured for active cooling via circulating cryogen, according to one embodiment of the present disclosure. [Figure 15] 2 illustrates a protrusion of the cooling therapy system of FIG. 1, where the proximal end of the protrusion is actively insulated / heated, according to one embodiment of the present disclosure. [Figure 16A] 2 illustrates multiple protrusions of the cold therapy system of FIG. 1 in the form of multiple needles configured to inject a slurry, according to one embodiment of the present disclosure. [Figure 16B] 2 illustrates multiple protrusions of the cold therapy system of FIG. 1 in the form of multiple needles coupled to a manifold and configured to inject a slurry, according to one embodiment of the present disclosure. [Figure 17]2 illustrates a protrusion of the cooling therapy system of FIG. 1 in the form of a needle configured to inject a slurry in a bulk cooling pattern, according to one embodiment of the present disclosure. [Figure 18] 2 illustrates a prong of the cooling therapy system of FIG. 1 in the form of a needle with a cooling device in a contracted state, according to one embodiment of the present disclosure. [Figure 19] 19 illustrates the protrusion of FIG. 18 with the cooling device in an expanded state, according to one embodiment of the present disclosure. [Figure 20] 2 illustrates a protrusion of the cooling therapy system of FIG. 1 in the form of a needle having multiple tips configured to impart a fractional cooling pattern, according to one embodiment of the present invention. [Figure 21] 2 illustrates protrusions of the cooling therapy system of FIG. 1 in the form of radially extending, multi-pointed needles configured to impart a segmented cooling pattern, according to one embodiment of the present invention. [Figure 22] 2 illustrates one non-limiting fractionated cooling pattern achievable by the cooling treatment system of FIG. 1. [Diagram 23] 2 illustrates one non-limiting example of an array bulk cooling pattern achievable by the cooling treatment system of FIG. 1. [Figure 24] 2 illustrates one non-limiting example of a bulk cooling pattern achievable using protrusions with the cooling treatment system of FIG. 1. [Diagram 25] 2A-2C show a non-limiting example of a bulk cooling pattern achievable with the cooling therapy system of FIG. 1 following fan injection through a needle. [Figure 26] 1 is a flow chart outlining steps for operating a cooling therapy system to perform cryotherapy and / or cryoablation, according to one aspect of the present disclosure. [Figure 27] 1 is a graph showing thermal boundaries as a function of time after slurry injection for cold slurries injected subcutaneously into rats. [Figure 28] 1 is a graph showing skin temperature as a function of time after slurry injection for a slurry having 10% ice content and a slurry having 50% ice content. [Figure 29] 1 is a graph showing the polynomial regression model used to fit temperature as a function of time after injection for the first 60 seconds after injection of the slurry. [Diagram 30] 1 is a graph showing the quadratic regression model used to fit temperature as a function of time after injection for slurry injection cooling and subsequent rewarming. [Diagram 31] 1 is a graph showing skin surface temperature as a function of post-cooling time following injection of a cooling needle array. [Diagram 32] FIG. 13: Contour plot of temperature distribution on ex vivo mouse skin using a fractional needle array cooled to −10° C. [Diagram 33] 1 is a graph showing ex vivo mouse skin temperature as a function of time at a location adjacent to a needle in a segmented needle array and the surrounding tissue. [Diagram 34] 1 shows the experimental setup for single bulk slurry injection into human post-abdominoplasty tissue. [Diagram 35] An experimental setup for fractional slurry injection into human post-abdominoplasty tissue is presented. [Diagram 36] 1 is a graph showing human post-abdominoplasty tissue temperature as a function of time measured at two locations lateral to the injection site for a single bulk slurry injection. [Figure 37] 1 is a graph showing human post-abdominoplasty tissue temperature as a function of time measured at two locations lateral to the injection site for split slurry injections. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description Recent evidence suggests that the wound healing process caused by injury to biological tissues (e.g., human skin) is distinctly different between burns and cryoinjuries. For example, skin lesions tend to heal well with minimal to no scarring after controlled cryoinjury. Although burns and freezing cause similar tissue destruction, the resistance of collagen, fibroblasts, and the connective tissue matrix to freezing is the basis for favorable healing. Although tissue is devitalized by freezing, the matrix is ​​usually little altered, and preservation of this structure is important for repair.

[0015] Wound healing is an active process that begins with an inflammatory response at the borders of the lesion. A very active inflammatory response is always observed after cryoinjury. It is thought that this helps to initiate the proper healing process and prevent infection associated with the injury. Inflammatory cell infiltration also contributes to the occurrence of apoptosis and tissue destruction. As granulation tissue forms, fibroblasts differentiate into myofibroblasts and damaged collagen is replaced by new collagen. Cell infiltration helps to establish new vasculature, which plays an important role in the relationship of devitalized tissues.

[0016] The systems and methods described herein utilize cooling to induce the desired effects of increased vasculature and / or new collagen development in biological tissue. In particular, the systems and methods provide a cooling treatment system configured to provide bulk or fractionated cooling in a precisely controlled manner at either very low ablation temperatures or intermediate remodeling temperatures to promote tissue remodeling by inducing increased vasculature and new collagen formation. Such a cooling treatment system can provide a device-based approach for the treatment of a wide variety of unmet clinical needs resulting from reduced vasculature and / or reduced collagen. Furthermore, the cooling treatment system can provide a safe, non-pharmacological treatment approach, and the tissue remodeling provided by the system can have long-lasting effects. Furthermore, the use of cooling can provide a cost-effective solution that can be provided to a wide range of medical facilities and by physicians for whom current energy-based (e.g., laser) treatments may be expensive and inaccessible.

[0017] 1 and 2 show a cooling treatment system 100 according to one non-limiting example of the present disclosure. The cooling treatment system 100 includes a cooling device 102, an interface 104, and a delivery device 106. The cooling device 102 is configured to cool the delivery device 106 via the interface 104. In some non-limiting examples, the cooling device 102 can be in the form of a thermoelectric cooler, cryogenic gas, liquid nitrogen, liquid argon, cooling liquid, Joule-Thomson refrigerator, nitrous oxide, and carbon dioxide, to name a few.

[0018] The interface 104 may be fabricated from a material with high thermal conductivity to facilitate efficient heat transfer between the cooling device 102 and the delivery device 106. The interface 104 may be coupled to the cooling device 102 (e.g., via an adhesive or mechanical linkage) and may be removably coupled to the delivery device 106. The interface 104 may include one or more temperature sensors 108 and a controller 110. The temperature sensor 108 is configured to measure a temperature at one or more locations on the delivery device 106 and communicate the measured temperature to the controller 110. The controller 110 is in communication with the cooling device 102 and can be configured to control the temperature output by the cooling device 102, thereby controlling the temperature of the delivery device 106. In one non-limiting example, a desired temperature of the delivery device 106 may be input to the controller 110, and the controller 110 may be configured to control the cooling device 102 to achieve the desired temperature of the delivery device 106 as measured by the temperature sensor 108. In some non-limiting examples, the controller 110 is in communication with the display 112 and is configured to instruct the display 112 to display, for example, the temperature of the delivery device 106, the time to apply the delivery device 106, the depth of the delivery device 106, and / or the temperature of the surface of the desired tissue region.

[0019] The delivery device 106 includes a base 114 and a plurality of protrusions 116 extending from the base 114. In some non-limiting examples, the plurality of protrusions 116 may be in the form of a needle array configured to penetrate to a desired depth within the tissue region of the patient. As described below, in these non-limiting examples, the needle array may be configured to allow injection of a slurry (i.e., a mixture of liquid and ice crystals). In other non-limiting examples, the plurality of protrusions 116 may be in the form of a plurality of conductive posts or pins configured to engage a surface of the tissue region of the patient to provide localized cooling. Of course, while the illustrated delivery device 106 includes a plurality of protrusions 116, in other non-limiting examples, the delivery device 106 may include one or more protrusions 116.

[0020] The distance D defined between adjacent pairs of the plurality of protrusions 116 may be dimensioned to ensure that a divided cooling pattern can be achieved in or on the desired tissue region. That is, the distance D may be dimensioned such that separate cooling zones are achieved upon application of the delivery device 106. The spacing of the plurality of protrusions 116, along with the time that the delivery device 106 is engaged with the desired tissue region, may also define the resulting cooling pattern, as described below.

[0021] 3 and 4 show another non-limiting example of a cooling treatment system 100 according to the present disclosure. As shown in FIG. 3 and FIG. 4, the cooling treatment system 100 can include a heating unit 300, a depth imager 302, and a thermal imager 304, each in communication with the controller 110. The heating unit 300 may be configured to selectively provide controlled heating to the proximal ends of the plurality of protrusions 116, for example. Selectively heating the proximal ends of the plurality of protrusions 116 may allow only the distal ends or tips of the plurality of protrusions 116 to provide cooling to a desired tissue region. Alternatively or additionally, the heating unit 300 may be configured to provide selective heating to the tissue surface (e.g., epidermis) and / or to provide selective heating to deeper tissue (e.g., subcutaneous fat) below the tissue surface by radio frequency (RF) heating or laser heating.

[0022] The depth imager 302 may be configured to measure and image the depth to which the plurality of protrusions 116 penetrate into the desired tissue region. The depth imager 302 may be configured to provide the measured depth of the plurality of protrusions 116 to the controller 110. Alternatively or additionally, the controller 110 may relay an image of the plurality of protrusions 116 penetrating into the desired tissue region to the display 112 to provide active feedback to a user of the cooling therapy system 100. In some non-limiting examples, the depth imager 302 may be in the form of an OCT imaging device, a magnetic resonance imaging (MRI) device, an ultrasound device, or an X-ray device.

[0023] The thermal imaging device 304 may be configured to measure and image the temperature at the surface of the desired tissue region. That is, as the plurality of protrusions 116 are applying cooling on or in the desired tissue region, the thermal imaging device 304 may allow a user to visually inspect the temperature at the surface of the desired tissue region. This may allow a user to ensure that a desired cooling patterning (i.e., fractional cooling vs. bulk cooling) is achieved and / or verify that a desired temperature (i.e., ablation temperature vs. cryostimulation / cryotherapy temperature) is being applied to the desired tissue region. In some non-limiting examples, the thermal imaging device 304 may be integrated into the cooling treatment system 100 and in communication with the controller 110. The controller may relay thermal images acquired by the thermal imaging device 304 to the display 112 to provide active feedback to a user of the cooling treatment system 100. In some non-limiting examples, the thermal imaging device 304 may be a separate component used or worn by a user of the cooling treatment system 100 while providing cooling on or in the desired tissue region. In some non-limiting examples, the thermal imaging device 304 may be in the form of an infrared camera, thermal imaging glasses, or a mobile device with a thermal imaging add-on. In other non-limiting examples, the thermal imaging device 304 may include one or more thermocouples (or other thermal sensors), or infrared temperature sensing devices.

[0024] Of course, the delivery device 106 and the plurality of protrusions 116 disposed thereon may define alternative shapes and sizes for a given tissue application. For example, as shown in FIGS. 5-8, the delivery device 106 and corresponding interface 104 may define different treatment areas and / or different treatment depths. In some non-limiting examples, the base 114 of the delivery device 106 and the corresponding interface 104 may define a width W 1 In another non-limiting example, the base 114 of the delivery device 106 and the corresponding interface 104 may define a width W 2 where W 2 W 1In some non-limiting examples, each of the plurality of protrusions 116 has a length L 1 In another non-limiting example, each of the plurality of protrusions 116 may define a length L 2 where L 2 L 1 It will also be appreciated that the density (i.e., the number of protrusions 116 extending from the delivery device 106) can be varied, for example, by changing the distance D between pairs of adjacent protrusions 116 and adding or subtracting protrusions to the delivery device 106 accordingly. These alternative geometric configurations can be tailored to provide the desired treatment parameters for a given application of the cooling treatment system 100.

[0025] The illustrated base 114 of the delivery device 106 of Figures 1, 3, and 5-8 defines a generally flat profile, thereby resulting in a plurality of protrusions that define a generally flat treatment profile. In other non-limiting examples, as shown in Figures 9-11, the delivery device 106 can define alternative shapes and profiles to accommodate various anatomical locations of a patient. As shown in Figure 9, in some non-limiting examples, the base 114 of the delivery device 106 can define a generally arcuate shape, thereby disposing the plurality of protrusions 116 in a corresponding arcuate treatment profile.

[0026] 10A-11B, in some non-limiting examples, the delivery device 106 may be in the shape of a wand, or rod, having a plurality of protrusions 116 extending from its distal end. As shown in FIGS. 10A and 10B, in one non-limiting example, the plurality of protrusions 116 may extend radially outward from the distal end of the delivery device 106. The plurality of protrusions 116 may be partially circumferentially disposed around the delivery device 106. That is, the plurality of protrusions 116 may be circumferentially disposed about halfway (e.g., between 0 degrees and 180 degrees) of the delivery device 106. As shown in FIGS. 11A and 11B, in one non-limiting example, the plurality of protrusions 116 may extend radially from the distal end of the delivery device 106 and may be circumferentially disposed in approximately equal increments around the entire circumference of the delivery device 106. Alternatively or additionally, the plurality of protrusions 116 may be circumferentially disposed in unequal increments around the circumference of the delivery device 106. 10A-11B, the plurality of protrusions 116 may be retractably housed within the delivery device 106. For example, the delivery device 106 may be inserted into the target tissue with the plurality of protrusions 106 stored within the delivery device 106, and then the plurality of protrusions 106 may be deployed from the delivery device 106 within the target tissue.

[0027] FIG. 12 shows a non-limiting example of one of the plurality of protrusions 116 according to an embodiment of the present disclosure. The illustrated protrusion 116 is in the form of a needle 1200 including a needle tip 1202 disposed at its distal end. The needle 1200 can be fabricated from a metallic material, and the entire axial length of the needle 1200 can be cooled via conduction from the cooling device 102. The needle 1200 can be sized between about 15 gauge and about 35 gauge or smaller. In some non-limiting examples, as shown in FIG. 13, the needle 1200 can include insulation 1300 wrapped around a desired axial length of the needle 1200. That is, the insulation 1300 can extend axially along the needle 1200 while leaving the needle tip 1202 of the needle 1200 uninsulated. This, along with the axial length defined by the needle 1200, can control the depth within the desired tissue region to which cooling is applied. Additionally, providing cooling only to the needle tip 1202 can prevent healthy tissue from being damaged by cooling applied at the needle tip 1202. In another non-limiting example, the insulation 1300 may be replaced by an active heating unit wrapped around the needle 1200. Similar to the insulation 1300, the active heating unit may not be disposed around the needle tip 1202 and may allow for application of cooling to a desired tissue region at a target depth defined by the axial length of the needle 1200.

[0028] In some non-limiting examples, the entire axial length of the needle 1200 may be actively cooled by circulating cryogen, as shown in Figure 14. The illustrated needle 1200 may include an inlet passage 1400 and an outlet passage 1402 disposed within and extending axially along the needle 1200. Cryogen may be circulated into the inlet passage 1400 and out of the outlet passage 1402 to actively cool the entire axial length of the needle 1200.

[0029] In some non-limiting examples, a warming unit 1500 can be positioned adjacent to the proximal end of the needle 1200, as shown in Figure 15. The warming unit 1500 can be configured to warm the surface (e.g., epidermis) of the desired tissue area. This can prevent healthy tissue from being damaged by the cooling applied by the needle 1200.

[0030] As described above, in some non-limiting examples, the plurality of protrusions 116 may be configured to inject a desired amount of slurry into a desired tissue region to apply cryotherapy or cryoablation. FIG. 16A shows one non-limiting example of the plurality of protrusions 116 in the form of a needle array 1600 configured to inject a slurry 1602 into a desired tissue region. The needles of the needle array 1600 may be sized to be between about 15 gauge and about 30 gauge. The slurry 1602 may be disposed within a cartridge 1604, which may be removably coupled to the delivery device 106. As described below, the slurry 1602 may be prepared to include ice crystals of appropriate size to achieve a desired cooling temperature and ensure fluid flow through the needle array 1600. Additionally, the amount of slurry injected and / or the distance D between adjacent pairs of needles 1600 may be designed to ensure a desired cooling pattern is achieved (i.e., fractional cooling versus bulk cooling).

[0031] In another non-limiting example, as shown in FIG. 16B, the needle array 1600 may be removably coupled to the manifold 1610. Each needle of the needle array 1600 may be removably coupled to the manifold 1610, for example, by a threaded engagement, a quick disconnect fitting, or a push-on fitting. The removably coupled needle array 1600 to the manifold 1610 allows a user to vary the number and / or arrangement of needles in the needle array 1600 as desired. Alternatively or additionally, the same manifold 1610 may be used to perform injections with needles of different sizes (e.g., a 15 gauge needle array vs. a 30 gauge needle array). Alternatively or additionally, the spacing between adjacent needles in the needle array 1600 may be controlled by the number and / or orientation of needles coupled to the manifold 1610.

[0032] In the illustrated non-limiting example, the manifold 1610 is coupled to a needle array 1600 that includes four needles. In other non-limiting examples, the manifold 1610 may be coupled to a needle array 1600 that includes more or less than four needles arranged in any pattern as desired.

[0033] The manifold 1610 includes an inlet port 1612 configured to be removably coupled to a slurry injection device (not shown). The manifold 1610 may include internal passages that provide fluid communication between the inlet port 1612 and each needle in the needle array 1600. The slurry injection device may be in the form of a syringe-type device that contains a desired amount of slurry to be injected into a desired tissue region, for example. In some non-limiting examples, the syringe-type device may be manually actuable to facilitate injection of the slurry. In some non-limiting examples, the syringe-type device may be electronically controlled (e.g., like a syringe pump) to facilitate injection of the slurry at a predetermined fluid flow rate.

[0034] In operation, for example, a user can place a needle array of a desired size and configuration on the manifold 1610 and then connect a slurry injection device filled with a desired volume of slurry to the inlet port 1612. With the delivery device 102 assembled, the user can inject the needle array 1600 into the desired tissue region to a desired depth within the desired tissue region and inject the slurry to achieve a segmented cooling pattern within the desired tissue region.

[0035] In some non-limiting applications, the split slurry injection capability of the delivery device 102 of FIG. 16A and FIG. 16B may be able to cover a larger area of ​​the target tissue when compared to a single injection of a comparable slurry volume. For example, the split slurry injection device may be able to cover approximately twice the area of ​​the target tissue with a single slurry injection when compared to bulk cooling with a single injection. The split slurry injection capability of the delivery device 102 may provide several other operational and functional advantages when compared to a single bulk injection of a comparable slurry volume. For example, a reduction in the injection force required to deliver the slurry to the target tissue, a reduction in the time required to deliver the slurry to the target tissue (e.g., approximately half the time when compared to a single injection), a more uniform spread of the slurry to the target tissue, and a reduced possibility of affecting blood vessels and pain. In some non-limiting applications, a more uniform spread of the slurry in the target tissue may lead to a more uniform reduction of fat in the target tissue, thereby avoiding the undesirable side effect of forming divots or indentations in the target tissue. In some cases, a single injection of a large volume of slurry can cause bulging / swelling and tension within the target tissue, which can lead to blood vessel rupture and bruising. A single injection of a large volume can also stretch the subcutaneous nerves and cause pain. These undesirable characteristics of a single injection can be avoided by the use of split slurry injections, which can deliver a more uniform distribution of the slurry to the target tissue in smaller aliquots, for example, via the delivery device 102.

[0036] In one non-limiting example, as opposed to a needle array 1600, the cooling treatment system 100 can be implemented with a single needle 1700 as shown in Figure 17. The needle 1700 can be sized between about 15 gauge and about 35 gauge, or smaller. In this non-limiting example, the cooling treatment system 100 can be configured to provide bulk cooling to a desired tissue region.

[0037] In some non-limiting examples, as shown in FIGS. 18 and 19, the delivery device 106 may include an expandable needle 1800 as opposed to or in addition to the multiple protrusions 116. The expandable needle 1800 may be cooled by the cooling device 102 and then advanced by a user of the cooling treatment system 100 to the desired tissue area (e.g., lipid-rich tissue in the tongue / airway of a patient). Once the expandable needle 1800 reaches the desired tissue area, the user may expand a balloon 1802 attached to the expandable needle 1800. A slurry at a desired temperature may then be delivered through the expandable needle 1800 to the balloon 1802 to cool the desired tissue area. Of course, the balloon 1802 may not need to be inflated prior to injection of the slurry. Rather, injection of the slurry may inflate the balloon 1802. Once the desired cooling treatment has been administered to the desired tissue area, the balloon 1802 may be stored in a deflated state (FIG. 18).

[0038] 20 and 21 show two non-limiting examples of a segmented delivery array 2000 and 2100 that may be implemented in the delivery device 106 in contrast to or in conjunction with the multiple protrusions 116. The segmented delivery array 2000 may be advanced by a user of the cooling treatment system 100 to a desired tissue region (e.g., lipid-rich tissue in the tongue / airway of a patient). Once the segmented delivery array 2000 is advanced to the desired tissue region, slurry may be delivered to the desired tissue region in a fractional pattern via the multiple needles 2002. The multiple needles 2002 may extend outwardly from a distal end of the array tube 2004. As shown in FIGS. 20 and 21, the multiple needles 2002 may be arranged in alternate patterns to define alternate fractional cooling patterns as desired.

[0039] As discussed above, the cooling treatment system 100 may be designed to provide a desired cooling pattern. That is, in one non-limiting example, the cooling treatment system 100 may be designed to provide a segmented cooling pattern to a desired tissue region. FIG. 22 illustrates one non-limiting example of a segmented cooling pattern 2200 that may be achieved via injection of a slurry, localized cooling, or injection of an actively cooled needle, as described above with reference to the delivery device 106. As shown in FIG. 22, in the segmented cooling pattern 2200, separate cooling zones 2202 are present with regions of untreated tissue disposed between adjacent cooling zones. Of course, the number of separate cooling zones 2202 illustrated in FIG. 22 is for illustrative purposes and is in no way limiting. In some non-limiting examples, the cooling treatment system 100 may be configured to provide ablative cooling therapy (i.e., cryoablation) in a segmented pattern at temperatures between about -180°C and about -20°C. In some non-limiting examples, the cooling treatment system 100 may be configured to provide non-ablative cooling therapy (ie, cryotherapy) at temperatures between approximately -20°C and 5°C in a fractionated pattern.

[0040] FIG. 23 illustrates an array bulk cooling pattern 2300 achievable by the cooling treatment system 100 according to one non-limiting example of the present disclosure. The illustrated array bulk cooling pattern 2300 can be formed by applying a cooling array (e.g., multiple protrusions 116, needle array 1600, multiple needles 2002, etc.), which can be achieved via injection of a slurry, localized cooling, or injection of actively cooled needles, as described above with reference to the delivery device 106. As shown in FIG. 23, the array bulk cooling pattern 2300 defines a substantially uniform cooling profile across the desired tissue region. In some non-limiting examples, the cooling treatment system 100 may be configured to provide non-ablative cooling therapy (i.e., cryotherapy) with the array bulk cooling pattern at temperatures between about -20°C and 5°C.

[0041] FIG. 24 illustrates a depot bulk cooling pattern 2400 achievable by the cooling treatment system 100 according to one non-limiting example of the present disclosure. The illustrated depot bulk cooling pattern 2400 can be formed via injection of slurry from a single injection (e.g., a single needle 1700). The depot bulk cooling pattern 2400 defines concentric cooling zones that decrease in temperature as they extend radially outward from the center of the depot bulk cooling pattern 2400. Of course, alternative bulk cooling patterns are achievable by the cooling treatment system 100. For example, as shown in FIG. 25, a single needle 1700 may be configured to provide a fan-shaped bulk cooling pattern 2500 when injecting slurry into a desired tissue region.

[0042] The operation and application of the cooling treatment system 100 will be described with reference to FIGS. 1-26. In application, the cooling treatment system is configured to provide bulk or fractional cooling at either very low ablation temperatures or intermediate remodeling temperatures to promote tissue remodeling by inducing increased vasculature (i.e., angiogenesis) and new collagen formation (i.e., collagen remodeling). As described below, there are various medical instances in which lack of blood flow and / or collagen formation may cause certain diseases. Thus, the cooling treatment system 100 can be implemented to induce collagen formation and angiogenesis, thereby promoting the healing or treatment of certain diseases. In some non-limiting examples, the cooling treatment system 100 may be configured to expose a desired tissue region of a subject to a temperature between about -200°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose a desired tissue region of a subject to a temperature between about -180°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -160°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -140°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -120°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -100°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -80°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -70°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose a desired tissue region of a subject to a temperature between about -60°C and about 30°C.In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -50°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -40°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -30°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -20°C and about 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -20°C and about 20°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose the desired tissue region of the subject to a temperature between about -20°C and about 10°C. In some non-limiting examples, the cooling treatment system 100 may be configured to expose a desired tissue region of a subject to a temperature between about -20°C and about 5°C.

[0043] In one non-limiting example, bulk cooling may be applied by the cold therapy system 100 for the purpose of inducing angiogenesis and collagen remodeling. This may be accomplished by localized cooling (e.g., with multiple protrusions 116), slurry injection (e.g., with multiple protrusions 116, needle arrays 1600, or single needles 1700), or cryoneedles (e.g., with multiple protrusions 116). Alternatively, fractionated cooling may be applied by the cold therapy system 100 for the purpose of inducing angiogenesis and / or collagen remodeling. The induced collagen remodeling and angiogenesis provided by application of the cold therapy system 100 may be applied to any ischemic organ or tissue and / or tissue undergoing relaxation. Application of the cooling therapy system 100 to these tissues / organs can be used to treat a variety of ischemic diseases, such as diabetic peripheral neuropathy, male pattern baldness, wound healing, skin aging, vaginal rejuvenation, onychomycosis, scar remodeling, revascularization of ischemic tissues / organs (i.e., nerves, muscles, skin, liver, kidneys, heart, etc.), treatment of lipomas and cellulite, etc. Alternatively, it will be appreciated that in some applications, the therapy provided by the cooling therapy system 100 may be combined with traditional pharmacological agents to increase blood supply or improve collagen remodeling.

[0044] In some applications, the cold treatment system 100 may be used to selectively target lipid-rich tissue within a patient's tongue or airway to induce cryolipolysis (destruction of fat by selective cold injury). This use of the cold treatment system 100 may be used to treat obstructive sleep apnea (OSA), as excess fat in the patient's tongue / airway may be reduced by selective application of cooling (e.g., by application of the expandable needle 1800, or any one of the segmented delivery arrays 2000 and 2100). Alternatively or additionally, selective application of cooling to the tongue / airway may trigger collagen remodeling within the airway, which may improve airway relaxation associated with OSA.

[0045] FIG. 26 illustrates a non-limiting example of steps for operating the cooling therapy system 100. As shown in FIG. 26, initially, at step 2600, a delivery device can be positioned adjacent to a desired tissue region where it is desired to apply cooling therapy. The delivery device can be any of the delivery devices described above, such as multiple prongs 116 (in the form of needles 1200, needle array 1600, or single needle 1700), expandable needle 1800, or segmented delivery array 2000 or 2100. Once the delivery device is positioned at step 2600, at step 2602, the delivery device can be engaged with the desired tissue region. The engagement at step 2602 can be a local engagement using any of the various delivery devices described above, or a needle injection. If a needle is injected at step 2602, the depth of injection can be controlled, as described above, for example, by monitoring the needle using a depth imager 302, by insulating the injected needle except for the tip of the needle, or by actively warming the tissue.

[0046] Once the delivery device engages the desired tissue region in step 2602, the cooling therapy system 100 can apply cooling to the desired tissue region in step 2604. The cooling applied in step 2604 can be either a cryoablative temperature or a non-ablative cryostimulation temperature, as described above. Additionally, the cooling applied in step 2604 can be applied locally via conductive cooling, via injection of one or more conductively cooled needles, or via injection of a cryo-slurry from one or more needles, utilizing any of the delivery devices described above. Additionally, the cooling applied in step 2604 can be a bulk cooling pattern or a fractionated cooling pattern, as desired.

[0047] While cooling is being applied in step 2604, a user (typically a trained medical professional) may monitor the cooling therapy being applied in step 2606. The user may monitor the cooling therapy using, for example, the thermal imaging device 304 described above. The user may monitor the cooling therapy to ensure that a desired cooling pattern is being achieved. Alternatively or additionally, the user may monitor the cooling therapy to ensure that a desired temperature is being applied to a desired tissue area and / or to ensure that surrounding healthy tissue is not being exposed to potentially damaging temperatures.

[0048] The user may monitor the cooling therapy 2606 until they determine that the desired therapeutic effect has been induced. Thereafter, in step 2608, the user may remove the delivery device. Of course, the cooling therapy may be applied in multiple cycles with particular inter-cycle time intervals. In these instances, steps 2602-2608 may be repeated one or more times until the desired therapeutic effect is induced.

[0049] Working Example The following examples will describe in detail how cooling therapy system 100 may be used or implemented and will enable those skilled in the art to more readily understand its principles. The following examples are presented for purposes of illustration and are not meant to be limiting in any way.

[0050] The following data pertains to rat experiments performed in vivo. All temperature measurements were taken using a FLIR ONE non-contact thermal imaging device.

[0051] Subcutaneous injection of cold slurry A slurry composition of saline mixed with 10% (by volume) glycerol was prepared and injected subcutaneously into rats. The temperature range of the prepared slurries was -3.5°C to -2.5°C, and the injection volume was 10 milliliters (mL). The thermal boundary created by the slurry injection was measured as a function of time after injection. Figure 27 shows the magnitude of the thermal boundary as a function of time after injection. As shown in Figure 27, the magnitude of the thermal boundary changes approximately linearly with time after injection. From the data in Figure 27, the cooling area can be estimated. This correlation, along with the fact that temperatures above about 14°C (the lipid crystallization point) signify the end of the therapeutic effect of cooling, can be used to estimate the cooling area and the minimum inter-injection distance to maintain a split cooling pattern.

[0052] Table 1 below illustrates approximate data based on experimental results for a 10 mL injection of -2.8°C slurry with 50% ice content (by volume).

[0053] [Table 1]

[0054] Estimated skin temperature after slurry injection The data in Table 1 was used to estimate the skin temperature after slurry injection when 10 mL of slurry was injected at -2.8°C with 50% ice content (by volume). As noted above, the crystallization temperature of lipids is approximately 14°C, and therefore the therapeutic window for selectively targeting tissue using cooling is below this temperature. Based on the data in Table 2, the estimated slurry injection could provide a therapeutic effect for approximately 315 seconds.

[0055] [Table 2]

[0056] Ice content is a key determinant of cooling capacity Slurries of the same temperature and composition but different ice content have dramatically different cooling capacities. The graph in Figure 28 shows the surface skin temperature after injection of a 10% glycerol-containing saline slurry at -2.5°C and about 10% ice content compared to -2.8°C and 50% ice content. As shown in Figure 28, the skin temperature reached a significantly lower temperature after injection when the slurry with 50% ice content was injected compared to the slurry with 10% ice content (i.e., about -3°C vs. about 12°C).

[0057] Experimental data used for modeling A best fit polynomial regression was performed to model the cooling characteristics for the first 60 seconds of slurry injection, as shown in Figure 29. A best fit quadratic regression model was performed to model the cooling characteristics of the slurry injection and subsequent rewarming, as shown in Figure 30.

[0058] (Divided cooling experiment) Rapid rewarming was observed after conduction cooling with needles injected in a segmented pattern at a depth of 5 mm with a needle spacing of 2 mm (diameter approximately 0.5 mm). The needles were at a temperature of approximately -20°C upon insertion into the skin. After approximately 1 minute of cooling, the cooling area below 14°C was approximately 0.301 cm. 2 Figure 31 shows the surface skin temperature as a function of time post-injection for the split-needle test.

[0059] Based on experiments performed with slurry injection, it can be determined that 5 minutes of cooling below 14°C may be sufficient to achieve selective destruction of lipid-rich tissue. Therefore, the delivery of conductive cooling should be within this range. Multiple short cooling cycles can be performed to maintain the division pattern.

[0060] Table 3 below shows the bulk cooling parameters for vascular stimulation and neocollagen formation. It is worth noting that the slurry temperature cannot exceed 4°C, so the ability to cool the target tissue at higher temperatures is mainly controlled by adjusting the injection volume, ice particle size, ice content, etc.

[0061] [Table 3]

[0062] (Fractional cooling parameters for vascular stimulation and neocollagen formation using cold slurries) Table 4 shows experimental data to determine the maximum thermal radius for a 10 mL cold slurry injection with a target treatment time of 5 minutes using 50% ice content. Of note, slurries may spread differently in different tissue types and may have different cooling capabilities based on ice content, this is just one non-limiting example. The tissue type tested was a subcutaneous injection in a rat model. Also, injections may be placed closer together than the outlined parameters to achieve more uniform bulk cooling in the treatment area with a single injection volume.

[0063] [Table 4]

[0064] (Cooling time and temperature for vascular stimulation and neocollagen formation using penetrating needle arrays or localized fractionated cooling needle arrays) As shown in Table 5, cycle times are longer for topical applications because it takes longer for the cooling to diffuse to the target sites in the deep dermis and superficial fat. Longer cycles are made possible by active rewarming to help maintain the split pattern and prevent bulk tissue effects. Given the data above showing rapid rewarming, there should be a minimum of 5 seconds between cycles.

[0065] [Table 5]

[0066] (Experiment on dividing the skin of mice) Ex vivo mouse skin was tested to monitor the cooling temperature and efficiency of a cooling therapy system configured to achieve a segmented cooling pattern according to the present disclosure. A cooling therapy system was assembled including a delivery device having a plurality of copper needles extending from a plate. For testing, the delivery device included 13 needles arranged in a 3-2-3-2-3 array pattern. The needles were spaced 4 mm to 7 mm apart from each other, and the needle diameters were between 1 mm and 1.3 mm. A Peltier cooler was thermally coupled to the plurality of copper needles to control the amount of cooling provided by the assembled cooling therapy system. For testing, the Peltier cooler was configured to maintain the cooling therapy system at approximately -10°C.

[0067] The mouse's skin was placed over the copper needle array, and the temperature was monitored from above using a forward-looking infrared (FLIR) camera. As shown in FIG. 32, the cooling therapy system achieved a segmented cooling pattern on the mouse skin with separate cooling zones surrounded by areas of hotter tissue (darker shading in FIG. 32 indicates areas of lower temperature). Using the mouse's skin temperature monitored by the FLIR camera, the temperature of the copper needle site and surrounding tissue was calculated as a function of time. As shown in FIG. 33, the temperature of the tissue surrounding the needle mimicked the temperature profile of the needle as a function of time, with its temperature continually approaching that of the needle. This temperature response of the surrounding tissue demonstrates the feasibility and efficiency of using segmented cooling to cool the skin and underlying tissue.

[0068] (Divided slurry injection experiment on human post-abdominal surgery specimens) Human abdominoplasty tissue was tested to compare the cooling treatment of single and split slurry injections. For the single slurry injection test, 60 mL of slurry was injected into the subcutaneous fat of human abdominoplasty tissue. The slurry temperature was approximately -4.8°C and was composed of saline and 10% glycerol. As shown in FIG. 34, a first thermocouple (T1) was placed 1 centimeter (cm) laterally from the injection site and 2 cm below the surface of the skin, and a second thermocouple (T2) was placed 2 cm laterally from the injection site (in the same direction as T1) and 2 cm below the surface of the skin. For the split slurry injection test, 60 mL of slurry was injected into the subcutaneous fat of human abdominoplasty tissue using a device similar to the delivery device 102 of FIG. 16B. The slurry temperature was approximately -4.8°C and was composed of saline and 10% glycerol. As shown in FIG. 35, a first thermocouple (T1) and a second thermocouple (T2) were adjacently placed 1 cm apart from each other and 2 cm below the surface of the skin.

[0069] In both tests, the entire amount of slurry was constantly injected into the subcutaneous fat and the temperatures of T1 and T2 were monitored and recorded. As shown in FIG. 36, with a single slurry injection, the temperature measured by T2 was consistently higher than that measured by T1. This is due to the poor cooling uniformity provided by a single bulk injection. With reference to FIG. 37, with a split slurry injection, both T1 and T2 measured approximately the same temperature during the injection process. This suggests that split slurry injection increases the cooling uniformity and covers a larger tissue area. Furthermore, the time required to complete a single bulk injection was approximately twice as long as the time required to split-inject the same volume of slurry.

[0070] Thus, although the present invention has been described above with reference to specific embodiments and examples, the present invention is not necessarily so limited, and numerous other embodiments, examples, uses, modifications, and departures from the embodiments, examples, and uses are intended to be encompassed by the appended claims. The entire disclosures of each patent and publication cited herein are incorporated by reference as if each such patent or publication was individually incorporated by reference herein.

Claims

1. 1. A cold therapy system for use in inducing cryolipolysis in a subject, comprising: a delivery device cooled by a cooling device and configured to expose a desired tissue region of a patient to a temperature range between −200° C. and 30° C., the delivery device configured to deliver a split slurry injection to the desired tissue region; A cooling therapy system configured to provide fractionated cooling to promote tissue remodeling by inducing cryolipolysis.

2. 1. A cold therapy system for use in inducing cryolipolysis in a subject, comprising: a delivery device cooled by a cooling device and configured to expose a desired tissue region of a patient to a temperature range between −200° C. and 30° C., the delivery device configured to deliver a single injection of slurry to the desired tissue region; A cooling therapy system configured to provide bulk cooling to promote tissue remodeling by inducing cryolipolysis.

3. 3. The cold therapy system for use according to any one of claims 1 to 2, wherein the desired tissue region comprises one of the tongue or soft tissue of the airway of a subject.

4. 4. The cooling therapy system for use according to any one of claims 1 to 3, wherein the bulk or fractionated cooling is part of a treatment for ameliorating obstructive sleep apnea.

5. The cold therapy system for use according to any one of claims 1 to 4, further comprising inducing a collagen remodeling response or an angiogenic response in the subject.

6. A cooling therapy system for use as described in claim 5, wherein further inducing a collagen remodeling response improves airway relaxation associated with obstructive sleep apnea.

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