cosmetic system and method for predictably freezing the individual's skin, cosmetic method for t

专利摘要:
  A method and system, according to a particular embodiment of the technology, includes applying a substance to the skin of a human being. An applicator is then applied to the subject to cool a region of the subject. After the tissue has cooled, a nucleation initiator is used to initiate a freezing event in the tissue. The nucleation primer can be an ice crystal that inoculates the skin after contact to create a predictable freezing event in the skin. The contact time between the ice crystal and the skin can be controlled to obtain the desired effects.
公开号:BR112018073275A2
申请号:R112018073275-3
申请日:2017-04-27
公开日:2020-10-27
发明作者:Leonard C. DeBenedictis；Joel N. Jiminez Lozano；Like Zeng；George Frangineas Jr；Linda D. Pham
申请人:Zeltiq Aesthetics, Inc；
IPC主号:

专利说明:

[001] [001] This international application claims the benefit and priority to U.S. Provisional Patent Application No. 62 / 334,213, filed on May 10, 2016; U.S. Provisional Patent Application No. 62 / 334,317, filed on May 10, 2016; U.S. Provisional Patent Application No. 62 / 334,330, filed on May 10, 2016; and U.S. Provisional Patent Application No. 62 / 334,337, filed on May 10, 2016; which are fully incorporated in this report as a reference. INCORPORATION AS A REFERENCE
[002] [002] The following U.S. Patent Applications and U.S. Patents are incorporated in this report by reference: U.S. Patent No. 7,854,754 entitled "COOLING DEVICE FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS"; U.S. Patent No. 8,337,539 entitled "COOLING DEVICE FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS"; U.S. Patent Publication No. 2013/0158636 entitled “COOLING DEVICE FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”; U.S. Patent No. 8,192,474 entitled “-TISSUE TREATMENT METHODS”; U.S. Patent Publication No. 2013/0066309 entitled "TISSUE TREATMENT METHODS"; U.S. Patent Publication No. 2015/0328077 entitled "TISSUE TREATMENT METHODS"; U.S. Patent No. 9,132,031 entitled “COOLING DEVICE HAVING A PLURALITY OF CONTROLLABLE COOLING ELEMENTS TO PROVIDE A
[003] [003] The present disclosure, in general, refers to systems for cooling tissue. In particular, various embodiments are directed to treatment systems, methods and substances to controllably cool tissue to treat acne or other conditions. FUNDAMENTALS
[004] [004] Exocrine glands found in the skin play a role in maintaining the health of the skin, including lubricating, waterproofing, cleaning and / or cooling the skin or hair follicles of the body by excreting water-based, oily and / or waxy through the skin pores or hair follicles. Overproduction and / or over-secretion of these substances by certain exocrine glands, such as sebaceous glands and sweat glands, can cause unpleasant skin disorders that have proved difficult to treat. For example, overproduction of sebum, a waxy substance produced and secreted by the sebaceous glands, can lead to the formation of pustules (for example, blackheads, pimples, etc.) and other inflammatory skin conditions associated with acne (for example, inflamed papules) , pustules, nodules, etc.), which can potentially lead to skin scarring. Overproduction of sebaceous glands associated with hair follicles is most often found in highly visible regions of the body, such as along the face, neck, upper chest, shoulders and back.
[006] [006] Treatments for these and other skin and tissue conditions are often ineffective, not long-lasting and / or have undesirable side effects. BRIEF DESCRIPTION OF THE DRAWINGS
[007] [007] Many aspects of the present invention can be better understood with reference to the following drawings. Identical reference numbers identify similar elements or acts. The sizes and relative positions of the elements in the drawings are not necessarily drawn to scale.
[008] [008] Figure 1 is a schematic cross-sectional view of an individual's skin, dermis and subcutaneous tissue.
[009] [009] Figure 2 is a schematic cross-sectional view of the individual's skin, dermis and subcutaneous tissue in Figure 1 after treatment of the sebaceous glands.
[010] [010] Figure 3 is a partially schematic and isometric view of a treatment system for non-invasively treating target structures in an individual's body, according to an embodiment of the technology.
[011] [011] Figure 4 is a cross-sectional view of a conduit of the treatment system in Figure 3.
[012] [012] Figure 5 is a flow diagram that illustrates a method for treating an individual's skin, according to an embodiment of the technology.
[013] [013] Figure 6 is a temperature versus time graph for a treatment that involves minimal super-cooling or no super-cooling of the skin when an applicator is initially placed on a patient's skin to initiate a freezing event.
[014] [014] Figure 7 is a graph of temperature versus time for a treatment that involves substantial cooling of the skin.
[015] [015] Figure 8 is a flow diagram illustrating a method for treating an individual's skin, according to an embodiment of the technology.
[016] [016] Figures 9A at 9 € C show stages of a method for preparing a treatment site, according to an embodiment of the disclosed technology.
[017] [017] Figure 10A shows standardized hydrogel suitable for cryotherapy, according to an embodiment of the disclosed technology.
[018] [018] Figures 10B and 10C are graphs of propylene glycol concentration versus length for standard hydrogels.
[019] [019] Figures 11A and 11B are side views of hydrogel substances with ice nucleation regions, according to the technology embodiments.
[020] [020] Figure 12A shows an emulsifier or surfactant with a hydrophilic head and a hydrophobic tail.
[021] [021] Figure 12B shows an agent captured by emulsifiers.
[022] [022] Figures 13A and 13B show an oil-in-water emulsion and a water-in-oil emulsion.
[023] [023] JA Figure 14 is a table with melting / freezing temperatures for fats.
[024] [024] Figures 15A and 15B show test results performed on the skin, according to some embodiments of the disclosed technology.
[025] [025] Figure 16 shows a temperature profile of the treatment cycle and a temperature response measured by a temperature sensor on a surface-fabric interface of the applicator.
[026] [026] Figure 17 shows the applicator's surface temperature decreased at a constant rate and then maintained at a generally constant value, according to an embodiment of the technology.
[027] [027] Figure 18 is a temperature versus time graph showing an exemplary treatment cycle for controlled supercooling and for controlled freezing of tissue by lowering the skin temperature, according to one embodiment of the technology.
[028] [028] Figures 19A to 19E are seen in cross section of an applicator applied to a thermal modeling and treatment site.
[029] [029] Figures 20A to 20F illustrate stages of a tissue freezing method without overcooling.
[030] [030] Figure 21 is a graph of temperature versus time to freeze the skin several times, according to an embodiment of the disclosed technology.
[031] [031] Figure 22A shows a non-frozen liquid binding medium that can serve as an insulator for ice inoculation of the skin.
[032] [032] Figure 22B shows the connection means of Figure 22A with an altered temperature profile.
[033] [033] Figure 23 is a graph of temperature versus propylene glycol concentration! (PG) in water, according to an embodiment of the disclosed technology.
[034] [034] Figures 24A to 24F show stages of a method to cool the skin and then start a freezing event, according to an embodiment of the disclosed technology.
[035] [035] Figure 25 is a graph of temperature versus time to supercool and freeze the tissue.
[036] [036] Figure 26 is a graph of temperature versus time for a procedure that cycles twice to super-cool the tissue and then trigger a freeze.
[037] [037] Figures 27A to 27C show an applicator and a connecting means in several stages during a procedure.
[038] [038] Figure 28 shows an applicator applied to a treatment site, according to an embodiment of the disclosed technology.
[039] [039] Figure 29 is a temperature versus time graph for a temperature profile to trigger ice nucleation by activating an ice nucleate.
[040] [040] Figure 30 shows an applicator and an ice nucleating agent (INA) applied to a treatment site, according to an embodiment of the disclosed technology.
[041] [041] Figure 31 shows a graph of temperature versus time to release an INA for nucleation.
[042] [042] Figures 32A to 32D are IR images showing stages of a process using hydrogel to freeze supercooled tissue.
[043] [043] Figures 33A to 33D are IR images showing tissue freeze inoculation using combined materials.
[044] [044] Figures 34A and 34B are seen in cross section of an applicator applied to a treatment site, according to some embodiments of the disclosed technology.
[045] [045] Figure 35 is a graph of temperature versus time to trigger a freezing agent using a hydrogel.
[046] [046] Figure 36 shows an applicator positioned to produce a controlled freeze on a bonding material, according to an embodiment of the disclosed technology.
[047] [047] Figure 37 shows an applicator with an external nucleation element configured to initiate a freezing event at a location external to an applicator-hydrogel interface.
[048] [048] Figure 38 is a cross-sectional view of an applicator applied to a treatment site and capable of providing energy-based activation.
[049] [049] Figure 39 is a graph of temperature versus time to cool the skin before starting a freezing event.
[050] [050] Figure 40 is a temperature versus time graph where, after supercooling and before freezing, an applicator temperature is adjusted to heat the epidermis.
[051] [051] Figure 41 shows a graph of temperature versus time for a cooling protocol and three views in cross section of an applicator and skin tissue and temperature distributions.
[052] [052] Figure 42 shows a temperature profile in the epidermis / dermis and temperature distribution for a treatment protocol.
[053] [053] Figure 43 shows a temperature profile in the epidermis / dermis for a treatment protocol.
[054] [054] Figure 44 shows a stage in a method for creating a freeze of intradermal tissue using an injectable substance.
[055] [055] Figure 45 is a flow diagram that illustrates a method for preparing and freezing tissue, according to an aspect of the present technology.
[056] [056] Figure 46 is a schematic block diagram that illustrates subcomponents of a computing device, according to an embodiment of the disclosure.
[057] [057] The present disclosure describes treatment systems to improve the appearance, function and health of the tissue and perform other treatments. Various details presented below are provided to describe the following examples and methods in a manner sufficient to enable a person skilled in the art in the relevant technique to practice, manufacture and use them. Several details and advantages described below, however, may not be necessary to practice certain examples and methods of the technology. In addition, the technology may include other examples and methods that are in the scope of the technology, but are not described in detail.
[058] [058] Various aspects of the technology are directed at cooling a surface of a patient's skin to produce a cooling event (for example, a partial freezing event, a total freezing event, etc.) that affects tissue, cells, structures, appendices or target characteristics. Systems disclosed in this report may target glands (for example, exocrine glands, sebaceous glands, sweat glands, etc.), structures in the skin (for example, hair follicles, superficial nerves, etc.), and / or layers of tissue ( for example, dermal layer, epidermal layer, subcutaneous layer, sub-layers of the epidermis, dermis, subcutaneous, etc.). In some embodiments, the cooling event reduces or limits overproduction and / or over-secretion of exocrine glands to treat pustules and / or other inflammatory skin conditions associated with acne, such as inflamed papules, pustules, nodules, etc. For example, the cooling event can cause an effective amount of thermal damage to the glands to reduce or limit overproduction and / or over-secretion by such glands to reduce or eliminate acne or other skin conditions. The cooling event may include the freezing of a region of the dermal layer containing the target exocrine glands without affecting the non-targeted tissue. Treatment applicators can be configured for use across the face, neck, upper chest, shoulders, back and other treatment sites and can target specific layers in the skin, subcutaneous tissue, specific structures, particular cells, etc.
[059] [059] In certain embodiments, a method for predictably freezing an individual's skin at a desired predictable time includes lowering a skin temperature below a fluid freezing point on the skin, so that the skin is in a first temperature. An ice crystal comes into contact with the skin to inoculate the skin and create a predictable freezing event on the skin. A time of contact between the ice crystal and the skin is controlled, so that the predictable freezing occurs at a desired time. In some procedures, the method can be performed using an applicator that is applied to the individual's skin.
[060] [060] In some embodiments, a method of freezing dermal tissue more than once, while freezing epidermal tissue only once, includes applying a bonding medium to an applicator. The bonding medium has a medium therein capable of forming ice crystals. An applicator temperature is lowered below a freezing point of the medium to freeze the medium at least partially. The bonding medium, which is conducted by the applicator, is placed on a surface of the individual's skin. The applicator temperature can be adjusted to a treatment temperature to freeze at least a portion of the medium in contact with the skin surface to freeze dermal and epidermal tissue. In some procedures, the applicator is heated in an amount sufficient to allow the dermal tissue to thaw, but not enough to allow the epidermal tissue to thaw. After the dermal tissue thaws at least partially, the temperature of the applicator is adjusted to a second treatment temperature, such that at least some thawed dermal tissue is frozen again and the epidermal tissue remains frozen.
[061] [061] In other embodiments, a method of freezing dermal tissue more than once, while freezing epidermal tissue only once, includes freezing at least partially the dermal tissue and epidermal tissue using an applicator configured to cool a surface of an individual's skin. Although the epidermal tissue remains frozen, the applicator is heated in an amount sufficient to allow at least some dermal tissue to be thawed, and after thawing at least some dermal tissue, cool the applicator to freeze at least some dermal tissue again.
[062] [062] IN one embodiment, a method for freezing the skin predictably comprises supercooling an individual's skin using a bonding medium and an applicator at a first temperature of the applicator. The first temperature of the applicator is greater than a freezing point of the connection medium. The bonding means includes a freezing point depressant which inhibits freezing of the bonding means and the skin. The skin is inoculated to freeze the skin without lowering the applicator temperature below the first applicator temperature.
[063] [063] In other embodiments, a method for treating the skin includes lowering an individual's skin temperature below a freezing point of the target skin tissue. The cooling of the skin is monitored, so that freezing does not occur. An amount of non-freezing cooling treatment released to the skin is controlled, so that the target tissue reaches a pre-determined first level of cooling. After the target tissue reaches the first predetermined level, the skin is frozen. An amount of freezing cooling treatment released to the skin is controlled, so that the target tissue reaches a second predetermined level of cooling.
[064] [064] A system for treating an individual includes an applicator configured to cool a surface of the individual's skin when the applicator is applied to the individual and a controller. The controller can be programmed to cause the applicator, for example, to create or maintain at least one ice crystal and / or induce a freezing event on the individual's skin through at least one ice crystal.
[065] [065] At least some embodiments disclosed in this report may be for cosmetically beneficial treatments. As such, some treatment procedures may be for the sole purpose of altering a treatment site to adapt to a cosmetically desirable appearance, sensation, size or shape or other desirable cosmetic characteristics. Consequently, cosmetic procedures can be performed without providing any or minimal therapeutic effect. For example, some treatment procedures can be directed towards goals, such as reducing acne, which do not include restoring an individual's health, physical integrity or physical well-being. In some embodiments, the methods can target skin irregularities, wrinkles and sebaceous glands to treat acne; sweat glands to treat hyperhidrosis; hair follicles to damage and remove hair; or other target cells to modify an individual's appearance or treat a condition. Treatments can have therapeutic effects (whether intended or not), such as psychological benefits, alteration of hormone levels in the body (by reducing adipose tissue), etc. Various aspects of the methods disclosed in this report may include cosmetic treatment methods to obtain a cosmetically beneficial change to a piece of tissue within the target region. Such cosmetic methods can be administered by a person not trained in medicine. The methods disclosed in this report can also be used to (a) improve the appearance of the skin by tightening the skin, improving the appearance and texture of the skin, eliminating or reducing wrinkles, increasing skin uniformity, thickening the skin, ( b) perfecting the appearance of cellulite, and / or (c) treating sebaceous glands, hair follicles and / or sweat glands.
[066] [066] At least some embodiments of the technology include producing one or more controlled freezing events. The location and extent of freezing can be controlled to produce a therapeutic or cosmetic effect. Nucleation initiators, nucleation inhibitors and / or treatment substances can be used before, during and / or after the freezing event. Nucleation initiators may include, without limitation, ice nucleating agents, injectable substances (for example, saline, icy slurries, etc.), energy that promotes ice nucleation or other initiators that affect freezing. Nucleation inhibitors may include, without limitation, cryoprotectant solutions, freezing temperature depressants and / or heaters.
[067] [067] According to one aspect of the technology, an individual's skin is diminished below its melting / freezing point ("melting point"). The skin temperature is monitored to control a number of non-freezing effects. An ice crystal comes into contact with the skin to cause a freezing event on the skin. The skin can be monitored to control an amount of freezing treatment. The skin can also be monitored for any other non-freezing effects, freezing effects or thawing effects to precisely control and, predictably, an overall level of treatment. Skin preparation techniques can be used to enhance the absorption of the substance in the skin through abrasion and / or dismantling of the epidermis. Examples of substances include thermally binding gels, cryoprotective solutions and / or ice nucleating agents that can be incorporated or part of a hydrogel material, a liposome, an emulsion, a nanoemulsion, a mixture or solution of nanoparticles and / or combinations of themselves. Nanoemulsions and nanoparticles may be desirable, since their small size makes them suitable for them to be absorbed in the epidermis and dermis traveling through the openings of the hair follicles and / or the pores of the skin. A cryoprotectant can be used to accentuate the amount of non-freeze treatment that will be released before any freezing event, because the cryoprotectant can allow significant supercooling of the skin before starting a freezing event. In one embodiment, an ice nucleating agent is used to form ice crystals in a safe and predictable manner.
[068] [068] An applicator can predictably freeze target tissue or structures by producing an expected freezing event. For example, the tissue can be cooled to initiate a freezing event at an early time (for example, at a particular time or within an expected period of time), propagate freezing at a desired rate, obtain a desired degree of freezing or the like. The treatment parameters can be selected based on the desired predictability of the freezing event. For example, the skin surface can be cooled to produce a freezing event at least 80%, 85%, 90% or 95% of the time in a typical patient. This provides a predictable freeze. If a freezing event does not occur, the skin can be heated and cooled again to produce a freezing event.
[069] [069] An advantage of freezing is that, for a given amount of damage to the desired tissue, a procedure that produces freezing can take considerably less time than a procedure that does not involve freezing. This is due to the fact that, with freezing, the cell walls are damaged.
[070] [070] The damage to tissue due to freezing and cooling is mainly dependent, for example, on the cooling rate, final temperature, waiting time (not frozen and / or frozen) and defrosting rate. These variables can be controlled to obtain the desired cryolysis to the target tissue.
[071] [071] The occurrence of tissue damage on the cell scale is known, due to the formation of intracellular (IIF) and extracellular (EIF) ice. Cryolysis due to IIF can be performed by inducing irreversible damage to tissues and by necrosis that destroys organelles and cell membranes. Cryolysis due to the formation of extracellular ice occurs mainly due to hyperosmolarity in the extracellular space and dehydration of cells due to extracellular ice. These processes cause direct cell death or programmed cell death (for example, cell apoptosis).
[072] [072] In order to perform tissue damage, a low enough final temperature can be reached. Individual tissues and cells may have a different susceptibility to cold. Consequently, lethal temperatures can vary between different skin components. Multiple cycles of a treatment temperature protocol should also increase effectiveness.
[073] [073] The waiting time in a frozen state accentuates the mechanisms of cryogenic tissue injury. As ice crystals grow in size over a period of waiting time, the more they will accentuate the injury, due to IIF and / or EIF.
[074] [074] Thawing is a destructive factor that facilitates recrystallization (restructuring of the ice crystal), that is, the crystals become larger, and rehydration of the cells that cause rupture of the membrane and cell death.
[075] [075] For the skin, cold can affect the blood microcirculation which can induce reversible or irreversible vascular changes. During cooling, there is vasoconstriction of blood vessels which, in some temperature treatment protocols, can cause stasis and tissue ischemia. During freezing, damage to blood vessel endothelium and other cell damage due to EIF and IIF can occur. Vasoconstriction facilitates hypoxia, a state in which cells release vasodilation cytokines that, after thawing, accentuate refractory vasodilation and reperfusion injury. The reperfusion also facilitates inflammatory and perivascular tissue edema.
[076] [076] Additionally, partially or fully frozen tissue has a higher thermal conductivity and lower specific heat than unfrozen tissue. Thermal conductivity continues to increase and specific heat continues to decrease as additional tissue is frozen. This change in thermal properties can result in marked efficacy (for example, a factor of four to eight improvements in cooling efficiency) compared to a treatment that does not involve freezing, even when the treatment temperatures of the non-freeze treatment with super cooling are similar to the freezing treatment temperature. Consequently, with freezing, the depth of cooling penetration into the skin and surrounding tissue can be significantly faster than without freezing.
[077] [077] Some embodiments are directed to the treatment of tissue under the skin or sub-layers or sub-thicknesses of the skin, such as the epidermis, dermis, subdermis, subcutaneous, and sub-layers thereof to treat wrinkles, fine lines, pores, blemishes, freckles, hemangiomas and other vascular problems, acne or the like. In addition or alternatively, treatments can be carried out to rejuvenate the skin, coat the skin, treat skin color problems, block pain, etc., and affect targets, such as appendages, cellular elements or combinations thereof. Appendices that can be treated include, without limitation, hair follicles, sebaceous glands, sweat glands, arrector pili, nerves, blood vessels, etc. Cellular elements that can be treated include, without limitation, corneocytes, keratinocytes, melanocytes, sebocytes, fibroblasts, blood cells, collagen, elastin fibers, etc. The systems and methods disclosed in this report are useful for addressing the targets and conditions disclosed in this report.
[078] [078] References throughout this specification to "an example" or "an embodiment" mean that a particular feature or structure described in relation to the example is included in at least one example of the present technology.
[079] [079] Figure 1 is a schematic cross-sectional view of an individual's skin, dermis and subcutaneous tissue. A skin of individual 10 includes dermis 12 located between epidermis 14 and subcutaneous layer 16. Dermis 12 includes sebaceous glands 17 that produce sebum, a waxy substance secreted to hydrate skin and hair. Acne is a skin condition typically characterized by excess sebum that can plug hair follicles and / or pores. The level of sebum production can vary between individuals and can vary by location of the body depending on the number and sizes of the sebaceous glands. Sebum can flow along the healthy hair follicle 20 to hydrate the hair 23 and / or epidermis 14. When the sebaceous glands 17 produce excess sebum, it can group and / or get stuck in the hair follicles. Overproduction and / or sebum capture can lead to the formation of pustules (for example, blackheads, pimples, etc.), as well as other inflammatory skin conditions associated with acne (for example, inflamed papules, pustules, nodules, etc.) . In some individuals, follicles and inflamed pores can become infected and the condition can potentially lead to scarring of the skin. The illustrated hair follicle 22 is blocked with excess sebum to form a blister or red spot. Other medical conditions associated with overactive sebaceous glands 17 include sebaceous cysts, hyperplasia and sebaceous adenoma. Non-medical but cosmetically unpleasant conditions associated with overactive sebaceous glands include oily skin and / or oily hair (for example, on the scalp).
[080] [080] Another skin condition is hyperhidrosis. Hyperhidrosis is characterized by abnormal sweating due to the high levels of secretion of the sweat glands 26. The eccrine sweat glands are controlled by the sympathetic nervous system and regulate the body temperature. When an individual's body temperature is increased, the eccrine sweat glands secrete sweat (ie water and other solutes) that flows through a tubular gland 28. Sweat can evaporate from the skin's surface to cool the body. The apocrine sweat glands (not shown) secrete a sweat containing oil in the hair follicles 20. The armpit (eg, armpit) and genital regions often have a high concentration of apocrine sweat glands. Hyperhidrosis occurs when the sweat glands produce and secrete sweat at levels above those required to regulate body temperature and the condition can be generalized or localized (ie, focal hyperhidrosis) in specific parts of the body (for example , palms, soles of the feet, eyebrows, scalp, face, armpits, etc.).
[081] [081] Figure 2 is a schematic cross-sectional view of the skin and a side view of a treatment device in the form of a thermoelectric applicator 104 ("applicator 104") applied to the skin to treat acne, hyperhidrosis and other conditions of the skin by freezing the skin Applicator 104, in a controllable manner, can produce predictable freezing events to prevent undertreatment, overtreatment and / or undesirable side effects, such as tissue damage or untargeted structures. Damaging tissue can be difficult to control, so it often results in undertreatment or overtreatment. This is due to the fact that the freezing of the skin and tissue below the skin tends to be, at times, random and unpredictable. like skin 10, it tends to remain in a liquid state for a certain period of time, even though its temperature is decreased below its melting point / freezes a phenomenon called “supercooling”. The terms "supercooling", "supercooling" and "supercooling" "refer to a condition where a material is at a temperature below its freezing / melting point, but is still in a thawed state or predominantly thawed. It can be unpredictable whether a freezing event will occur, and, if so, when the freezing event will occur during treatment and how long the tissue will be in a frozen state. In addition, it is often very difficult to control freeze-thaw parameters, such as a freezing rate, target freezing temperatures, duration of freezing events and a heating rate. These freeze-thaw parameters need to be controlled to obtain predictable therapeutic effects. It can be difficult to control the freeze-thaw parameters, thus making it difficult to control an amount of treatment. When the amount of treatment is too large, undesirable side effects can occur, such as changes in unwanted skin pigmentation, and when it is too small, insufficient effectiveness can be a result. This lack of control can also make it difficult to target a specific tissue for treatment and minimize the treatment of another specific non-targeted tissue.
[082] [082] Applicator 104 can precisely target tissue, while minimizing or limiting effects on non-targeted tissue. It has been found that when an ice crystal comes into contact with the subject's skin 10 at a temperature that is below its phase transition temperature (for example, melting / freezing temperature) and in a super-cooled state, a freezing event can be immediately activated on the skin. The ice crystal can thus be used to predictably control the initiation of the freezing event. Once the freezing event is activated, it can spread rapidly through the volume of the supercooled tissue. The heat of fusion released during freezing can remove the bulk tissue from its super-cooled state, and then partially frozen skin can prevent the unfrozen tissue from going back into a super-cooled state. Additionally, the heat of fusion in some procedures, the period of time from the start of a freezing event in the supercooled tissue to the point where the tissue is no longer in a supercooled state can be 1 second , 2 seconds, 3 seconds, 5 seconds, 10 seconds or another suitable period of time. The time period for supercooling may depend on the target location, volume of the target tissue, volume of the supercooled tissue, temperature profile, tissue characteristics (eg water content of the tissue) and / or additives (eg , compositions, energy, etc.) that can be used as part of the procedure. Because the freeze propagation rates can be strongly dependent on the supercooling temperature, the temperature of the supercooled tissue can be decreased or increased to increase or decrease, respectively, the freeze propagation rates.
[083] [083] Applicator 104 can be used to precisely control a start time of the freezing event, an amount of damage caused by an initial freezing event (for example, by controlling an amount of supercooling created before the start of the freezing event), a duration of the freezing event (for example, by controlling an applicator temperature), and defrost rate (for example, beginning of the defrost cycle, etc.). The moments of the freezing events can be precisely controlled by controlling the generation of the ice crystal and when the ice crystal comes into contact with the super-cooled skin, so that the freezing events can be produced “under command” , and this control enables specialized treatment methods that will be implemented to treat, in a controllable and effective manner, a strip of tissue, while controlling and / or limiting tissue damage. In addition, additives can be used to manage freezing events at varying ideal temperatures to the target tissue at varying skin depths, while controlling the degree of tissue damage, degree of damage to non-targeted tissue, etc. By controlling when and how to freeze, treatment procedures can target certain tissue without targeting other tissue, while also controlling a level of target tissue treatment and effects on non-targeted tissue.
[084] [084] Figure 2 shows the skin 10 after a freeze-induced injury affected the sebaceous glands 17 to reduce or limit sebum production. Skin 10 was frozen to rupture or damage, in a controllable manner, the sebaceous glands 17 or associated structures that can be an effective treatment for acne. Although the effect on sebaceous glands 17 is shown, while applicator 104 is applied to skin 10, it can take a relatively long period of time (for example, days, weeks, months, etc.) for the glands to be reduced after treatment. The sebum production level of the two sebaceous glands 17 in Figure 2, along the hair follicle 22, was substantially reduced to inhibit obstruction to minimize, reduce or eliminate acne. The sweat gland 26 can also be targeted. For example, applicator 104 may produce a partial or total freezing event, non-freezing cooling event or super-cooling event to affect the sweat gland 26 and / or tubular gland 28 in a region of the skin located along the hands, armpits or other locations with excessive sweat. Other structures in the dermis or other layers of tissue may be targeted. Consequently, cold, associated with controlled freezing generated by applicator 104, can, in general, reduce / relieve inflammation associated with acne and be an important treatment route. Any and all of these treatment routes are covered in at least one of the embodiments of the technology disclosed in this report.
[086] [086] Cryotherapy can affect, without limitation, glandular function, gland structures (eg, gland portions, duct portions, etc.), number of glands, gland sizes and / or number and / or sizes of cells. The freezing event can be maintained for a period of time long enough to induce a desired result. In some embodiments, to treat exocrine glands, an individual's skin can be cooled to produce a partial freezing event that destroys, reduces, breaks, modifies or affects cells or structures of exocrine glands or supporting anatomical features (for example , ducts, pores, hair follicles, etc.). The freezing level can be controlled to limit damage to unwanted tissue, such as damage to non-targeted tissue, excess damage to target tissue (for example, to avoid excess damage to target tissue) and so on. The skin surface can be continuously or periodically cooled or heated to increase or decrease, respectively, the number and / or sizes of ice crystals in the target region. In one procedure, the tissue can be kept in a super-cooled state for more than about, for example, 1 second, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute, several minutes or another selected period of time to enable the fabric to reach a steady state temperature and the desired width, length and depth of a volume of tissue that is in a supercooled state. Once the tissue is frozen, it can be kept in a partially or totally frozen state for more than about, for example, 1 second, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute, several minutes or another period of time selected to achieve the desired effects, while reducing or limiting unwanted effects, such as cold ulceration or necrosis.
[087] [087] Applicator 104 can include one or more elements 167 to detect cooling events, freezing events, supercooling and so on. The thermal device 109 can be controlled based on the outlet from the element 167 to cool a temperature controlled surface 111, which in turn will cool the patient's skin. Element 167 may include one or more temperature sensors, pressure sensors, detectors, combinations thereof or the like. Alternatively, separate sensors can be used to monitor the treatment site.
[088] [088] Figure 3 is a partially schematic and isometric view of a treatment system for non-invasively treating target structures in a human body 101, according to an embodiment of the technology. Treatment system 100 can include applicator 104, connector 103 and base unit 106. Applicator 104 can be applied to acne-prone regions to reduce the temperature of lipid-producing cells that reside in or near the sebaceous glands sebaceous glands (eg, glandular epithelial cells) to decrease the amount of sebum secreted and thereby eliminate, reduce or limit acne. Applicator 104 can also cool sweat glands and associated structures to treat hyperhidrosis and can perform other treatment procedures. The size and configuration of applicator 104 can be selected based on the treatment site.
[089] [089] Connector 103 can be a wire that supplies power, fluid and / or suction from base unit 106 to applicator 104. Base unit 106 can include a fluid chamber or reservoir 105 (illustrated in phantom line) and a controller 114 driven by a housing 125 with wheels 126. The base unit 106 may include a cooling unit, a cooling tower, a thermoelectric cooler, heaters or any other devices capable of controlling the temperature of the coolant in the cooling chamber. fluid 105 and can be connected to an external power source and / or include an internal power source 110 (shown in phantom line). Power source 110 can supply electrical energy (for example, a direct current voltage) to supply power to the electrical elements of applicator 104. A municipal water supply (for example, tap water) can be used in place of, or in conjunction with fluid chamber 105. In some embodiments, system 100 may include a pressurizing device 117 that can provide suction and may include one or more pumps, valves and / or regulators. Air pressure can be controlled by a regulator located between the pressurization device 117 and applicator 104. If the vacuum level is too low, the fabric may not be adequately (or in any way) maintained against applicator 104, and applicator 104 may tend to move along the patient's skin. If the vacuum level is too high, unwanted patient discomfort and / or tissue damage may occur. A vacuum level can be selected based on the characteristics of the fabric and the desired level of comfort. In other embodiments, applicator 104 does not use a vacuum.
[090] [090] An operator can control the operation of the treatment system 100 using an input / output device 118 from controller 114. The input / output device 118 can display the operating status of applicator 104 and treatment information. In some embodiments, controller 114 may be communicatively coupled to, and exchange data with, applicator 104 via a wired or wireless connection or an optical communication link and can monitor and adjust treatment based, without limitation , in one or more treatment profiles and / or patient-specific treatment plans, such as those described, for example, in commonly issued US Patent No. 8,275,442, which is incorporated by reference in its entirety. In some embodiments, controller 114 may be incorporated into applicator 104 or another component of system 100.
[091] [091] After receiving input to start a treatment protocol, controller 114 can cycle through each segment of a prescribed treatment plan. The segments can be designed to super-cool the tissue, to nuclear the super-cooled tissue, to freeze the tissue, to thaw the tissue, to heat the tissue and so on. In doing so, the power source 110 and fluid chamber 105 can supply energy and coolant to one or more functional components of applicator 104, such as thermoelectric coolers (for example, TEC “zones”), to start a cycle cooling and, in some embodiments, activate features or modes, such as vibration, massage, vacuum, etc.
[092] [092] Controller 114 can receive temperature readings from temperature sensors, which can be part of applicator 104 or close to applicator 104, the patient's skin, a patient protection device, etc. It will be assessed that while a target region of the body has been cooled or heated to the target temperature, in reality, that region of the body may be close to, but not equal to, the target temperature, for example, because of the natural heating of the body and variations in cooling. Thus, although system 100 may attempt to heat or cool the tissue to the target temperature or provide a target heat flow, a sensor can measure a sufficiently close temperature or heat flow. If the target temperature or flow has not been reached, energy can be increased or decreased to modify the heat flow to maintain the target temperature or “setpoint” selectively to affect the target tissue. The treatment site can be continuously or intermittently assessed by monitoring various parameters. The skin can be continuously monitored to detect its temperature to determine if it is in a frozen state, an unfrozen state or another state.
[093] [093] In some procedures, applicator 104 can obtain a level or amount of supercooling at a suitable temperature below, for example, -15 ºC, -10 ºC, -5 ºC or 0 ºC. After achieving a predetermined level of supercooling, applicator 104 can automatically initiate a freezing event. The freezing event can be detected and / or monitored using applicator 104 or a separate device. A treatment level can be controlled after the initiation and / or completion of the freezing event. One or more post-freezing protocols can be performed to thaw or otherwise thermally affect the tissue to enable treatment that will be specifically adapted to effectively treat certain targets, and not to treat or minimize the treatment of non-targeted tissue. For example, post-freeze protocols can be used to inhibit, limit or substantially minimize permanent thermal injury. In some embodiments, post-freeze protocols may include gradually or rapidly heating non-targeted and targeted tissue.
[094] [094] Figure 4 is a cross-sectional view of connector 103 taken along line 4-4 of Figure 3, according to at least some embodiments of the technology. The connector 103 can be a multi-line or multi-lumen conduit with a main body 179 (for example, a solid or hollow main body), a supply fluid line or lumen 180a ("supply fluid line 180a") , and a 180b return fluid line or lumen (“180b return fluid line”). The main body 179 can be configured (by means of one or more adjustable joints) to "fix" in place for the treatment of the individual. The supply and return fluid lines 180a, 180b can be tubes made of polyethylene, polyvinyl chloride, polyurethane and / or other materials that can accommodate circulating cooling fluid, such as water, glycol, synthetic heat transfer fluid, oil, a refrigerant and / or any other suitable heat conducting fluid. In one embodiment, each fluid line 180a, 180b can be a flexible hose surrounded by main body 179. Referring now to Figures 3 and 4, coolant fluid can be continuously or intermittently released to applicator 104 via the supply fluid 180a and can circulate through applicator 104 to absorb heat. The coolant, which has absorbed heat, can flow from the applicator 104 to the base unit 106 through the return fluid line 180b. For heating periods, the base unit 106 (Figure 3) can heat the coolant, such that the heated coolant is circulated through applicator 104. Connector 103 can also include one or more electrical lines 112 (Figure 4) to supplying power to applicator 104 and one or more control lines 116 to provide communication between base unit 106 and applicator 104. To supply substances, connector 103 may include one or more tubes or lines 119 for substances to be released by the applicator 104. Substances can include binding medium, INAs, solutions (for example, cryoprotective solutions) or the like.
[095] [095] Figure 5 is a flow diagram illustrating a method 140 for treating an individual's skin, according to an embodiment of the technology. In general, the individual's skin can be cooled below a freezing temperature of fluid in the skin. One or more ice crystals can be moved in contact with the skin to create a predictable freezing event in the skin. The contact time between the ice crystals and the skin can be controlled to obtain desired freezing. Details of method 140 are discussed below.
[096] [096] In block 142, the skin can be cooled to lower the skin temperature below a freezing temperature of fluid in the skin. For example, the skin temperature can be lowered to a first temperature that is greater than 3 ºC, 5 ºC, 7 ºC, 9 ºC, 10 ºC or 11 "C below the melting / freezing temperature of fluid in the skin and can be maintained for a first period of time. After the first period of time expires, the skin temperature can be lowered to a second temperature that is lower than the first temperature, in order to create an ice crystal. In other embodiments, the first temperature can be maintained at a constant temperature, while creating an ice crystal, for example, by changing the composition of a bonding medium. The bonding medium can freeze and cause nucleation of ice in the tissue.
[097] [097] In block 144 of Figure 5, an ice crystal can come into contact with the individual's skin to inoculate the skin after contact and create a predictable freezing event in the skin. The ice crystal can be formed externally by an applicator. Alternatively, a catheter or other device can introduce the ice crystal into the individual, such that the ice crystal physically contacts the tissue that will initially be frozen. In some procedures, an agent can be cooled and then diluted to produce one or more ice crystals in it. For example, the agent can include a cryoprotectant to protect the tissue. The concentration of the cryoprotectant in the agent can be diluted to raise a melting / freezing point of the diluted agent to a value above a cryoprotectant temperature, so that the formation of the ice crystal does not require the skin temperature to be lowered to a value below the cryoprotectant melting / freezing temperature.
[098] [098] In block 146, a contact time between the ice crystal and the skin can be controlled. A user can hold the applicator against the surface of the skin, while the ice crystal contacts the surface of the skin. Upon completion of a contact period, the system can notify the individual or operator to remove the applicator from the individual. The applicator can be removed from the individual to break contact with the crystal. Alternatively, the applicator can be heated to melt the ice crystal at the conclusion of the desired contact period. The temperature of the applicator can be controlled to define the duration of the ice crystal / tissue contact, as well as the duration of the freezing event by detecting the freezing event and also controlling when the skin temperature is raised to a temperature above melting point of the ice crystal to stop the freezing event.
[099] [099] In some treatments, method 140 may include lowering an individual's skin temperature below a melting / freezing point or temperature of the target skin tissue. Applicator 104 can monitor the cooling of the skin using the sensor, so that freezing does not occur. The amount of non-freezing cooling treatment released to the skin can be controlled so that the target tissue of the skin reaches a pre-determined first level in block 142. After the target tissue reaches the first pre-determined level, the skin is frozen (block 144). The sensor can be used to identify and monitor the freezing event. An ice crystal can come in intimate contact with the supercooled skin during the supercooling period and ahead of time when the occurrence of the start of a freezing event is desired, without adverse effects. After the supercooling period has elapsed to create a first predetermined level of supercooling, ice crystals can be brought into contact with the skin to initiate the freezing event, and damage associated with the initial freezing event it can be highly proportional to the level or degree of supercooling. The freezing event can be maintained for any desired period of time and after the freezing event, additional freezing events can still affect the tissue. The amount of freeze / cool treatment delivered to the skin can be controlled so that it reaches a pre-determined second level. In some treatments, the ice crystal is used to freeze the skin in the first level of the supercooled state. The predetermined second level, when combined with the first level, can be selected to provide a therapeutically effective amount of thermal injury.
[0100] [0100] A superficial skin treatment may include contacting the individual's skin with ice crystals, while the skin has a mass temperature slightly below its melting / freezing point, such as 0.2 "ºC, 0.5ºC, 1ºC, 2ºCor3 ”CO supercooling of the skin can be minimal to non-significant, so the initial freezing event is small (for example, a fraction of the initially frozen tissue will be small) and relatively small tissue can be frozen when the event initial freezing occurs. Consequently, damage to the initial tissue can be predominantly located in the epidermis and upper dermis layer, with deeper layers, such as subdermal, adipose and muscular tissue, being largely unaffected. As such, treatments can be performed in acne-prone regions where damage to subcutaneous tissue can be problematic and unwanted. Once the freezing event occurs, additional tissue in the skin will not go into a supercooled state, due to the fact that ice crystals in the skin can inhibit or prevent additional supercooling. Further additional cooling can result in additional predictable freezing and, if minimal treatment depth is desired, a tissue thaw protocol can be initiated immediately or shortly after the freezing event.
[0101] [0101] System 100 can also perform deeper treatments, including aggressive and deeper skin treatments, by over-cooling the target tissue and then contacting the target tissue with an ice crystal to activate a freezing event. Supercooled tissue can include epidermal tissue, dermal tissue, subcutaneous tissue and can be cooled to 4 ° C, 5 ° C, 6 ° C, 7 ° C, 8 ° C, 9 ° C, 10 ° C, 12 ° C, 15 ° C, 17 ° C, 20 ºC, 25 ºC, 30 ºCor35 "Ce for a significant period of time, such as 30 seconds or 1, 2, 3, 4, 5.7, 10, 12, 15, 20, 25 or more minutes. Temperature and period treatment options can include variable and controlled levels of skin supercooling before starting a freezing event. An overall treatment level can also include multiple treatments, each of which individually releases a dose that is less than a total dose of treatment that will essentially be released. For example, after an initial skin supercooling and freezing event has been performed at a given treatment site, the device software can be programmed to repeat the supercooling and freezing event cycle a second time, optionally, after a reheating step tissue thawing / thawing between cycles. The temperatures and the treatment period for the second cycle can be the same as those for the first cycle or different. Additional treatment cycles can also be released. In this example, it would be necessary to move the applicator between cycles and the cycles can be optionally separated by a reheat / thaw step of the tissue. As another alternative, additional treatment at any given site can be performed later in the patient's procedure after an applicator has treated other tissue sites. Yet another alternative is that an additional treatment can be released during a separate patient procedure performed later on the same day as the first treatment, or the next day or several days or a week later, and the procedure can be repeated in one regular basis, if desired (for example, every day, every other day, every week, every month, etc.). Any number of desired continuity treatments can be performed to obtain sufficient and desired overall levels of tissue treatment to create a desired tissue response.
[0102] [0102] Method 140 can be used to perform the treatments disclosed in this report, such as the treatments discussed in relation to Figures 1 and 2. A freezing event can cause the sebaceous glands to rupture to affect sebum production (for example, decrease or limitation of sebum production). The contact time period (for example, contact time between the individual's skin and the ice crystals and / or between the individual's skin and the cooler surface of the applicator) can be selected to obtain the desired thermal damage to the glands sebaceous. The systems, components and actions disclosed in this report can be mixed and matched, as discussed in relation to Examples 1 to 4 below.
[0103] [0103] Ice crystals can be formed over an applicator, using temperature programming. Water (for example, water droplets, a layer containing water, etc.) can be discarded on the applicator's surface (for example, surface 111 in Figure 2), and the temperature of the applicator's surface can be lowered to about -20 ºC, -15 ºC, -12 ºC, or other suitable temperature to generate one or more ice crystals based on the freezing of water or below its melting / freezing temperature of O ºC. In some procedures, the applicator can be prepared to have ice crystals on its outer surface to cause a skin freezing event when the applicator comes in contact with the skin surface. For example, one or more ice crystals, driven by the applicator, may physically come into contact with the skin to initiate a freezing event on the skin. In other procedures, ice crystals may come into physical contact and trigger a freezing event in a bonding medium on the skin's surface. When the bonding medium freezes, it can cause the surface of the skin to freeze and subsequently spread freeze through deeper tissues. In other procedures, the binding medium can be absorbed into the skin, and the absorbed binding medium can freeze to cause the skin to freeze.
[0104] [0104] The tissue can be reheated slowly or quickly, as soon as possible, after a freezing event has occurred to limit, reduce or prevent damage and adverse side effects associated with the freezing event. After the start of freezing, the skin can be heated slowly or quickly, as quickly as possible to minimize or limit damage to the epidermis. In other procedures, the skin is partially or completely frozen for a predetermined period of time and then heated. According to an embodiment, applicator 104 of Figure 2 can heat the shallow tissue using, for example, thermoelectric elements in device 109. Thermoelectric elements can include Peltier devices capable of operating to establish a desired temperature (or temperature profile) along the surface 111. In other embodiments, applicator 104 has electrodes that emit radiofrequency energy to heat the tissue.
[0105] [0105] Absorption enhancers, cryoprotectants, INAs and binding media can be released via liposomes, hydrogels, emulsions or the like. Absorption enhancers can increase permeation to affect the absorption of, for example, water, INAs, cryoprotectants, etc. The skin can be heated before or during exposure to substances applied to increase absorption by the epidermis, with a minimal or limited increase in the dermis due to the barrier of the dermoepidermal junction. The characteristics of the tissue can be affected by the mechanical alteration of the individual's skin. These characteristics can include absorption characteristics, thermal characteristics or the like. For a treatment that does not include freezing and only cooling or super-cooling, it is desirable to increase the capture of a cryoprotectant in the skin to provide maximum protection against the possibility of unintentional freezing. For a treatment that includes freezing, it is desirable to increase the absorption of an INA and / or water to increase the likelihood that a freezing event will start and start at a desired time, and to increase a level of cryogenic injury.
[0106] [0106] Figure 6 is a graph of applicator temperature versus time for a treatment involving minimal or nonexistent skin cooling when an applicator is initially placed on an individual to initiate a freezing event according to an embodiment of the technology disclosed. A freezing event can be initiated after placing a frozen applicator surface on the skin. For example, the applicator surface (for example, the surface 111 shown in Figure 2) can be cooled to a temperature of - ºC to form ice crystals on it. After the temperature of the applicator surface is raised to a desired speed to a temperature suitable for placement on the subject, the applicator surface can be applied to the treatment site. For example, the applicator surface can be heated at a speed of 0.4 * C / s, 0.5 * C / s or 0.6 * C / s to a temperature of about 4 ºC, - 3 ºC, -2ºC, -1ºC, 0 "C, etc. The skin surface, the target tissue, etc. can be kept at a temperature of about -3 ºC, -2ºC, -1ºC, 0ºCor1" ºC.
[0107] [0107] The applicator can be kept in thermal contact with the skin surface during a first treatment period (for example, 2 minutes, 2.5 minutes, 3 minutes, etc., with 2.5 minutes being shown in Figure 6 ) to cool the skin from an initial temperature (for example, 33 ºC) to a lower temperature (for example, -4 ºC, -3 ºC, -2 ºC, -1 ºC, 0 ºC). The applicator surface can then be reduced at a desired rate to a temperature to induce a freezing event. The freezing event (indicated by an “* in Figure 6) can occur while the applicator surface is cooled at a rate of about 0.2 ºC / s, 0.25 ºC / s, 0.3“ * C / s, or other desired rate. The applicator surface can be kept at a temperature of around -8 ºC for a second treatment period (for example, 20 seconds, 30 seconds, 40 seconds, etc.). The skin temperature surface can be slightly higher than the applicator surface temperature, so that the applicator surface temperature can be selected to keep the target tissue frozen during a desired freezing period.
[0108] [0108] After the freezing period is complete, the applicator and the skin temperature can be quickly raised to a normal temperature, such as room temperature or higher. In some procedures, the applicator can be heated at a rate of about 1 ºC / s, 2 ºC / s, 2.5 ºC / s, 3 ºC / s or another rate selected to thaw frozen tissue. Figure 6 shows the applicator temperature increased at a rate of about 2.5 º * C / s. The thawed tissue may include epidermal tissue, dermal tissue, subcutaneous tissue, and / or other tissue. After the tissue is heated for a hot period, another cryotherapy procedure can be performed at the same site or at the site of difference using the same or different treatment parameters.
[0109] [0109] A substance can be applied to the skin, the applicator or both, and can be used to generate ice crystals. The substance can be a means of bonding with one or more cryoprotective agents and can be applied when it is initially at a temperature above its melting point, which can be several degrees below O ºC and less than a melting point / freezing of fluid in the skin tissue. The melting / freezing point of the applied substance may be in a treatment temperature range with therapeutic skin supercooling or another suitable temperature range. After a predetermined amount of supercooling of the skin has occurred, the temperature of the applied substance can be lowered to a value below its melting point or temperature to create ice crystals to initiate the skin freezing event.
[0110] [0110] Cryoprotective agents may comprise propylene glycol, glycerol, polyethylene glycol, combinations thereof or other biocompatible agents. In some embodiments, the substance is a cryoprotectant solution with a cryoprotectant mixed with water to provide a desired melting / freezing point. The concentration of the cryoprotective agent can be increased to decrease the melting / freezing point of the substance. By controlling the concentration of the cryoprotectant, the characteristics of the substance (eg melting point, spontaneous freezing point, etc.) can be controlled, thus allowing the generation of ice crystals at / below any desired temperature, inhibiting or preventing generation of ice crystals at / above certain temperatures. INAs can be incorporated into the substance to, for example, provide a predictable initiation of freezing events, since the temperature of the substance is lowered below the melting / freezing point of the INA.
[0111] [0111] Figure 7 is a graph of the applicator temperature versus time for a treatment involving substantial cooling of the skin according to an embodiment of the disclosed technology. The applicator and the skin can be cooled at a desired rate (for example, 0.5 * C / s, 1 ºC / s, 2 * C / s, etc.) to a super-cooled temperature (for example, -8 ºC, -10 ºC, -12 ºC). A skin freezing event can start after a super-cooling period of about 3 minutes, 4 minutes or 5 minutes at the super-cooled temperature, illustrated as -10 ºC. During this period, the skin surface and the cooled applicator surface can be at substantially the same temperature. A cryoprotective bonding medium can help limit thermal damage to non-bleached tissues and can be discarded at the applicator-skin interface. In some embodiments, the cryoprotective bonding medium is about 25% by weight or by volume of propylene glycol (PG) and about 75% by weight or by volume of water and has a melting or freezing temperature of about -11 ºC. The composition of the bonding medium can be adjusted to increase or decrease its melting / freezing point. After the supercooling period, the applicator temperature is lowered further to initiate a freezing event. Figure 7 shows the onset of the freezing event on the skin while the applicator and the skin surface are cooled from about -10 ºC to about -18 ºC. The level of freezing in the tissue can be maintained as long as the applicator surface and the skin surface are maintained at a temperature of around -18 ºC for 10 seconds before the rapid rewarming.
[0112] [0112] Ice crystals can be generated by diluting a pre-cooled bonding medium to increase its melting / freezing point.
[0113] [0113] Energy can be used to manage the formation of ice crystals. When the aqueous bonding media is decreased below its melting / freezing points and is in a supercooling state, ultrasound can induce the formation of ice crystals on the skin and / or a freezing event in the bonding media, regardless of whether the binding medium is slightly or significantly overcooled. While providing ultrasound can prevent OS INAs, ultrasound and INAs can be used together. Ultrasound was used to form ice crystals in aqueous bonding agents. For example, a dental cleaning ultrasound probe operated at about 20 kHz and about 25 W forms ice crystals in bonding agents. In another example, a non-dental ultrasound probe operated at about 20 kHz and 1 W forms ice crystals. Ultrasound with other parameters can be selected based on the formation and / or growth of desired ice crystals.
[0114] [0114] After the tissue is in a super-cooled state, a freezing event that triggers or promotes the substance can be injected into or near the target region. The substance can be partially frozen ice or an aqueous solution that generates an immediate freezing event. In some embodiments, the epidermis can be reheated to a temperature close to 0 ° C prior to the freezing event, and an injection of cold seawater solution into the dermis can initiate controlled freezing under the epidermis. Needles, catheters or injection devices can be inserted into the individual to inject the substance. Figure 2 shows an optional catheter 149 that can be inserted into the subject. Once an end portion of catheter 149 is positioned on skin 10, catheter 149 can deliver an ice crystal, ice paste or suitable substance to the tissue. Catheter 149 can be used to initiate freezing events at any number of treatment sites.
[0115] [0115] Various combinations of steps in examples 1 to 4 can be combined. To accentuate or maximize the freeze injury in the dermis while limiting or minimizing the side effects associated with freezing in the epidermis, contact between an ice crystal and the tissue can be delayed until a desired level of supercooling of the skin is achieved. A volume of target skin can be substantially super-cooled and then contacted by ice crystals to maximize freeze damage to the skin while minimizing side effects. A large amount of previous supercooling can maximize the amount of tissue damage that occurs during the initial freezing event, and can allow the non-targeted tissue to be reheated to inhibit, limit or substantially prevent thermal injury to that non-targeted tissue. The epidermis can be a non-targeted tissue that can be immediately or quickly reheated after the freezing event in the target tissue, such as the dermis. Heating can limit or minimize a period of time when the epidermis is in a frozen state. This is in contrast to a treatment method by which little or no supercooling is used. In the latter case, to obtain a therapeutic level of treatment equivalent to the first case (which uses substantial supercooling and substantial fractional freezing during the initial freezing event, since the cooling is released “from top to bottom” by the skin surface ), the epidermal tissue needs to be kept in a frozen state for longer after the start of the freezing event, which can exacerbate the damage to the untargeted epidermal tissue.
[0116] [0116] To restrict the freezing of lesions mainly in the upper layer of the skin, significantly saving deep tissues from significant lesions, ice crystals can come into contact with the skin immediately or shortly after the skin temperature is lowered below the melting point / freezing of the skin. Limited superficial epidermal freezes can be achieved with minimal damage to the dermal, fatty and muscular layers, especially when the duration of the freezing event is kept relatively short. In some facial procedures, the freeze injury can be limited to the skin to avoid any appreciable reduction in the subcutaneous tissue or underlying muscle that forms a supporting structure for the skin.
[0117] [0117] Figure 8 is a flow diagram illustrating a method 150 for treating an individual's skin according to an embodiment of the technology. In general, the bonding medium can be applied to the treatment site. The treatment site can be cooled, and a freezing event can be started to at least partially freeze the tissue. An early stage of method 150 may include attaching an applicator heat exchange surface to the subject's skin. The heat exchange surface can be a temperature-controlled surface (see, for example, surface 111 in Figure 2) of a heat exchange plate and internal thermal elements (for example, thermoelectric elements, fluid elements, etc.) or external thermal elements (for example, thermal elements mounted on the back of the heat exchange plate). In some embodiments, the temperature-controlled surface can be an interface layer, a dielectric layer or the like. Additionally or alternatively, a vacuum or suction force can be used to positively bond the patient's skin to the temperature-controlled surface. Attaching the temperature-controlled surface to the subject's skin may also include delivering a substance to the patient's skin, as described in this report and commonly in U.S. Patent Publication No. 2007/0255362. Details of the 150 method are discussed below.
[0118] [0118] In block 152, the treatment site can be prepared, for example, mechanically, chemically, or otherwise altering the skin.
[0119] [0119] In block 154, the bonding medium can be applied to the skin. The bonding means may include, without limitation, water, hydrogels, cryoprotectants, emulsions, combinations thereof or the like, before preparing the treatment. The application of the bonding medium may include placing, spraying, coating or rubbing a liquid, gel or leaf bonding medium on the skin using an instrument including, for example, a brush, spatula, spray bottle or syringe, or by hand (for example, an operator's gloved hand).
[0120] [0120] The connection means may include one or more temperature depressors, INAs, etc. Temperature depressants may include, without limitation, polypropylene glycol! (PPG), polyethylene glycol (PEG), propylene glycol, ethylene glycol, glycerol, dimethyl sulfoxide (DMSO) or other glycols. Temperature depressants can also include ethanol, propanol, isopropanol, butanol and / or other suitable alcohol compounds that can lower the freezing point of a solution (for example, body fluid) at about 0 "C to -40 ºC and more preferably to about -10 ° C to -16 ° C. Certain temperature depressors (eg, PPG, PEG, etc.) can also be used to improve softness and provide lubrication. Additionally or alternatively, the bonding medium can include one or more thickening agents, pH buffers, humectants, surfactants, and / or additives.
[0121] [0121] In block 156, the individual's skin can be cooled. An applicator can be applied to the treatment site to place the applicator in thermal contact with the target tissue. The fabric can be super-cooled and then frozen, to limit or avoid unwanted side effects. The surface of a human's skin can be cooled to a temperature below 40 ºC to prevent unwanted skin damage. The skin surface can be heated to bring untargeted tissue from the supercooled state while the deeper, target region remains in the supercooled state.
[0122] [0122] In block 158, the supercooled target region can be nucleated to produce freezing that can destroy or damage target cells, for example, due to the crystallization of intracellular and / or extracellular fluids. A catalyst for nucleation (eg, mechanical disturbances, RF energy, alternating electric fields, etc.) can be provided after an increased temperature protection of undirected epidermal layers. Mechanical disturbances can be vibrations, ultrasound pulses, and / or changes in pressure. Layers of non-targeted tissue can be heated sufficiently to prevent freezing after the target tissue is nucleated. The treatment systems disclosed in this report may use applicators disclosed in this report to perform such supercooling methods.
[0123] [0123] Some treatments include freezing dermal tissue more often than adjacent epidermal tissue. In block 156, the dermal and epidermal tissue can be cooled and frozen (block 158). The skin can be heated by an applicator (which is slightly below 0 ºC) enough to allow the dermal tissue to thaw due to internal body heat but not to the epidermal tissue that is removed from the blood stream than the skin. dermal tissue. After thawing the dermal tissue, block 158 can be repeated by refrigeration, for example, the skin to re-freeze the dermal tissue while the epidermal tissue remains frozen. A desired level of damage to the dermal tissue can be achieved by repeatedly freezing and thawing the dermal layer, because the primary mechanism of damage during freezing is caused by nucleation and growth of the ice crystal.
[0124] [0124] Some treatments include a heating / thawing step 159 after the freezing event (s), in which the frozen and cooled tissue is re-heated passively or actively by the applicator. After heating / defrosting step 159, cooling and freezing steps 156 and 158 can be repeated immediately, as shown by arrow 153, any number of times, such as 1, 2, 3, 4 or more times, preferably during same treatment as the patient and optionally without moving the applicator. Alternatively, steps 156 and 158 of cooling and freezing can be repeated during the same treatment as the patient, but after the applicator has been moved to another treatment site and then brought back to the original treatment site, or during a treatment session separated from the patient at the end of the first treatment day or the next day or several days later. Any number of repeated sessions can be used to achieve a desired general level of treatment. Arrows 157 and 155 show possibilities for the new treatment which may include a repetition of step 152 of skin preparation and / or a repetition and application of step 154 of the binding medium, as desired.
[0125] [0125] Figures 9A to 9C show stages of a method for preparing a treatment site according to an embodiment of the disclosed technology. In general, the individual's skin can be mechanically altered to facilitate absorption of the bonding medium. For example, stripping elements can be applied and removed from the skin surface any number of times to remove an upper portion of the epidermis in order to expose lower layers of tissue. The lower layers may have a relatively high water content and thus may be better able to absorb and absorb various agents, including water- or oil-based bonding means, in the epidermis.
[0126] [0126] Figure 9A is a cross-sectional view of a removal element 200 applied to the skin surface and overlapping a pore. The removal element 200 can be an adhesive tape (for example, adhesive tape) or other adhesive element that can be removed from the skin to remove, for example, sebum, hair follicles or characteristics of the pilosebaceous unit to expose the skin pore of substances applied. The removal element 200 can be a single adhesive tape (e.g., piece of tape) that is cut to overlap the entire treatment area. In other embodiments, multiple pickling elements 200 are applied to the treatment site. The adhesive characteristics of the blasting elements can be selected based on the desired amount of mechanical change in the skin and the comfort of the desired patient.
[0127] [0127] Figure 9B is a cross-sectional view of the removing element 200 being removed from the skin to remove the material 201 from a pore 203 to open or unclog a pore inlet 202. Additionally, the stripping elements can be reapplied in any number of times to unclog pore 203 or otherwise prepare the treatment site.
[0128] [0128] Figure 9C is a cross-sectional view of a treatment site after pore 203 has been cleaned and a substance 205 has been applied. To substance 205 it can infuse pore 203 and can be absorbed through the skin. Water can be part of the substance, and a subsequent freezing event can cause the water in the pores of the skin to freeze and cause additional tissue damage.
[0129] [0129] The skin can be mechanically stimulated before, during and / or after any steps in method 140 (Figure 5) or 150 (Figure 8). Mechanical stimulation may include, for example, stimulation or agitation by brushing, rubbing, applying ultrasound, dermabrasion or other means that can clean the treatment site and / or cause the stratum corneum barrier (ie, the outermost layer of the epidermis consisting of dead cells) to be temporarily reduced and / or to increase the movement (eg, turbulence) of the binding medium in relation to the skin. Without being limited by theory, it is believed that mechanical stimulation of the skin (for example, agitation, reduction or penetration of the stratum corneum) may enhance the permeation of the binding medium in the underlying epidermal layer, dermal layer or other layer of tissue. In one embodiment, the skin can be mechanically stimulated for about 20 seconds to about 10 minutes. In another embodiment, mechanical stimulation can be applied to the treatment site for about 20 seconds, about 40 seconds, about 1 minute, about 2 minutes, about 5 minutes or more than about 5 minutes. In some embodiments, mechanical stimulation can be carried out with, for example, a dermal brush, a brush with rotating bristles or the like. Brushing or rubbing the skin may include, in some embodiments, moving through the skin at the treatment site in a circular motion or forward or backward or, in other embodiments, in linear strokes, to increase the skin permeability to the substance. The permeation rate can be increased or decreased to obtain a desired amount of absorption.
[0130] [0130] Different techniques can be used to assess the permeability of the skin before and / or after the blasting process is carried out. In one procedure, the binding agent can be applied to the treatment site and then the cells at the treatment site can be progressively removed by repeatedly applying the removal element or applying a series of removal elements. The stripping elements and the treatment site can be evaluated to determine the volume of the binding medium absorbed by the skin.
[0131] [0131] Since ice crystals can be reliably generated to trigger freezing events on the controller, a substance can be used to improve the thermal bond between a skin surface and a cooling applicator. In some embodiments, the substance is an aqueous solution binding agent, which contains a cryoprotective agent. Other substances may contain water and a means to promote reliable creation on demand of an ice crystal when the start of freezing in treatment is desired. Liquid water has clusters of molecules that are constantly colliding with other molecules and clusters, sometimes falling apart and sometimes forming new clusters. When the water is being cooled, as the temperature drops and the thermal movement of the water molecules decreases, the tendency of the water molecules to aggregate becomes stronger and the probability of a critically large cluster of molecules to form increases quickly. Ice nucleation is catalyzed by the formation of a critically large cluster of molecules. Consequently, the onset of freezing or nucleation of ice in a water sample (or a binding agent) occurs from a core with an ice-like structure. The nucleus can promote the organization of water molecules in a crystalline network of ice.
[0132] [0132] Aqueous and water binding agents have a natural tendency to cool to a temperature significantly below their equilibrium freezing point before ice nucleation; that is, they have a tendency to over-cool. There are two modes of nucleation of water ice: homogeneous and heterogeneous. When a critically large nucleus is formed by the spontaneous aggregation of the water molecules themselves, the nucleation is referred to as "homogeneous". For a macroscopic amount of water, the size of a cluster required for ice nucleation is often around 25 molecules. The cluster radius can be about 3 molecules. The critical radius that coincides with this size provides a temperature of -41 ºC, which is called the homogeneous nucleation temperature for the water. Consequently, the homogeneous nucleation temperature for water is the minimum temperature at which pure water can be cooled before freezing occurs spontaneously.
[0133] [0133] When the aggregation of water molecules is catalyzed by an external source, nucleation is referred to as "heterogeneous". The cause of the external nucleation may be the introduction of ice crystals or another external substance in the supercooled sample. For example, crystallization can be triggered by the physical introduction of a nucleation initiator (for example, a crystal or seed core) around which a crystalline structure can form to create a solid.
[0134] [0134] Substances can be hydrogels, liposomes or emulsions, such as oil-in-water (O / W) emulsions, water-in-oil (W / O) emulsions, oil-in-oil emulsions (0/0) or nano-emulsions, and can provide homogeneous or heterogeneous nucleation.
[0135] [0135] An INA can be a substance that promotes the formation of a seed crystal (or initial agglomeration), thus catalyzing a heterogeneous ice nucleation. When INAs are used, water freezing occurs at a temperature higher than necessary in the case of homogeneous nucleation, and the largest biological ice nucleates can trigger freezing between - 1 ºC and -5 ºC or other lower temperatures, before a spontaneous freezing of water normally occurs. Spontaneous freezing of water can occur in a variable manner at -10 ºC, -15 ºC, -20 "C, or -25" ºC or less, and the timing of spontaneous freezes is very unpredictable. Examples of INAs include proteins derived from biogenics, materials derived from gram-negative epiphytic bacteria, and / or materials belonging to the genus Pseudomonas, Ernwinia or Xanthomonas. For example, INAs may be substances derived from organic or inorganic substances that promote the nucleation of heterogeneous ice. Embodiments of the present technology may include methods of producing controlled and predictable freezes of the skin and subcutaneous tissue using INAs.
[0136] [0136] In general, INAs can promote the formation of ice crystals in water-like substances at a specific temperature, such as generally a few degrees below 0 ºC. INAs can be used synergistically with a selected temperature treatment protocol to control the onset and extent of a freezing event during cryotherapy and can be used to promote freezing in vivo at temperatures higher than a natural freezing point homogeneous nucleation of skin tissue. One aspect of some embodiments of the present technology relates to methods of producing a controlled freezing of the skin and subcutaneous tissue using INAs. Cooling methods using INAs allow the triggering of ice nucleation at specific temperatures, such as temperatures close to 0 ºC. Thus, INAs can provide an advantage in therapies that require freezing temperatures and variable treatment with desired therapeutic treatment / safe temperature ranges and that create a precise and controllable extent of skin and tissue damage from a freezing event.
[0137] [0137] Several Gram-negative epiphytic bacteria are known to produce INAs. These belong to the genera Pseudomonas, Erwinia and Xanthomonas, among others. One of the highest levels of ice nucleation activators is an ice nucleation protein (INP) from some ice nucleating bacteria. Protein molecules and materials located on the outer membrane of these bacteria are responsible for the nucleation of ice. The cells can also be lysed or otherwise produce pieces of cellular material (for example, membranes) in which these INAs are found or trapped, for example, Pseudomonas Syringae.
[0138] [0138] A commercially accessible INA is SNOMAXQO available from
[0139] [0139] INAs can be used in cooling protocols to cause nucleation of ice at temperatures of around -2 ºC, -3 ºC or -4 ºC. At these temperatures, damage to epidermal tissue can be significantly less than damage typically produced at low freezing temperatures. The temperature for ice nucleation can be selected to be high enough to avoid significant changes in skin pigmentation associated with freezing events.
[0140] [0140] A non-invasive applicator (for example, applicator 104 of Figures 2 and 3) can be used to control the cooling of the skin and may include one or more temperature sensors. Temperature sensors (for example, element 167 in Figure 2) can be embedded along the applicator's treatment surface and can be used as part of a temperature control system. The temperature control system can include one or more feedback control algorithms to control the applicator based on a predetermined set of temperature values over one or more predetermined periods of time, and have predetermined rates of change when moving from one temperature to another temperature, and so on. Different feedback control algorithms can be used to treat tissues using different treatment temperature protocols (and create different temperature treatment cycles) by varying the cooling / thawing rates, pre-determining therapeutic treatment temperatures and / or selecting duration of treatment. treatment. The methods described in this report may involve the use of both INAs to control the freezing and variation of treatment protocols and temperature profiles.
[0141] [0141] One aspect of this technology relates to methods of using hydrogel substances with freezing point depressants (cryoprotectants) and / or INAs to create a predictable controlled freeze “under command”. Hydrogel substances are a class of cross-linked polymers that, due to their hydrophilic nature, can absorb large amounts of water. Hydrogel substances can have a water content suitable for controlling freezing, including controlling ice nucleation, ice crystallization, freeze propagation or the like. Integral parts of hydrogel synthesis include a monomer, an initiator and a crosslinker. The properties of the hydrogel can be modulated by varying its synthetic factors, such as reaction temperature, type of monomer, monomer crosslinker, monomer crosslinking ratio, monomer concentration and type and amount of initiator. The hydrogel composition can be selected for a specific application by selecting appropriate starting materials and processing techniques.
[0142] [0142] Hydrogels can be mixed with one or more freezing point depressants and can be modified to have the desired melting / freezing temperatures (for example, optimal melting temperatures). Freezing point depressants can inoculate tissue. In addition or alternatively, hydrogels can be combined with INAs that have a defined activation temperature to make hydrogels able to freeze consistently at predetermined temperature ranges (or a specific temperature) different from those associated with hydrogels without ice nucleating agents . The combination of hydrogels, freezing point depressants and / or INAs can result in controllable freezing at desired temperatures, such as - 3 ° C, -2 ° C, -1 ° C or other temperatures. Temperatures close to 0 ° C can be less harmful to epidermal tissue and are suitable for less aggressive temperature freezing protocols, so temperatures can be selected to protect one or more upper layers of the skin to eliminate or minimize any substantial side effects associated with freezing. skin treatments and eliminate any permanent adverse events.
[0143] [0143] The water accommodated by the hydrogel structure can be classified into four types: free, interstitial, bonded and semi-bonded water. Free water is located in the outermost layer and can be easily removed from hydrogels under mild conditions. Interstitial water is not connected to the hydrogel network, but is physically trapped between hydrated polymeric chains. The bound water is directly linked to the polymeric chain through the hydration of the functional groups or ions. The bound water remains an integral part of the hydrogel structure and can be separated only at very high temperatures. Semi-bonded water has intermediate properties of bound water and free water. Free and interstitial water can be removed from hydrogels by centrifugation and mechanical compression.
[0144] [0144] Controlled freezing techniques can take advantage of the water composition of hydrogels. Hydrogels can be designed to have a specific freezing point or specific freezing temperature range by having a specific proportion of water monomer crosslinker content. Cryoprotective additives, such as glycols (eg PG) or other substances, can also be used as a way to lower your freezing point.
[0145] [0145] A hydrogel can act as a trigger for a predictable freezing event. As the hydrogel freezes, the hydrogel provides "seed seeds" or crystal locations to inoculate the tissue and thus catalyze a predictable controlled freeze at a specific skin temperature. In some embodiments, a predictable freezing event can be tissue freezing that occurs at least 90%, 95% or 98% of the time when freezing is desired. A predictable controlled freezing event in a hydrogel can also be achieved by pre-cooling the hydrogel to a temperature below its melting point. The freezing event can be initiated by injecting a nucleation initiator (for example, ice / water paste) into the hydrogel to create the freeze that reaches the surface of the hydrogel adjacent to the patient, which causes the individual's skin to freeze. In other procedures, ultrasound or other nucleating energy can be used to produce a freezing event in the hydrogel. According to one embodiment, additives (for example, cryoprotectants and / or INAs) can be incorporated in isolated layers within an interior of the hydrogel, so that these substances are not found on an outer surface of the hydrogel sheet or hydrogel and consequently do not come in direct contact with the skin or other tissue to be treated. Encapsulating these substances within the hydrogel avoids the need to choose INA substances that have been tested and validated to be safe when in contact with skin or tissue. The predictable frozen hydrogel can be increased by additives, such as INAs.
[0146] [0146] Figure 10A shows a hydrogel standardized according to an embodiment of the disclosed technology. Figures 10B and 10C are graphs of PG concentration (% PG) versus length for standard hydrogels. Hydrogels can include a water dispersion medium and volumes of nucleation inhibitors (for example, particles or water columns / PG emulsion). Figure 10A shows isolated volumes of nucleation inhibitors spaced in a volume of water. In some embodiments, a hydrogel layer or sheet may contain columns of a nucleation-inhibiting emulsion separated by a volume of water with substantially no PG. The water around the columns can serve as ice nucleation sites. The inner shells (for example, encapsulants) can inhibit or prevent the diffusion of the water / PG emulsion. The composition of the inner shell can be selected based on the composition of the substance contained, and the pattern, number and sizes of the inhibiting volumes of localized nucleation can be selected based on the characteristics of the hydrogel.
[0147] [0147] Figures 10B and 10C show embodiments with propylene glycol (PG) located along the hydrogel, with the concentration of PG varying along the length and width of a layer or a sheet of hydrogel. The regions of the hydrogel with the lowest PG concentration have the highest melting / freezing point and can thus function as ice nucleation regions. Isolated freezing zones can be formed on the skin adjacent to these ice nucleation regions. Other types of cryoprotective agents or components can replace PG. For example, PG can be replaced or combined with PPG, PEG, DMSO or the like.
[0148] [0148] Another embodiment is a hydrogel that contains an INA placed uniformly in all areas where seed freeze propagation is desirable. In addition, INA can be dispersed exclusively within interior portions of a hydrogel volume. For example, INA may be inside a sheet of hydrogel so that INA does not extend to a surface of the sheet, thereby preventing contact between INA and the skin. INA can seed a freezing event in an interior region of the hydrogel, and the freezing event can quickly spread to an external surface of the hydrogel, which in turn comes into contact with the skin and causes a freezing event on the skin.
[0149] [0149] Figures 11A and 11B are side views of hydrogels with ice nucleation regions. Figure 11A shows a hydrogel material with an inner ice nucleation region between the upper and lower ice nucleation inhibiting regions. The ice nucleation region may comprise an INA and may have a relatively low temperature depressant concentration, if any. In one embodiment, the ice nucleation region can be substantially free of temperature depressants and can comprise water and ice nucleation characteristics (for example, INAs, ice nucleation particles or the like). The ice nucleation region can be a layer, either a continuous layer or as stains on an inner layer, so that it is fully embedded within the hydrogel.
[0150] [0150] Ice nucleation inhibiting regions may have a lower melting / freezing point than the ice nucleation region and may include volumes of temperature depressants, such as evenly or unevenly spaced PG volumes. The pattern, number and composition of the freezing inhibitory characteristics can be selected based on the inhibitory characteristics of the desired nucleation.
[0151] [0151] Figure 11B shows a multilayer hydrogel material with external ice nucleation inhibitor beds and an internal ice nucleation layer. The outer ice nucleation-inhibiting layers may include temperature depressants, and the inner layer may comprise a high concentration of INA (for example, mainly INA by volume). For example, the outer ice nucleation-inhibiting layers may be a layer of a PG solution or a layer with a dense series of PG volumes, and the inner layer may comprise mainly or entirely water. A freezing event can be initiated in the ice nucleation layer and then spread through the outer ice nucleation inhibiting layers.
[0152] [0152] The hydrogel can be sticky on the patient side and on the applicator side. The sticky upper and lower surfaces can help maintain contact with the individual's skin and applicator and, in some embodiments, help to minimize or limit the movement of the hydrogel during treatment. A coating can be used to prevent contamination of the hydrogel. One side of the hydrogel that comes into contact with a coating may become sticky. In some embodiments, the hydrogel may be a sheet of uniform or variable thickness with adhesive applied to one or more of its outer surfaces.
[0153] [0153] Hydrogels can be used in the methods discussed in relation to Figures 5, 8 and 9A-9C. For example, in block 142 in Figure 5, a hydrogel can be applied to the individual's skin and can include an INA capable of forming ice crystals in the presence of water. INA can be encapsulated within a polymeric structure of the hydrogel, such that INA does not come into direct contact with the skin as discussed in relation to Figures 11A and 11B. The hydrogel and the skin can be cooled to reach an appropriate cooling temperature to freeze the skin. The hydrogel may include a freezing point depressant such that a first melting / freezing temperature of the hydrogel is less than a second melting / freezing temperature of the fluid in the skin.
[0154] [0154] In block 144 of Figure 5, the skin can be cooled to a temperature above the first freezing temperature and below the second freezing temperature in order to super-cool the skin, and after a predetermined amount of super-cooling, the skin is frozen in the block
[0155] [0155] With reference to method 150 in Figure 8, a hydrogel substance comprising a cross-linked polymer and an INA can be applied to block 154. INA can be incorporated within a polymeric structure to prevent direct contact between INA and the skin. In some embodiments, a hydrogel sheet may be applied to the individual's skin. Alternatively, the hydrogel can be injected into the skin. Other techniques can be used to apply hydrogels, which can be creams, gels, etc. In block 156, the skin is cooled. In block 158, the freezing event can be initiated using one or more ice crystals. In other embodiments, energy is used to break structures containing INAs to release enough INA to produce a freezing event.
[0156] [0156] The liposomal transport of substances to the tissue can be used to deliver substances to the specific tissue in a more effective way than just applying the substances to a skin surface. Since a liposome is lipophilic, it can be absorbed at least into the stratum corneum and can then release a substance into the liposome at a specific location or depth in the individual's tissue. Liposomes can retain significant water "buckets" that increase the skin's water content when the liposome breaks down, and make more freeze protection more predictable when used with significant amounts of cryoprotectant in the liposome water. Hydrating the skin in liposomes can be more effective than applying water directly to the skin's surface, since the stratum corneum is normally hydrophobic.
[0157] [0157] A topically applied liposome can enhance thermal contact between the applicator / skin and can provide controlled release of agents (eg, cryoprotectant, INAs, etc.), and liposomes can penetrate the stratum corneum better than water or water mixed with a cryoprotectant. In addition, liposomes can release different agents to different locations, thus allowing direct transfer of agents to specific target cells. In one embodiment, the liposome contains a cryoprotectant (for example, propylene glycol) and can be disrupted to release the cryoprotectant. In another embodiment, the liposome selectively releases an INA to provide controlled freezing capacity through the specific tissue.
[0158] [0158] According to embodiments where freezing is desired, substances (for example, INAs, cryoprotectants, etc.) can be incorporated into liposomes, such that the liposomes, in a controllable manner, can release substances into the skin. Specifically, liposomes can be formulated to maintain their structure when they penetrate the skin to minimize, limit or substantially prevent the release of substances. When sufficient liposomes accumulate in a desired tissue or skin layer, a breakdown “under command” of the liposomes can be initiated to activate a burst release from the embedded agents. In some embodiments, the liposome may contain an INA to initiate freezing events. Triggering methods for breaking liposomes include the use of temperature (for example, temperature cycling), ultrasound or a cleaning agent to break or break the lipid encapsulation of liposomes. An applicator may include heaters for heating the treatment site to cause release of the agents, may include transducers to release mechanical energy in the form of ultrasound waves, or may include other elements for breaking liposomes to perform the methods discussed in relation to Figures 5 and 8.
[0159] [0159] Liposomes can have compositions selected based, for example, on a rate of release agent, stability and / or other desired characteristics. In some embodiments, the rate of release of the agent can be increased by applying energy, such as ultrasound, heat, or other energy suitable for breaking down lipids that capture the agents. For example, a medium can include first liposomes to release cryoprotectants to the epidermis and second liposomes to release INAsS to the dermis. Once the first liposomes are absorbed by the epidermis, they can release the cryoprotectant to protect the epidermis. After the second liposomes passed through the epidermis and were absorbed by the dermis, they released INA into the dermal tissue. After cooling the treatment site to a temperature below a melting / freezing point of the skin, INA can cause a predictable freeze in the dermal tissue. Consequently, each agent can be released to specific locations using liposomes. Liposomal media can be used before, during and / or after a treatment session. In some procedures, a topical medium is applied to the skin's surface to release cryoprotectant to the superficial tissue before cooling. Another medium (for example, medium with an INA) can be injected into the deeper tissue, once the tissue is cooled, and is ready for freezing.
[0160] [0160] Emulsions are a class of dispersed systems comprising two immiscible liquids and may contain liquid droplets, which comprise the dispersed phase, dispersed in a liquid medium, which is the continuous phase. Emulsions can be oil-in-water (O / W) emulsions, water-in-oil (W / O) emulsions, oil-in-oil (O / O) emulsions or nanoemulsions. Nanoemulsions are desirable, as they can penetrate the epidermis and dermis through the openings of hair follicles and openings in the skin pores. Figure 12A shows an emulsifier or surfactant with a hydrophilic head and a hydrophobic tail. Figure 12B shows an agent (e.g., oil based agent) captured by the emulsifiers to separate the agent and water. Figures 13A and 13B show oil-in-water and water-in-oil emulsions. Referring to Figure 13A, the emulsion includes oil droplets that can comprise the same or different agents. In a single agent emulsion, each droplet can comprise the same agent. In a multi-agent emulsion, different agents (e.g., dispersed media) can be equally or unevenly dispersed in the dispersion medium. The dispersed medium can include droplets containing one or more cryoprotectants, INAs, analgesics, agents or the like.
[0161] [0161] Figure 14 is a table with melting / freezing temperatures for fats. Fats can be natural oils suitable for O / W emulsions and can have relatively high melting points. For example, fats can have melting / freezing points above 0 ºC and can be used in emulsions.
[0162] [0162] Ex-vivo bench tests with skin using treatment cycles show the unpredictability of skin supercooling and precise control freezing with INAs. In a test, a thermocouple was placed between a bonding layer (bonding medium) and the skin to detect frostbite. A water-only binding layer was tested to confirm that there is no tissue freezing without an INA. Thermocouple temperature data from five tests, including two tests with only water (where no freezing occurred) and three tests using an INA (where three separate freezes occurred), were conducted to show the effects of INAs and the concept's practicality controlled freezing.
[0163] [0163] Figures 15A and 15B show the test results: with INAs, the skin was predictably inoculated steadily and frozen three different times, whereas without INAs the skin tended to merely super-cool and did not freeze both times. separate that an INA has not been used. Figure 15A shows an example of a treatment profile designed for supercooling at -2 ºC for 3 minutes and to activate freezing at -5 ºC. Figure 15B shows three tests with INAs and short-term freezing events after 200 seconds and the associated temperature rise caused by the heat of fusion, which causes the measured temperature to rise from about -1 ºC to about 0 ºC. A non-invasive surface cooling device was used to perform the tests discussed in relation to Figures 15A and 15B and the INA was a SNOMAXG / water solution.
[0164] [0164] Figure 16 shows an example of a treatment cycle temperature profile and a temperature response from the thermal sensor at the applicator's surface-fabric interface. A target temperature of a temperature-controlled surface of the applicator (shown in the dashed line) can be decreased at a predetermined rate and then kept constant at a preset value. One or more sensors can monitor the temperature at the contact interface. The output from the sensors can be used to precisely control the execution of the freeze, in order to maximize cellular changes for a therapeutic purpose, while inhibiting, limiting or minimizing adverse side effects of the treatment. It may also be desirable to control the degree of freezing of the skin down to the epidermal-dermal layer, dermal-subcutaneous layer or other specific depths. A desired degree of freezing can be obtained based on knowledge of the freezing point temperature of the tissue mass. In freezing events, tissue undergoes nucleation and ice growth (exothermic phase change). An exothermic phase change is when the system releases heat to the surroundings (for example, changing from a liquid to a solid) during the phase change. Freezing is an exothermic event, which releases heat for a very short period of time and this release of heat can be a reliable indicator of skin freezing. Thermal sensors can be used to detect the heat released by the phase change associated with a freezing event. When the fabric is in a supercooled steady state, a thermal sensor (for example, element 167 in Figure 2) at the applicator's surface-fabric contact location can detect that the temperature is stable without any sudden changes or temperature spikes substantial. When the supercooled tissue freezes, the heat released is captured by the sensor as a sudden rise in temperature. Figure 15B shows the temperature increases in tests 2, 3, and 5 corresponding to the heat released.
[0165] [0165] Figure 17 shows the set temperature of the applicator surface (shown on the dashed line) decreased at a constant rate and then maintained at a generally constant value. The temperature at the applicator-tissue interface is detected by the thermal sensor and shown on the solid line). After the target tissue is superrespired, a freezing event can be initiated. The temperature sensor can detect the temperature rise associated with the heat of fusion and the detected increase in temperature can be identified as a change in phase. Various changes in temperature can be used to monitor tissue and detect phase changes. Some methods may include overcooling and using defined freezing points to intentionally treat tissue at subzero temperatures. The temperature of the tissue can be lowered at a desired time during treatment to control the onset of freezing. Defrost cycles can be included in any treatment cycle to heat the tissue at a desired rate to protect or accentuate tissue damage.
[0166] [0166] A treatment cycle can be determined by selecting the supercooling parameters, freezing parameters and defrosting parameters. Supercooling parameters can include cooling profiles, target temperatures and / or time periods. A cooling profile can include a cooling rate for reduction to reach the supercooling temperature. The target tissue can be maintained at a target supercooling temperature below zero for the supercooling time period without phase change.
[0167] [0167] Freezing parameters can include cooling profiles to keep the tissue in the frozen state and / or time periods to keep the tissue frozen. Freezing parameters can be selected to increase or decrease thermal damage. Upon completion of the freezing time period, the cooled tissue can be heated using a defrost cycle.
[0168] [0168] The supercooling parameters, freezing parameters and / or defrosting parameters can be obtained experimentally ex vivo and / or in vivo. For example, tests on human beings in vivo have shown that the skin can be super-cooled to temperatures below zero, for example, such as - ºC, without changing the phase. When the temperature is lowered enough, the fabric will freeze. It has been experimentally established that human skin tissue will often spontaneously freeze at around -25 ° C. The temperature of spontaneous freezing depends on the characteristics of the tissue, such as tissue water content, cell structure, etc.
[0169] [0169] Figure 18 shows an exemplary treatment cycle for controlled supercooling and for controlled freezing. Temperature gradients within the tissue during cooling protocols can be estimated by modeling by bio-thermal heat transfer, experimental tests, or a combination of them. Heat transfer modeling can be used to predict temperature gradients within the tissue versus time during a treatment cycle. The tissue volume, tissue depth and other tissue information at subzero temperatures can be calculated. For example, a flat applicator can cool the skin to super-cool the target tissue between 0 ºC to- ºC, 0 ºC to -12 ºC, 0 ºC to -10 ºC, 0 “C to -8 ºC or other temperature ranges suitable for cooling the target tissue to a temperature equal to or less than about -20ºC, -15ºC, -13ºC, -12ºC, -11ºC, -10ºC, -8ºC, -6ºC, -5ºC, -4ºC, -3 "C, -2ºC, -1ºC or 0 ºC. The target tissue can reach a general steady state in which the individual's body heat compensates for continued heat withdrawal from the skin surface. The temperature-controlled surface of the applicator can be kept at an appropriate temperature less than the desired mass temperature of the target tissue during the supercooling period.To freeze the supercooled tissue, an applicator temperature can be further lowered to reduce, for example, up to a point melting / freezing medium in the skin, a freezing point of an agent on the skin or a freezing point of the skin alone.
[0170] [0170] Figures 19A to 19E are seen in cross section of a cooling applicator applied to a treatment and thermal modeling site. Figure 19A shows the treatment site at the beginning of a supercooling of the cooling cycle when the surface tissue begins to be supercooled. Figures 19B to 19E show the amount of supercooled tissue that increases over time until the total epidermis / dermis underlying a cooling plate is supercooled, while the subcutaneous layer is not supercooled. (The super-cooled skin fabric is gray and the non-super-cooled fabric is black.) The super-cooled fabric can be at a temperature within a range of about 0 "Ca-20 ºC. The model for cool skin is grounded in a flat plate applicator
[0171] [0171] When a freezing event is initiated, the total dermis and epidermis underlying the applicator may not be completely frozen. This is due to the fact that still in a steady state (for example, when the heat extraction by the applicator balances the heating from the subdermal tissue and blood flow) the tissue mass temperature is not cold enough to absorb all the heat from melting from the freezing event, in order to obtain a 100% frozen tissue. As the heat of fusion is released during the freezing event, the tissue mass temperature is raised to a level close to, for example, O ºC, such that further freezing is stopped (additional significant heat extraction absent by the applicator) and the skin is only partially frozen when the balance is established. The temperature of the cooling plate can be adjusted to compensate for the heat of fusion or other natural heating associated with the individual's body. Without limiting the invention to a theory, it is believed that the skin would need to be super-cooled to a temperature around -70 ºC for the skin to freeze completely and remain completely frozen during a freezing event, but, such a super temperature Low cooling is highly undesirable, as severe adverse events would result, particularly to the epidermis.
[0172] [0172] Figures 20A to 20F illustrate the stages of a method of freezing tissue without overcooling. In general, an applicator can be applied to a treatment site after applying a binding agent to the applicator and / or treatment site. The applicator can freeze a region of the skin, while limiting or preventing overcooling, as discussed below.
[0173] [0173] Figure 20A shows a bonding medium 209 (e.g., water, bonding gel, etc.) located along a temperature controlled surface 211 of the applicator. The bonding medium layer can be formed by applying water to the temperature-controlled surface 211, which can be cooled to a temperature below about -20 ºC, -15 ºC, -10 ºC or another suitable temperature to freeze most or all of the bonding medium 209. The temperature-controlled surface 211 can then be heated to a higher temperature (for example, -3 ºC, -2 ºC or -1 ºC) suitable for applying the applicator to the site of treatment.
[0174] [0174] Figure 20B shows a frozen top layer 215 and a liquid bottom layer 217 of the bonding medium after the applicator has been applied to the treatment site 213. The heated skin can come in contact with the liquid layer gel 217, while the frozen bonding medium layer comes into contact with the temperature controlled surface 211 and remains frozen. The temperature-controlled surface 211 can be maintained at a suitable temperature to maintain the frozen top layer 215 and the liquid bottom layer 217.
[0175] [0175] Figure 20C shows the temperature-controlled surface 211 kept low (for example, -1 ºC, -2 ºC, -3 ºC, etc.) for a predetermined period of time to cool the skin to a temperature close to its melting / freezing point. During this waiting period, a portion of the bonding medium that is frozen can slightly increase in volume, thereby increasing the thickness of layer 215. The temperature of the temperature-controlled surface can be decreased or raised to increase or decrease the thickness of the layer. frozen layer 215, while maintaining a liquid layer 217. In some procedures, the temperature-controlled surface 211 can be maintained at a temperature within a temperature range of about -2 “ºC to about -12ºC, about - 4 “C at about -10 ºC or other suitable temperature ranges. For example, the temperature-controlled surface 211 can be maintained at a temperature of about -6 ºC, -8 ºC or -10 ºC. As the temperature is reduced and / or kept low, the freezing front of the bonding medium moves towards the skin until substantially all or the entire layer of the bonding medium / gel is frozen.
[0176] [0176] Figure 20D shows the entire layer of the connection medium 209 in a frozen state. The surface of the skin that comes in contact with the bonding medium 209 can be reduced to its freezing point. Due to the intimate contact of the skin with the ice crystals in the frozen bonding gel 209, the skin will freeze progressively instead of overcooling.
[0177] [0177] Figure 20E shows a freezing front 221 and a frozen volume of tissue. The freezing front 221 can move deeper into the subject until a desired volume of tissue is frozen.
[0178] [0178] Figure 20F shows the temperature-controlled surface 211 maintained at a temperature of about -8 ºC for 2 minutes to produce the enlarged volume of frozen tissue. The frozen volume of tissue can stop the increase and become constant when the steady state is established. In facial treatments, the skin can be frozen without affecting the underlying muscles and subcutaneous tissue. In some treatments, the applicator can freeze the skin without affecting the subcutaneous tissue to limit or avoid changing the contours of the skin at the treatment site. In other treatments, the subcutaneous tissue can be frozen, for example, to inhibit, disrupt or reduce cells rich in subcutaneous lipids to bypass the treatment site. For example, the applicator can treat acne and can also contour or not contour the tissue in a single session.
[0179] [0179] The temperature of the surface controlled by temperature 211 can be increased up to 18 ºC, 20 ºC or 22 ºC at a rate of 1 ºC / s, 2 º * C / s or 3 ºC / s. This will quickly thaw the tissue to minimize or limit additional damage to the cells. For example, the skin can be cooled at a rate of 0.25 * C / s, maintained at a target temperature of -8 ° C for 2 minutes and then thawed at a rate of 2 ° C / s. Other cooling rates, target temperatures and defrost rates can be selected based on the desired level of freezing, thermal injury, etc.
[0180] [0180] Target tissue may be frozen more often than non-targeted tissue. Repetitive freeze-thaw cycles effectively damage or kill tissue by the fact that, in addition to suffering multiple cycles of deleterious solution effect and mechanical damage to the ice crystal, the integrity of the cell membrane will be compromised after the first freeze-thaw cycle , making it a less effective barrier to the spread of freezing in subsequent freeze-thaw cycles, and cells are much more susceptible to the formation of lethal intracellular ice in subsequent freeze-thaw cycles. In some embodiments, the target tissue can be frozen several times in a single treatment session, while non-targeted tissue, such as the epidermis, is frozen only once. Additionally, the target tissue can be frozen several times without over-cooling any tissue. In some procedures, the dermis is repeatedly frozen to damage or destroy the target glands without repeatedly freezing the epidermis.
[0181] [0181] Figure 21 is a graph of temperature versus time for the skin to freeze several times, according to an embodiment of the disclosed technology. After a layer of frozen bonding medium is created at -15ºC, the temperature-controlled surface of the applicator is heated to -2ºC to cool the skin using techniques discussed in relation to Figures 20A to 20F. Then, the freezing event occurs, while the skin-applicator interface is maintained at a temperature of around -2 ºC (indicated by the “”). The temperature-controlled surface is then cooled to -10 ºC and the freezing event is kept at -10 ºC for a period of time (for example, 1 minute, 2 minutes, etc.). Figure 21 shows a 1 minute waiting period. Then, the temperature of the applicator is raised to -1.5 ºC for about 35 seconds. At this temperature, the epidermis, which is in contact with the bonding medium, can remain frozen. The dermis thaws due to the internal heat of the body and, in particular, heat from the blood flow that infuses the dermis. Then, the applicator is re-cooled to -10 ºC or another suitable temperature to refreeze the dermis. The second freezing event can be maintained for a period of time, such as 1 minute, 2 minutes, etc. If desired, the dermis can be defrosted again by heating the applicator to -1.5 “C and refreezing to -10 ºC again, while maintaining the epidermis in an unfrozen frozen state. Defrost temperatures, heating rates, cooling rates, duration of freezing events and re-freezing temperatures can be selected based on the desired number of re-freezes and the severity of thermal injuries.
[0182] [0182] Because the epidermis is never defrosted using this treatment protocol, a higher rate of freezing will have a much less damaging effect on the epidermis. In the second or subsequent freeze-thaw cycles, a much higher freeze rate can be used for the transition from a defrost temperature (for example, - 1.5 ºC, -1 ºC, 0.5 ºC, etc.) to a refreezing temperature (for example, - 8 ° C, -10 ° C, -12 ° C), and this may further increase the likelihood of intracellular ice formation in the dermis, as further explained below.
[0183] [0183] The repeated freezing approach allows complete control over most or all or some variables that govern the viability of post-thaw tissue. These variables include, without limitation, the skin's freezing rate, target temperature, freezing duration and heating rate. The rate of skin freezing is not as controllable using other approaches when the skin is substantially supercooled, due to the fact that a macroscopic freezing event happens almost instantly (over a period of a few seconds) when the skin is nucleated or inoculated. with ice when the skin is in a super-cool state. Without limiting the invention to a theory, it is believed that the freezing rate is important, due to the fact that in a procedure in which the formation of ice in the extracellular space is triggered to -2 ºC, if the tissue is then slowly cooled to -10 ºC, it would have enough time for intracellular water to diffuse and enter the extracellular space along a concentration gradient. This causes the intracellular concentration of the solute to be increased and to lower the intracellular melting / freezing temperature, thereby helping to reduce the likelihood of lethal intracellular ice formation in the coldest temperatures. However, if the skin is activated to freeze at -10 ºC (with a wide supercooling window), it would not have enough time for cellular dehydration and, thus, no reduction in the intracellular freezing point. Therefore, at a colder supercooling temperature (-10 ºC), the formation of intracellular ice and associated increased cell damage are more likely. A large amount of supercooling has been shown to correlate with increased risk of intracellular ice formation, which is sometimes desirable, but in other instances, it may be undesirable, depending on which tissue is and is not targeted.
[0184] [0184] As discussed in relation to Figures 20A to 20F and 21, the treatment methods disclosed in this report can provide complete control over all freeze-thaw parameters without allowing substantial cooling of the skin that freezes larger amounts of tissue in periods faster times compared to procedures that do not use supercooling. When the associated effects of increased tissue breakdown or damage over shorter periods of time with supercooling are of particular therapeutic interest, a predetermined level of supercooling of the skin with a predetermined duration can be achieved. A skin freeze can be triggered when an applicator temperature, bonding medium and skin are still cooled, for example, in a predetermined amount (for example, less than 1 ºC, 2ºC, 3ºC, or 4 ºC). For example, the applicator can be kept at a slightly colder temperature than the freezing point of the selected bonding medium, which contains an ice nucleating substance and freezing point depressant, to ensure that a layer of the bonding medium that comes in contact with the applicator is frozen. By controlling the thickness of the bonding medium layer, the temperature gradient across the bonding medium layer can result in a slightly warmer temperature than its freezing point and thus the thawed bonding medium can remain at skin contact. In some embodiments, the bonding medium can be a hydrogel, in that hydrogels can be formulated to have precise thicknesses.
[0185] [0185] Figure 22A shows a liquid bonding medium that can serve as an insulator for ice inoculation of the skin, thereby allowing the skin to be super-cooled. To activate a skin freeze, the applicator can be cooled to a few degrees to further freeze the total volume of the bonding medium. As shown in Figure 22B, this process changes the temperature profile to the left of the freezing point of the connection medium. When the ice crystals in the bonding medium reach the skin, the supercooled skin can freeze immediately or in a short period of time.
[0186] [0186] Figure 23 shows freezing temperatures for varying concentrations of PG in the water. Figures 24A to 24F show the stages of a method for super-cooling the skin to -13 ºC, maintaining the temperature for 3 minutes and then starting a freezing event at -15 ºC using a bonding medium comprising 26% by volume of PG with a freezing temperature of about -11.5 ºC. The concentration of the PG solution can be selected based on the desired temperature to initiate a freezing event.
[0187] [0187] Referring to Figures 24A to 24F, the bonding medium can be applied to the applicator and the skin. The applicator is cooled by lowering a temperature on a temperature-controlled surface to freeze the bonding medium and then is heated to -13 ºC. Maintaining the temperature at -13 ºC will ensure that at least one layer of frozen medium remains in contact with the applicator. The bonding medium in a liquid state is applied to the skin surface. The applicator is applied to the liquid binding medium on the skin and then draining the binding medium and the skin to freeze the target tissue. By selecting the composition of the binding medium (eg concentrations of PG, glycerol, etc.), melting / freezing points can be selected, which results in desired temperatures to super-cool the skin, while providing a thin layer of the frozen bonding medium (for example, a frozen layer on the applicator surface) and a thin layer of the liquid bonding medium (for example, a liquid layer on the skin surface).
[0188] [0188] Figure 24A shows a layer of frozen connection medium 231 conducted by the applicator. A carrier in the form of a paper towel soaked with 26 vol% PG / water can be placed on the temperature-controlled surface 211. The temperature-controlled surface 211 can be pre-cooled to quickly freeze the bonding medium 231, once the paper towel is applied. In other procedures, the bonding medium is dispersed, sprayed or otherwise applied directly to the temperature-controlled surface 211.
[0189] [0189] Figure 24B shows another carrier in the form of a paper towel soaked with 26% by volume of PG / water (at room temperature) applied to the individual's skin. The layer of liquid bonding medium 233 (e.g., 26% PG / water) on the skin can be thick enough to prevent direct contact between the frozen bonding medium 231 and the subject's skin after placing the applicator. In addition, liquid connection means 233 helps to improve patient comfort when placing frozen connection means 231 under connection means 233.
[0190] [0190] Figure 24C shows the applicator after the frozen connection medium 231 has been brought into contact with the connection medium 233 at room temperature. The thickness and temperature of the liquid connection medium 233 can be selected, such that only a portion of the frozen connection medium 231 will be melted, so as to maintain a thin layer of the frozen connection medium 231 along the temperature controlled surface 211. A control system can control the applicator to maintain a surface temperature of the applicator at a target temperature, such as -13 ºC, which is below the freezing point (- 11.5ºC) of 26% PG.
[0191] [0191] The applicator can extract heat continuously or intermittently to gradually increase the volume of the frozen connection medium during a waiting period. Figure 24D shows the thick layer of the frozen connection medium
[0192] [0192] Figure 24E shows the freezing front 221 that moves to the skin surface, as the bonding medium is cooled. When the bonding medium in contact with the skin is frozen, the supercooled skin will be inoculated and frozen quickly over a period of a few seconds. For example, the applicator temperature can be reduced to a temperature of about -15 ° C, -14 ° C, or - 13 ° C, in order to freeze the volume of the total bonding medium (i.e., bonding medium 231, 233 ) and thus trigger a freezing event on the skin.
[0193] [0193] The freezing event can be triggered by a temperature a few degrees colder than the supercooling temperature. In one procedure, the skin can be cooled to a supercooling temperature of -13 ºC, while still remaining able to activate a freeze at a temperature only slightly lower, such as -15 "ºC. This “dip” temperature of 2 degrees is much lower than that required by conventional techniques that do not use a connection medium containing ice crystals that come into contact with the skin (which are in the order of about 10 degrees) and serves as an ice-inoculating agent on the skin to trigger a predictable freezing event. For any maximum final temperature supplied to the applicator, a lower dip temperature can result in a higher supercooled volume and, in the time of tissue freezing, the frozen volume will also be higher compared to a treatment with a higher dip temperature . After the tissue has been frozen for a desired length of time, the applicator can heat the tissue to inhibit or limit further breakage, injury, etc. Heating and cooling cycles can be repeated several times in any order to thermally affect the target tissue.
[0194] [0194] Figure 24F shows the total volume of the bonding medium at the applicator-skin and underlying tissue interface in a frozen state. The applicator can be cooled or heated to increase or decrease the volume of frozen tissue.
[0195] [0195] Figure 25 is a graph of temperature versus time to super-cool and freeze the tissue. The skin can be cooled to -20 “C and, afterwards, a freezing is initiated to -25 ºC through the selection of a gel of PG 37% in volume that presents a freezing point of -19 ºC. After the skin freezes, the applicator can quickly heat the epidermis and keep it at a temperature high enough to keep the epidermis thawed. For example, the epidermis can be maintained at a temperature of 1.5 ºC or 2 "ºC, This maximizes the underlying dermal freezing exposure to increase dermal damage and limits or minimizes epidermal freezing exposure to reduce epidermal damage. Consequently , heating can be used to minimize, limit or substantially prevent thermal injuries that lead to hypopigmentation (skin lightening), hyperpigmentation (skin darkening), and / or other undesirable effects.
[0196] [0196] The skin can be cooled to a temperature above the freezing point of the bonding medium, in order to trigger a freezing event. When the tissue is super-cooled to -13 ° C with a binding medium that has a slightly warmer freezing temperature (for example, a freezing temperature of -11.5 ° C), the skin will not be inoculated at significantly higher temperatures hotter than -13 ºC. In some procedures, it may be desirable to initiate a skin freeze at the highest temperatures to minimize or limit damage to the epidermal tissue during the freezing event. To meet this need, a higher melting / freezing point can be obtained by diluting the binding medium to a lower concentration of a freezing point depressor. The melting / freezing temperature of the connection medium can be raised to an amount sufficient to activate freezing at a temperature well above the supercooling temperature. Briefly, supercooling at time t1 can be accomplished by choosing a bonding medium that has a lower freezing temperature than that at time t1. After supercooling, the temperature of the applicator increases to a higher temperature at time t2. A volume of water can be released in the connection medium to dilute it, ensuring that the diluted connection medium has a freezing point that is warmer than the temperature in t2. This will trigger a freeze in the diluted bonding medium to quickly trigger a skin freeze. A relatively hot command freeze in the supercooled diluted connection medium can be triggered using, for example, energy (eg, ultrasound), low temperature probes (eg, an extremely small cold finger probe) and / or a INA.
[0197] [0197] Figure 26 is a graph of temperature versus time for a procedure that cycles twice to supercool the tissue and then triggers a freeze. In general, the fabric can be cyclized between two temperatures (for example, -10 ºC and -20 ºC) to super-cool the target fabric. A freezing event is triggered, albeit at the highest temperature (for example, -10 ºC) or another suitable temperature. The freezing point of the bonding medium can be selected to ensure that the bonding medium does not freeze during a supercooling cycle. In some embodiments, the bonding medium can comprise at least 39% by volume of PG which has a freezing point of -20.5 ° C, so that the bonding medium does not freeze during a supercooling cycle at -20 ºC, to prevent premature skin frostbite.
[0198] [0198] At the end of the supercooling cycle, the temperature of the applicator can be raised to a higher temperature (for example, -10 ºC) suitable for ice inoculation. A substance, such as cold water at 1 ºC, can be infused through the applicator to dilute the bonding medium. The temperature and flow rate of the water can be selected, such that the diluted connection medium has a freezing point warmer than a predetermined value. For example, the diluted binding medium may have a freezing point greater than about - ºC for freezing inoculation at about - 10 ºC.
[0199] [0199] Figures 27A to 27C show an applicator and a connection means. Referring now to Figure 27A, the liquid connection means is located along a temperature controlled surface 243 of the applicator. Conduits, plates, and / or fluidic components of the applicator may have one or more thermally insulating coatings, layers, etc., to prevent unwanted freezing during infusion, due to the fact that the cold applicator plate may be at relatively low temperatures, for example For example, less than -5 ºC, -10 ºC, or -12ºC. In addition or alternatively, the applicator may include thermal elements (for example, heating elements) to heat the dilution liquid, cooling fluid (for example, cooling fluid released through the applicator) and other working fluids.
[0200] [0200] Figure 27B shows the applicator and diluted connection medium. A dilution liquid passes through the conduit to dilute the connection medium. The amount of dilution liquid can be selected to obtain the desired concentration of the binding medium. The bonding medium can be frozen, as the applicator is cooled and the bonding medium temperature stabilized at a predetermined or target temperature, such as -8 ºC, -10 ºC or -12 ºC. An INA can be incorporated in the binding medium or in the infused liquid to promote freezing.
[0202] [0202] One or more INAs can be incorporated into the connection medium before, during, and / or after application of the connection medium to the patient. Dilution of the binding medium to a point where its diluted melting temperature is above its actual temperature will cause the diluted binding medium to freeze, which in turn will cause the skin to freeze.
[0203] [0203] Figures 28 to 31 show treatments that may involve overcooling. Supercooling cyclization can cover a wide temperature range, with the desired cooler supercooling temperature often being too cold for use as a freezing temperature, as it would cause excess damage to the epidermis. The bonding medium that remains in a liquid state during the supercooling cycle will often not allow ice inoculation, due to the fact that the supercooling temperature range is above the freezing point of the bonding medium. However, dilution of the bonding medium raises the freezing point of the bonding medium and allows freezing inoculation of the skin at warmer applicator and epidermal temperatures. Advantageously, epidermal temperatures can be hot enough to inhibit, limit or substantially prevent hypopigmentation, hyperpigmentation or other undesirable effects.
[0204] [0204] The dilution also allows for supercooling cyclization at relatively low temperatures (for example, -10 ºC, -15 ºC, -20 ºC) and the fabric is frozen at relatively high temperatures (for example, -10 ºC, -5 ºC, -4 ºC, - 3 ºC or -2ºC) to accentuate or maximize the damage to the target tissue and limit or minimize the damage to the non-targeted tissue. The target tissue may be tissue in the dermis and / or lower skin layers and the non-targeted tissue may be the epidermis or superficial tissue. Although accentuated or maximized damage can be achieved by multiple consecutive treatments with different concentrations of the binding medium, a single treatment can provide desired damage to reduce the treatment period and costs.
[0205] [0205] Figure 28 shows an applicator 261, medium 262 with an INA and a bonding layer 263. An INA can be placed in direct contact with the skin surface to facilitate a predictable freezing of the skin. In some procedures, INA is placed in direct contact with a cooling surface of the applicator. For example, medium 262 can include one or more INAs (for example, SNOMAXG / water mixture). Bonding layer 263 may include cellulose-derived layer and solution, such as water, and may be in direct contact with a treatment site. In some embodiments, INA can be applied using a thin layer (for example, paper) soaked with an INA binding agent, mixed with a gel-like substance, released via a release instrument (for example, syringe) or sprayed onto the surface. A person skilled in the art can replace appropriate bonding layer materials, chemicals, conditions and release systems with other materials, chemicals, conditions, release systems, etc.
[0206] [0206] Figure 29 shows a temperature versus time graph of a temperature profile to trigger ice nucleation through INAs. The tissue can be super-cooled to a temperature above the INA activation temperature. At the temperature of the INA, it is then lowered to its activation temperature to initiate the ice nucleation to produce a partial or total freezing event (indicated by “**) that spreads through and through the skin. The cycle can be completed by maintaining an applicator temperature to allow ice crystals to grow at the treatment site. After completing the cycle, the applicator temperature can be gradually raised to a desired defrost rate to warm the skin.
[0207] [0207] Figure 30 shows an applicator and an INA applied to a treatment site. INA can be released in the connection medium 271, on a surface of the individual's skin and / or on the skin to predictably trigger the nucleation of ice. The applicator may include fluids soaked to release, in a controllable manner, the INA to the interface between the applicator and the individual's skin. The infused INA can be at a specific treatment temperature or within a predetermined temperature range to inhibit ice nucleation, for example, within the binding medium at the interface or in the tissue itself. In other embodiments, INA is sprayed or otherwise released to the bonding medium or the individual's skin. In some procedures, the applicator cools the connection medium and the individual's skin. The applicator can be removed from the connection medium and the INA can be sprayed onto the cooled connection medium. After spraying the INA, the applicator can be reapplied to the treatment site to continue cooling the INA, bonding medium and tissue. Needles, rollers and other delivery instruments can be used to apply one or more INAs. Other techniques can be used to deliver INA infusion through the bonding medium, as well as over the bonding medium or into the same and / or tissue of the individual, etc.
[0208] [0208] Figure 31 shows a graph of temperature versus time to release an INA for nucleation. INA can be released to a treatment site, which can be at or below the INA activation temperature (indicated by a dashed line), at a specific time to start nucleation. As indicated by the arrow, the INA can be infused to initiate the freezing event. Consequently, the INA activation temperature can be selected to activate a controlled freezing event.
[0209] [0209] Various techniques can be used to protect non-targeted tissue, while affecting volumes of target tissue and / or specific structures, for example, within the epidermis, dermis, subcutaneous tissue, etc. Target structures may include, without limitation, hair (for example, hair follicles), skin appendages (for example, sweat glands, sebaceous glands, etc.), nerves, and / or dermal components, such as collagen, elastin or blood microvascularity . Target structures can be affected, while inhibiting, preventing or substantially eliminating unwanted side effects. Because appendages and other cells / structures can have different lethal temperatures, a multi-stage temperature profile can be used to target specific tissue and / or structures. In addition, preserving non-targeted tissue, such as the epidermis, from injury or undue damage, can be beneficial in preventing, for example, changes in pigment and / or scarring, as well as promoting healing. Freezing the epidermis at a temperature different from that in relation to the underlying dermis can be achieved using the characteristic activation temperature of INA and, intentionally, supercooling the dermis at lower temperatures before applying INA. In some procedures, the epidermis may be at a higher temperature to inhibit, limit or substantially prevent permanent thermal damage to the epidermis.
[0210] [0210] Some embodiments of the technology include methods of using linked polymers containing water, a crosslinked polymer containing water, optionally an INA, and / or, optionally, a freezing point depressant for controlled freezing of skin tissue . According to a preferred embodiment, the polymer can be a hydrogel for use for controlled freezing of skin tissue. The hydrogel can be an effective initiator of a freezing event. As the hydrogel is frozen, it can provide initial seeds or crystal sites to inoculate and freeze the tissue, thereby catalyzing a predictable controlled freeze at specific skin temperatures.
[0211] [0211] Figures 32A to 32D show IR imaging of tissue freeze inoculation using a supercooled tissue hydrogel. Figure 32A shows the skin tissue (dashed area) over two hydrogels (left and left halves) and a cooling plate overlying the hydrogels. Figure 32B shows the freezing in a lower left portion. Figure 32C shows the spread of freezing over most of the left hydrogel demonstrating ice inoculation. Figure 32D shows the spread of freezing through the two hydrogels.
[0212] [0212] R & referring now to Figure 32A, the skin tissue in the area indicated by the dashed lines comes into contact with the two half sheets of hydrogel. A hydrogel sheet without PG or another freezing point depressant is located to the left of the vertical line and a hydrogel sheet with about 50% by volume of PG is located to the right of the vertical line. A rectangular cooling plate is located on the hydrogel sheets. The skin surface is in direct contact with the two hydrogels, which in turn are in direct contact with the cooling plate. In this way, hydrogels can be kept firmly between the patient and the applicator.
[0213] [0213] The images were generated after a few minutes of supercooling the tissue. The temperature of the supercooled fabric has been lowered to a trigger temperature to activate a freeze (illustrated in a lighter color) in the hydroge! without PG, shown on the left side of Figure 32B. Figures 32B and 32C show the freeze propagation caused by using only one hydrogel. The right half of Figure 32B shows a section of the hydrogel PG 50% by volume and adjacent to the skin that has not been frozen. Figure 32C shows the freezing that spreads through the hydrogel, through the fabric and towards the hydrogel with the temperature depressor. This shows that varying concentrations of PG or other freezing point depressants can be included in the hydrogel to reduce the melting / freezing temperature of the hydrogel to a desired value less than 0 ° C. For water-based hydrogels without PG or another freezing point depressant, freezing at temperatures close to 0 ºC is inconsistent and unpredictable for controlled heterogeneous nucleation. However, hydrogels used in combination with an INA provide the ability for controlled freezing at sub-zero temperatures, including temperatures close to 0 ° C (or lower, when used in combination with a freezing point depressor) in a more predictable manner. .
[0214] [0214] Figures 33A to 33D are IR images showing the inoculation of tissue freezing using combined materials and the effect over time of placing an INA (for example, SNOMAXO or another suitable INA derived from the bacterium Pseudomonas Syringae ) in a super-cooled hydrogel to activate a freeze. Figure 33A shows the placement of an INA grain in a supercooled hydrogel. Figure 33B shows an INA that inoculates the hydrogen and a start of freezing to propagate around the INA. Figure 33C shows the freezing that propagates through the hydrogel to the tissue demonstrating the ice inoculation of the skin. Figure 33D shows the spread of the freeze completed. Combined, Figures 33A to 33D show the feasibility of using an INA as a seed to inoculate a controlled freeze into the skin tissue. Details of Figures 33A to 33D are discussed below.
[0215] [0215] Figure 33A shows the hydrogen! thawed and the INA being placed close to the edge of a cooling plate (indicated by the dashed lines), while the cooling plate cools the fabric. After the initial placement of the INA, there is no substantial freezing through tissue that faces the cooling plate. INA can initiate the freezing process by serving as an ice core and can raise the predictable freezing temperature of water to around -3 ºC. Although the melting / freezing temperature of water is 0 ºC, water tends to over-cool, so its freezing temperature is often much lower than 0 ºC or -3 ºC when an INA has not been used. INA can initiate the freezing process by serving as an ice core and can raise the water's expected freezing temperature to about -3 ºC. INA can be selected to raise the water's predictable freezing temperature to other desired temperatures. When selecting an INA, a person skilled in the art can choose appropriate agents (for example, organic or inorganic agents) for use at specific desired temperatures and to be released at specific times for a specific treatment purpose. Different techniques can be used to incorporate INA into hydrogels. For example, an INA can be placed between layers of a hydrogel, so that it is completely contained and encapsulated in it, so as to never come into contact with the skin or tissue. An encapsulant can be broken, destroyed or otherwise altered to release the INA. In some embodiments, an applicator cooling plate can release the INA to the hydrogel via one or more needles, exit ports or other release means. INA can be applied at a single location or multiple locations or it can be mixed into the hydrogel compound. Additionally, the INA can be inside a micrometric wall made of soluble film, hard or soft, in order to avoid direct contact with the skin and present degradation controlled by passive or active means. Additionally, INA can be injected or released into or over the skin.
[0216] [0216] Figure 33B shows the tissue after the freeze was propagated away from the INA. The frozen material is illustrated by a lighter color against a darker background color, which illustrates the unfrozen fabric. Figure 33C shows the freezing that spreads through the hydrogel that faces the cooling plate. Figure 33D shows the spread of the freeze completed to freeze all skin that comes in direct contact with the hydrogel.
[0217] [0217] Figures 34A and 34B are seen in cross section of the cooling applicator applied to a treatment site. Referring now to Figure 34A, only one hydrogel is located between the applicator and the individual's skin. The cooling applicator can be placed on a protective layer in the form of a thin covering layer. The protective layer can be a coating or other component to prevent cross contamination or dirt by the hydrogel. As a temperature-controlled surface of the cooling applicator is cooled, it, in turn, resizes the skin by removing heat from the skin through the hydrogel and thin covering layer.
[0218] [0218] Figure 34B shows a hydrogel and an INA located between the applicator and the individual's skin. INA can be a liquid, gel, cream, sheet or preformed layer located along a hydrogel surface. When the applicator is applied to the hydrogel, the INA can be located at the hydrogel-applicator interface. The hydrogel and / or hydrogel / INA / freezing point depressant can be selected to melt / freeze at a specific temperature designated in its formulation.
[0219] [0219] The hydrogel of Figures 34A and 34B can be formulated to present a water-monomer-crosslinker constituent ratio and / or other chemicals, such as one or more INAs, freezing point depressants, etc., to obtain a specific freezing point (or near temperature range) that may or may not include overcooling the skin. An INA can have a known activation temperature (natural freezing point) and can be in solid form (ie, powder) or mixed solution with a desired concentration to create a predictable and compatible skin freeze. With such thermally bonded materials or compounds, a desired treatment temperature protocol or algorithm can be implemented to include supercooling, if desired, or non-supercooling if desired, and include predictable, controlled freezing at preferred temperatures and times. .
[0220] [0220] Figure 35 is a graph of temperature versus time to activate a freezing agent, according to the embodiments of the disclosed technology. The temperature profile, protocol and / or algorithm to trigger one more freezing allows the super-cooling of the fabric at temperatures allowed by the hydrogel or hydrogel / INA. The temperature of the target tissue can be maintained in the supercooling temperature range during a supercooling period. The temperature of the hydrogel is then decreased to a freezing temperature to cause the nucleation of ice from the hydrogel or materials. When it undergoes a freezing event, the underlying targeted tissue may be warmer or slightly warmer than the hydrogel. In some procedures, both the hydrogel and the target tissue are super-cooled, while the surface temperature controlled by the applicator temperature is generally kept constant. In other procedures, the target tissue can be partially frozen, while hydrogenating! it's super-cooled. Freezing of the subsequent hydrogel can cause additional freezing of the target tissue until the desired level of freezing in the target tissue is achieved. Another means of connection can be used with the temperature profile shown in Figure 35.
[0221] [0221] Figure 36 shows an applicator positioned to produce controlled freezing in a bonding medium that releases the agent on a surface of the bonding medium, in the bonding medium or in another suitable location to initiate a freezing event in the medium binding. The applicator may include one or more needles (for example, a microneedle arrangement), fluid components (for example, ducts, pumps, valves), reservoirs (for example, reservoirs containing the connection medium) or the like. In some embodiments, the agent is released through an outlet port at the bottom of an applicator cooling plate.
[0222] [0222] Figure 37 shows a cooling applicator with an external nucleating element configured to initiate an external freezing event to an applicator-hydrogel interface. The outer nucleating element can include one or more energy-emitting elements capable of initiating a freezing event. In some embodiments, an external nucleating element releases energy (for example, ultrasound energy, RF energy, etc.) to a region of the edge of the bonding agent to produce a freeze, which propagates through the bonding agent , including a region of the bonding agent directly between the cooling applicator and the tissue site. In other embodiments, a separate nucleation instrument can initiate nucleation and can be a probe with a nucleation element.
[0223] [0223] Figure 38 is a cross-sectional view of a cooling applicator that provides energy-based activation. Binding medium, hydrogels, hydrogel / INA mixtures or other materials to generate controlled freezing can be located between the cooling applicator and the treatment site. In some embodiments, an encapsulated ice core may be part of or located within a layer of the bonding medium. The energy can break the encapsulation to release the ice core at a desired time. This can cause a freezing event that spreads through the bonding medium and the surface of the skin. Once the ice crystals come into contact with the skin's surface, freezing can spread through the skin. The actuation energy can be, without limitation, mechanical energy (for example, vibrations, ultrasound, etc.), electrical energy and / or electromagnetic radiation (for example, light).
[0224] [0224] Figure 39 shows a temperature profile to super-cool the skin before the start of a freezing event. Freezing activation can be initiated in a controllable manner to control the onset of freezing, while a temperature-controlled surface of the applicator and / or the target tissue is maintained at a constant temperature at steady state. It may be desirable to super-cool and freeze skin and subcutaneous tissue for a specific time and at a specific temperature (or temperature range) to allow controlled super-cooling of a volume of tissue that is large enough to cause a freeze. expanded after tissue inoculation.
[0225] [0225] It can be advantageous to cool the tissue and / or affect specific structures within the dermis and subcutaneous tissue, such as hair, skin appendages, nerves, dermal components such as collagen, elastin or blood microvascularity, but at the same time time, preserve the epidermis. Since appendages and other cells / structures may have a different lethal or injury temperature, a multi-stage temperature profile may be required. In addition, the preservation of the epidermis can be beneficial in preventing changes in skin pigment and skin scarring. Additionally, preserving the epidermis can result in more favorable healing and fewer side effects. Freezing of the epidermis at a different temperature than the underlying dermis is possible through the use of the previously mentioned techniques. Specifically, the mass skin tissue can be super-cooled at low temperatures and then the temperature of the epidermis can be raised, for example, before the release of INA or activation of the nucleation. Epidermal sensitivity is reduced when the epidermis is frozen at a temperature around -5 “C or higher. If freezing below such temperatures occurs, the melanocytes and / or their production of melanin in the epidermis can be unduly altered causing pigmentation. Thus, according to some embodiments of the disclosed technology, temperature protocols can be used, which cause the epidermis to freeze at -5 ºC or more.
[0226] [0226] Figure 40 is a graph of temperature versus time in which, after super-cooling and before freezing, an applicator temperature is adjusted to heat the epidermis, such that the applicator and / or epidermis is at a higher (for example, -6 “C, -5“ ºC, -4 “ºC, etc.) than the supercooling temperature. After heating the epidermis, a freezing event is generated. For example, the temperature profile shows the activation or release of INAs at a warmer activation temperature suitable to protect tissue, such as the epidermal or upper layers of the skin. The heating rate, activation temperature and time period for the activation temperature can be selected based on the desired tissue protection and affects the target tissue. The activation timeout period can be increased or decreased to increase or decrease the protection of the epidermis.
[0227] [0227] Figure 41 shows a graph of temperature versus time for a cooling protocol and three cross-sectional views of an applicator and skin tissue temperature distributions. As shown in the graph, a temperature-controlled surface of an applicator can be kept at -10 ºC for 5 minutes (for super-cooling) and then increased at a desired rate (for example, 2 “C / s, 2, 5 * C / s, etc.). A subsequent freezing event is shown by a temperature rise after about 400 seconds. Computational modeling (COMSOL) was used to generate the results. The model was a three-dimensional biocalor transfer model for skin treatment using a cooling applicator and was used to generate the graphs discussed in this report.
[0228] [0228] The images show temperature distributions in the fabric related to the step change of the temperature profile of the surface controlled by temperature from -10 ºC to 4 ºC. An isotherm was added (T = 0 ºC) at time = 380 seconds, time = 385 seconds and time = 400 seconds. The isotherm at T = 0 ºC is the limit at which the phase change to ice crystallization (freezing of the skin) can extend further (that is, the deeper tissue is warmer than O ºC and will not freeze if the nucleation occur, since the fluid in the skin at this depth is above its freezing temperature).
[0229] [0229] Figure 42 shows a temperature profile in the epidermis / dermis (log scale) at time = 380 seconds for an applicator at -10 ºC showing the temperature of T = 0 ºC in 2 mm of depth on the skin. The depth of the isotherm T = 0 ºC is about 2 mm. Consequently, freezing can extend up to about 2 mm in the skin at this point in time, if nucleation occurs at this point in time. The temperature gradient can also be observed, showing a gradient of T = -8 ºC on the skin surface at 0 ºC in a depth of 2 mm.
[0230] [0230] Figure 43 shows a temperature profile in the epidermis / dermis (log scale) showing the temperature, as the applicator goes from -10 ºC to 4 “C at 2.5ºC / s, with lines plotted for time = 380 seconds, time = 385 seconds and time = 400 seconds. The temperature profiles across the skin depth at time = 380, time = 385 and time = 400 seconds, in other words, are before and after the applicator temperature has changed from -10 ºC to -4 ºC. The temperature gradients in the epidermis are above -5 ºC in time = 400 seconds, so that a controlled freeze can be triggered. The epidermis will freeze at a more ideal temperature (> -5 ºC), but with a higher degree of freezing of the skin to a depth of approximately 2 mm.
[0231] [0231] Figure 44 shows a method for creating a tissue freeze using a device positioned within an individual. The device can be a needle that injects a substance at a specific location. An inner surface of the needle can be coated to facilitate the release of the substance. The outer surface of the needle can be coated with an agent or substance to treat tissue, target structures, etc. Other devices can be inserted into the individual to produce freezing events.
[0232] [0232] The injected substance may include, without limitation, hydrogel, hydrogel // INA, partially frozen water, ice cores, combinations of the same or similar. An advantage of injecting an ice crystal or substance (for example, an INA) that will create an ice crystal is that a freezing event will occur in a specific region. The freezing event can be initiated in the dermis or another layer of inferior tissue and not in the epidermis. This limits or minimizes damage to the epidermis. Additionally, the epidermis can be heated to a temperature close to or above the melting / freezing temperature. In some embodiments, a freezing event can be initiated in the tissue below the dermis, such as in the subcutaneous tissue. After producing the freezing event, the same needle or different needle can inject additional substances into the tissue. Additional substances may include cryoprotective agents, liquids (for example, hot water or saline) or other substances that can effect therapy.
[0233] [0233] Multiple injections can be manufactured to create multiple freezing events. A first substance can be released into the tissue to create a first freezing event and a second substance can be released into another tissue to produce a second freezing event. For example, the first substance can be adapted to freeze completely in a first target region and the second substance can be adapted to produce a partial freeze event in a second target region spaced beyond the first target region. Different levels of freezing and thermal injury severity can be obtained, even though the first and second target regions are at the same temperature. In other treatments, the first and second target regions can be at different temperatures and the first and second substances can be selected based on those temperatures. In this way, different types of freezing events can be generated at different locations.
[0234] [0234] With continued reference to Figure 44, substances with thermally bonding materials or nucleators that have freezing points at higher temperatures than a fluid freezing point in the skin tissue can be used synergistically with the treatment cycle for produce an intentional freezing of the material and, sequentially, trigger the spread of the freeze on the skin even at higher temperatures. Unbleached tissue can be heated by the applicator (for example, via conduction), injected hot liquid and / or energy (for example, RF energy). Heating cycles can be performed to heat the epidermis immediately after the production of a freezing event that injures target structures, such as sebaceous glands. This can help prevent visible changes (eg, hyperpigmentation, hypopigmentation, etc.) in the epidermis. The injectable substance can be released into and around the sebaceous glands and the freezing event can then be triggered by a dip in temperature, dilution, energy, etc.
[0235] [0235] Figure 45 is a flow diagram illustrating a 350 method, according to an aspect of the present technology. In block 352, the connection means can be applied to the individual. In block 354, an applicator cools the fabric to a temperature suitable for a freezing event. For example, a skin surface can be reduced to a first temperature between about -2 ºC and -40 "ºC to super-cool the superficial tissue. In some embodiments, the first temperature can be a temperature between -5 "C and -15ºC, - ºC and -20 ºC, -10ºC and -30" C, or another suitable temperature range below a freezing temperature.
[0236] [0236] In block 356, the individual's skin surface is heated in an amount sufficient to raise the surface of the skin temperature from the first temperature to a second temperature, which can be a non-supercooled temperature, while the region target remains in the super-cooled state. For example, the epidermis can be heated to a temperature greater than about 0 ° C, greater than about 5 ° C, greater than about 10 ° C, greater than about 20 ° C, greater than about 30 ° C or greater than about 35 ºC. There may be a temperature gradient between the target tissue and the skin surface, such that the majority of the untargeted surface tissue is at an uncooled temperature.
[0237] [0237] In block 356, the device in Figure 44 can cause nucleation in the target region to cause at least some fluid and cells in the supercooled tissue to be at least partially or totally frozen. The heated cells that reside on the surface of the individual's skin are not frozen. As such, the cells on the skin's surface can be protected without the use of a chemical cryoprotectant. However, chemical cryoprotectants can be used to inhibit or limit hyperpigmentation or hypopigmentation. In some embodiments, a probe may be inserted into the subject to cause the supercooled tissue to nucleate through mechanical disturbance, ultrasound or another suitable nucleation initiator. The freezing event can cause at least partial crystallization of a plurality of gland cells in the target region. The device illustrated in Figure 44 is positioned to produce a freezing event that causes cell crystallization in the sebaceous glands.
[0238] [0238] In block 358 of Figure 45, the supercooled tissue can be kept in the frozen state for a predetermined period of time greater than, for example, about 10 seconds, 12 seconds, 15 seconds, 20 seconds or another length of time adequate enough to treat acne, improve hair quality, treat hyperhidrosis, etc. In certain embodiments, the skin is cooled / heated to maintain the target tissue in at least a partial or fully frozen state for the predetermined time of more than about 10 seconds, 12 seconds, 15 seconds or 20 seconds.
[0239] [0239] Heat can be applied to heat the epidermal cells to a temperature above freezing, while the glands in the dermis are at or near supercooled temperature. The step of applying heat may include heating a portion of the majority of the epidermal layer under the treatment device to a temperature above about 0 ºC, about 5 ºC, about 10 ºC, about ºC, about 25 ºC or about 32 ºC. Heating can be carried out before, during or after the freezing event. The individual's body heat, warm blood or other mechanisms can naturally heat the epidermis to prevent or limit the damage from freezing to such cells.
[0240] [0240] If the deeper tissue is not targeted, that tissue can be heated using focused electrical currents, such as focused ultrasound or RF energy. Applicators may include one or more electrodes, transducers or other energy-emitting elements. For example, an applicator can cool the skin surface shown in Figure 44 to super-cool the tissue, including the dermis. The applicator can release RF energy or focused electrical currents to the underlying non-targeted subcutaneous tissue to locate the supercooling in the dermal tissue. A freezing event is then initiated to the supercooled dermal tissue.
[0241] [0241] The methods disclosed in this report are able to super-cool the tissue without starting nucleation by cooling the tissue at a relatively slow rate (for example, the temperature profile can cause a slow cooling of the tissue in the target region) . For example, the cooling rate may be equal, less than or faster than about 0.5 ºC, 1 ºC, 2 ºC, 3 ºC, 4ºC, 5 ”" C, 6 ºC, 7 ºC, 8ºC, 9 ºC or 10 ºC per minute A preferred cooling rate is about 2 ºC, 4 "C or 6 ºC per minute. In addition or alternatively, a treatment device can apply a generally constant pressure during cooling to the temperature range super-cooled to avoid pressure changes that would cause inadvertent nucleation. In an additional embodiment, the target tissue can be cooled, while the patient is still maintained (for example, without movement of the treatment site) to prevent mechanical tearing of the tissue supercooled and causing, unintentionally, crystallization.
[0242] [0242] Figure 46 is a schematic block diagram that illustrates subcomponents of a computing device in the form of a controller suitable for system 100 in Figure 3, according to an embodiment of the disclosure. Computing device 700 may include a processor 701, memory 702 (for example, SRAM, DRAM, instantaneous or other memory devices), input / output devices 703 and / or subsystems and other components
[0243] [0243] As shown in Figure 46, processor 701 can include a plurality of functional modules 706, such as software modules, for execution by processor 701. The various implementations of source code (ie, in a conventional programming language ) can be stored on a computer-readable storage medium or can be incorporated into a transmission medium on a carrier wave. The processor modules 706 may include an input module 708, a database module 710, a process module 712, an output module 714 and, optionally, a display module 716.
[0244] [0244] In operation, input module 708 accepts input from operator 719 via one or more input / output devices described above with respect to Figure 3 and communicates accepted information or selections to other components for further processing. The 710 database module organizes records, including patient records, treatment data sets, treatment profiles and operation records and other operator activities and facilitates the storage and retrieval of these records to and from a storage device (for example, internal memory 702, an external database, etc.). Any type of database organization can be used, including a simple file system, hierarchical database, relational database, distributed database, etc.
[0245] [0245] In the illustrated example, process module 712 can generate control variables based on readings from sensor 718 from sensors (for example, sensor 167 in Figure 2) and / or other data sources, and the output 714 can communicate the operator's input to external computing devices and control variables to controller 114 (Figure 3). Output signals 720 can be used to control one or more applicators applied to the patient. In some embodiments, the output signals 720 can be commands for controlling the applicators. The display module 816 can be configured to convert and transmit processing parameters, sensor readings 818, output signals 720, input data, treatment profiles and prescribed operating parameters via one or more connected display devices, such as a display screen, printer, speaker system, etc. A suitable display module 716 may include a video driver that allows controller 114 to display readings from sensor 718 or other states of treatment progression.
[0246] [0246] In various embodiments, processor 701 can be a standard central processing unit or a secure processor. Secure processors can be special-purpose processors (for example, reduced instruction set processor) that can withstand sophisticated attacks that attempt to extract data or programming logic. Secure processors may not have debug pins that allow external debugging to monitor secure processor execution or logs. In other embodiments, the system can use a field programmable door arrangement, a smart card or other secure devices.
[0247] [0247] Memory 702 can be standard memory, secure memory or a combination of the two types of memory. Through the use of a secure processor and / or secure memory, the system can ensure that data and instructions are highly secure and confidential operations, such as decryption, are protected from observation. Memory 702 may contain executable instructions for cooling the individual's skin surface to a temperature and controlling treatment devices in response, for example, to supercooling detection, a partial or complete freezing event, applicator movement (eg , applicator removed) or the like. In some embodiments, memory 702 may include nucleation instructions which, when executed, cause the controller to command an applicator to change the composition of a bonding medium, inject the nucleation primer, etc. Additionally or alternatively, memory 702 may include defrost instructions that, when executed, cause the controller to control the applicator to heat the tissue. In some embodiments, the stored instructions can be executed to control the applicators to perform the methods disclosed in this report without causing undesired effects, such as significantly lightening or darkening the skin in one or more days after the freezing event has ended. The instructions can be modified based on the patient's information and treatments that will be performed. Other instructions and algorithms (including feedback control algorithms) can be stored and executed to carry out the methods disclosed in this report.
[0248] [0248] In some embodiments, controller 114 is programmed to cause the applicator to create or maintain at least one ice crystal and induce a freezing event. Memory 702, for example, may contain instructions that, when executed, cause the applicator to operate to cause one or more ice crystals to come into contact with the individual's skin, in order to induce a freezing event. In one embodiment, memory 702 contains instructions that, when executed by the 701 processor, cause the applicator to be at an appropriate temperature to super-cool the target tissue and freeze the skin without lowering a temperature temperature controlled surface below at a particular level. Instructions can be used to control or communicate with applicator components. These components may include, without limitation, one or more thermoelectric elements, fluid elements, energy emitting elements and sensors. Thermoelectric elements can be Peltier devices capable of selectively cooling or heating the fabric. The fluid elements can be channels, ducts or other cooling fluid elements through which the fluid can flow to heat and / or cool the tissue. The energy-emitting elements may be radio frequency electrodes, ultrasound electrodes or other elements capable of releasing energy to control freezing, hot tissue or the like.
[0249] [0249] Suitable computing media and other computing devices and user interfaces are described in commonly issued U.S. Patent No.
[0250] [0250] Treatment systems, applicators and treatment methods can be used to treat acne, hyperhidrosis, wrinkles, subcutaneous tissue, structures (eg, structures in the epidermis, dermis, subcutaneous fat, muscle, nerve tissue, etc. .), and so on. Methods for cooling tissue and related devices and systems, in accordance with the embodiments of the present invention, may at least partially cover one or more problems associated with conventional technologies, as discussed above, and / or other problems whether or not set out in this report. Methods to affect the skin of a human body include placing a cooler applicator on the individual and removing heat from a treatment site to affect the appearance of the individual's skin, whether or not it causes a noticeable reduction in subcutaneous fat tissue. . Acne along the face can be treated without causing any reduction in subcutaneous adipose tissue where acne along the back can be treated, while reducing subcutaneous adipose tissue. Systems, components and techniques for reducing subcutaneous adipose tissue are disclosed in US Patent No. 7,367,341 entitled "METHODS AND DEVICES FOR SELECTIVE DISRUPTION OF FATTY TISSUE BY CONTROLLED COOLING" granted to Anderson et al., US Patent Publication No. US 2005 / 0251120 titled
[0251] [0251] It will be assessed that some well-known structures or functions may not be shown or described in detail, in order to avoid unnecessarily obscuring the relevant description of the various embodiments. Although some embodiments may be in the scope of the technology, they may not be described in detail with respect to the figures. In addition, features or structures of the various embodiments can be combined in any suitable manner. The technology disclosed in this report can be used to improve the skin and skin conditions and to perform the procedures disclosed in U.S. Provisional Order Serial No. 61 / 943.250, filed on 21
[0252] [0252] Unless the context clearly requires otherwise, throughout the description, the words "understand", "understanding", and the like must be interpreted in an inclusive sense as opposed to an exclusive or exhaustive sense; that is, in a sense of "including, but not limited to". Words using the singular or plural number also include the plural or singular number, respectively. The use of the word "or" in reference to a list of two or more items covers all of the following interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list. In such instances where a convention analogous to “at least one between A, Be C, etc.”. in general, such a construction is intended in the sense of the convention (for example, “a system that has at least one between A, B and C” would include, but would not be limited to, systems that feature A alone, B alone, C alone, A and B together, A and C together, B and C together and / or A, B and C together, etc.). In such instances where a convention analogous to “at least one between A, B or C, etc.”. in general, such a construction is intended in the sense of the convention (for example, “a system that has at least one between A, B or C” would include, but would not be limited to, systems that feature A alone, B alone, C alone, A and B together, A and C together,
[0253] [0253] Any patents, orders and other references, including those that can be listed in attached filing documents, are incorporated into this report as a reference. Aspects of the technology described can be modified, if necessary, to use the systems, functions and concepts of the various references described above to provide other embodiments. Although the description above details certain embodiments and describes the best mode considered, no matter how detailed, several changes can be made. Implementation details can vary considerably, although they are still covered by the technology disclosed in this report. The various aspects and embodiments disclosed in this report are for illustrative purposes and are not limiting, with the true scope and spirit being indicated by the following claims.

权利要求:
Claims (33)
[1]
1. System to treat an individual to predictably freeze the individual's skin at a desired predictable time, CHARACTERIZED by the fact that the system comprises: an applicator configured to cool the individual's skin surface when the applicator is applied to the individual; and a controller programmed with instructions to make a cooling surface of the applicator at a first temperature to super-cool the individual's target tissue, and to create or maintain at least one ice crystal to make at least one crystal of ice comes into contact with the subject's skin to induce a freezing event on the subject's skin at the desired predictable time by means of at least one ice crystal.
[2]
2. System according to claim 1, CHARACTERIZED by the fact that it also comprises a means of connection with a freezing point lower than the first temperature.
[3]
3. System, according to claim 1, CHARACTERIZED by the fact that the controller is programmed to control a quantity of non-freezing cooling treatment released to the skin, so that the target skin tissue reaches a pre-determined first level of treatment; and after the target tissue reaches the first predetermined level of treatment, freeze the skin, and control an amount of freezing cooling treatment released to the skin, so that it reaches a second predetermined level of treatment.
[4]
4. System, according to claim 1, CHARACTERIZED by the fact that the applicator includes a sensor configured to monitor the individual's skin, and in which the controller is programmed to control the applicator based on the sensor output.
[5]
5. System, according to claim 4, CHARACTERIZED by the fact that the sensor includes a temperature sensor positioned to detect an individual's skin temperature.
[6]
6. System, according to claim 1, CHARACTERIZED by the fact that the controller is part of the applicator and is communicatively linked to the applicator.
[7]
7. System according to claim 1, CHARACTERIZED by the fact that the at least one ice crystal physically contacts a surface of the individual's skin.
[8]
8. System according to claim 1, CHARACTERIZED by the fact that it further comprises a catheter, in which at least one ice crystal is introduced into the individual using the catheter, so that the at least one ice crystal comes into contact with contact with a dermal layer of the skin.
[9]
9. System, according to claim 1, CHARACTERIZED by the fact that at least one ice crystal is formed in a cryoprotective solution located on the skin.
[10]
10. System, according to claim 9, CHARACTERIZED by the fact that the controller is programmed to ensure that: the skin temperature is maintained at the first temperature for a first treatment period, in which the first temperature is higher than 7 ºC below the freezing point of the fluid in the skin; and after the first treatment period, cool the cryoprotective solution from a temperature above a freezing point of the cryoprotective solution to a temperature below the freezing point of the cryoprotective solution to form at least one ice crystal in it.
[11]
11. System, according to claim 9, CHARACTERIZED by the fact that to make at least one ice crystal be formed, the controller causes a cryoprotective concentration on a skin surface to be diluted, in order to raise a freezing point of the diluted concentration to a value above the first temperature, so that the formation of at least one ice crystal in the diluted concentration does not require that the skin temperature be lowered below the first temperature.
[12]
12. System according to claim 1, CHARACTERIZED by the fact that ultrasound energy is used to create at least one ice crystal on the skin or in a substance in contact with the skin.
[13]
13. System, according to claim 1, CHARACTERIZED by the fact that the first temperature is below the freezing point of the fluid in the skin; and the controller is programmed to cause the applicator to control the contact time between at least one ice crystal and the individual's cooled skin below the freezing point.
[14]
14. System according to claim 13, CHARACTERIZED by the fact that the controller is programmed to detect the freezing event and to control the period of time that the detected freezing event is maintained to produce a therapeutically effective amount of thermal injury .
[15]
15. System, according to claim 1, CHARACTERIZED by the fact that the applicator includes a sensor configured to be used to identify and monitor the freezing event, in which the controller is programmed to control the applicator based on the sensor output to maintain the freezing event for a period of time.
[16]
16. Cosmetic method to predictably freeze an individual's skin in a desired predictable time, CHARACTERIZED by the fact that it comprises: decreasing a skin temperature below a freezing point of fluid in the skin, so that the skin is at a first temperature ; cause an ice crystal to contact the skin to inoculate the skin and create a predictable freezing event on the skin; and controlling a contact time between the ice crystal and the skin, so that the predictable freezing occurs at a desired time.
[17]
17. Method, according to claim 16, CHARACTERIZED by the fact that it also comprises physically contacting a surface of the skin with the ice crystal.
[18]
18. Method, according to claim 16, CHARACTERIZED by the fact that it further comprises introducing the ice crystal into the individual using a catheter, so that the ice crystal comes into contact with a dermal layer of the skin.
[19]
19. Method, according to claim 16, CHARACTERIZED by the fact that it further comprises forming the ice crystal in a cryoprotective solution located on the skin.
[20]
20. Method, according to claim 19, CHARACTERIZED by the fact that it also comprises maintaining the skin temperature at the first temperature for a first treatment period, in which the first temperature is greater than 7 ºC below the freezing point of the fluid in the skin; and after the first treatment period, cool the cryoprotective solution from a temperature above a freezing point of the cryoprotective solution to a temperature below the freezing point of the cryoprotective solution to form the ice crystal therein.
[21]
21. Method, according to claim 20, CHARACTERIZED by the fact that it further comprises diluting a cryoprotective concentration on a skin surface, in order to raise a freezing point of the diluted concentration to a value above a temperature of the cryoprotective solution, so that the formation of the ice crystal does not require that the skin temperature be lowered below the first temperature.
[22]
22. Method, according to claim 20, CHARACTERIZED by the fact that the first temperature is at least 10 ºC below the freezing point of the fluid in the skin before inoculating the skin.
[23]
23. Method according to claim 20, CHARACTERIZED by the fact that it further comprises: applying a bonding medium to the skin, the bonding medium having a medium therein capable of forming ice crystals; and setting a temperature of an applicator in thermal contact with the bonding medium to predictably freeze a portion of the medium in physical contact with a skin surface, such that the freezing portion of the medium causes the skin to freeze.
[24]
24. Cosmetic method for treating the skin, CHARACTERIZED by the fact that it comprises: lowering an individual's skin temperature below a freezing point of the target skin tissue; monitor the cooling of the skin, so that it does not freeze; control a quantity of non-freezing cooling treatment released to the skin, so that the target tissue reaches a pre-determined first level of cooling; and after the target tissue reaches the first predetermined level, freeze the skin, and control an amount of freezing cooling treatment released to the skin, so that the target tissue reaches a second predetermined level of cooling.
[25]
25. Method according to claim 24, CHARACTERIZED by the fact that the first predetermined level is a super-cooled treatment level, and the second predetermined level provides a therapeutically effective amount of thermal injury.
[26]
26. Method, according to claim 24, CHARACTERIZED by the fact that the first and second pre-determined levels are selected to affect the sebaceous glands in the dermis without permanently damaging the epidermis.
[27]
27. Method, according to claim 24, CHARACTERIZED by the fact that, before freezing the skin, raise a temperature of the epidermis to a value greater than a temperature of the dermis.
[28]
28. Method, according to claim 27, CHARACTERIZED by the fact that the value is greater than -10, -9, -8, -7, -6, -5, -4 or -3 ºC.
[29]
29. Method, according to claim 24, CHARACTERIZED by the fact that it further comprises lowering the individual's skin temperature by means of a cooling surface of an applicator by a first temperature value of the applicator which is maintained until a level is reached overall treatment, and then raise the temperature of the cooling surface to a second treatment value without cryotherapy, and a rate of change in the temperature of the cooling surface when the transition to the first value is greater than a rate of change of the applicator temperature when it transitions to the second value.
[30]
30. Cosmetic method to treat an individual's target tissue, CHARACTERIZED by the fact that it comprises: increasing the permeability of the individual's skin in a treatment site to facilitate the absorption of a bonding medium in the individual's skin; apply the bonding medium to the individual's skin with increased permeability; apply an applicator to the treatment site; and remove heat from the treatment site using the applicator to produce a
7I7 freezing event on the individual's skin for a predetermined period of time.
[31]
31. Method, according to claim 30, CHARACTERIZED by the fact that it further comprises increasing the permeability coefficient of the binding medium for skin absorption by at least 10%.
[32]
32. Method, according to claim 30, CHARACTERIZED by the fact that it further comprises: applying a removal element to the treatment site; and removing the removal element from the treatment site to increase the permeability of the individual's epidermis.
[33]
33. Method, according to claim 30, CHARACTERIZED by the fact that it also comprises mechanically stimulating the individual's skin to increase the permeability coefficient of the bonding medium for the skin by at least 10%.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US10555831B2|2020-02-11|Hydrogel substances and methods of cryotherapy

---

US10682297B2|2020-06-16|Liposomes, emulsions, and methods for cryotherapy

---

BR112018073275A2|2020-10-27|cosmetic system and method for predictably freezing the individual's skin, cosmetic method for treating the skin and cosmetic method for treating an individual's target tissue

---

US20170325992A1|2017-11-16|Skin freezing systems for treating acne and skin conditions

---

US20170326346A1|2017-11-16|Permeation enhancers and methods of cryotherapy

---

US20200138501A1|2020-05-07|Treatment systems and methods for affecting glands and other targeted structures

---

CN108472151B|2020-10-27|Temperature-dependent adhesion between applicator and skin during tissue cooling

---

US20180271767A1|2018-09-27|Use of saccharides for cryoprotection and related technology

---

US20170105869A1|2017-04-20|Vascular treatment systems, cooling devices, and methods for cooling vascular structures

---

US6032675A|2000-03-07|Freezing method for controlled removal of fatty tissue by liposuction

---

EP3506846A1|2019-07-10|Cryotherapy and cryoablation systems and methods for treatment of tissue

---

WO2017053324A1|2017-03-30|Transcutaneous treatment systems and cooling devices

---

WO2017041022A1|2017-03-09|Medical systems, methods, and devices for hypopigmentation cooling treatments

---

US20200069458A1|2020-03-05|Compositions, treatment systems, and methods for fractionally freezing tissue

同族专利:

---

公开号 | 公开日

---

WO2017196548A1|2017-11-16|

---

CA3023821A1|2017-11-16|

---

AU2017264512A1|2018-11-22|

---

JP2019514616A|2019-06-06|

---

KR20190005981A|2019-01-16|

---

CN109310516A|2019-02-05|

---

EP3454800A1|2019-03-20|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

AU6865298A|1997-03-17|1998-10-12|Boris Rubinsky|The use of cryoprotective agent compounds during cryosurgery|

---

US6032675A|1997-03-17|2000-03-07|Rubinsky; Boris|Freezing method for controlled removal of fatty tissue by liposuction|

---

US6887260B1|1998-11-30|2005-05-03|Light Bioscience, Llc|Method and apparatus for acne treatment|

---

KR100699759B1|2001-06-27|2007-03-27|라디언시 인크.|Acne treatment|

---

US8840608B2|2002-03-15|2014-09-23|The General Hospital Corporation|Methods and devices for selective disruption of fatty tissue by controlled cooling|

---

BR0308642A|2002-03-15|2005-01-18|Gen Hospital Corp|Methods and device for selective disruption of lipid-rich cells by controlled cooling|

---

EP2311398B1|2003-01-15|2015-04-15|Cryodynamics, LLC.|Cryotherapy probe and system|

---

US20050281789A1|2004-05-20|2005-12-22|Mangala Rao|Transcutaneous and/or transdermal transport of materials|

---

US7854754B2|2006-02-22|2010-12-21|Zeltiq Aesthetics, Inc.|Cooling device for removing heat from subcutaneous lipid-rich cells|

---

GB0605107D0|2006-03-14|2006-04-26|Bioforskning As|Use|

---

KR101248799B1|2006-04-28|2013-04-02|젤티크 애스세틱스, 인코포레이티드.|Cryoprotectant for use with a treatment device for improved cooling of subcutaneous lipid-rich cells|

---

ES2784023T3|2006-04-28|2020-09-21|Zeltiq Aesthetics Inc|Cryoprotectant for use with a treatment device for enhanced cooling of lipid-rich subcutaneous cells|

---

US20070270925A1|2006-05-17|2007-11-22|Juniper Medical, Inc.|Method and apparatus for non-invasively removing heat from subcutaneous lipid-rich cells including a coolant having a phase transition temperature|

---

US9132031B2|2006-09-26|2015-09-15|Zeltiq Aesthetics, Inc.|Cooling device having a plurality of controllable cooling elements to providea predetermined cooling profile|

---

US8192474B2|2006-09-26|2012-06-05|Zeltiq Aesthetics, Inc.|Tissue treatment methods|

---

US20080077201A1|2006-09-26|2008-03-27|Juniper Medical, Inc.|Cooling devices with flexible sensors|

---

AU2007313633A1|2006-10-31|2008-05-08|Zeltiq Aesthetics, Inc.|Method and apparatus for cooling subcutaneous lipid-rich cells or tissue|

---

US20080114348A1|2006-11-13|2008-05-15|Vancelette David W|Cryoprotective Agent Delivery|

---

US20080287839A1|2007-05-18|2008-11-20|Juniper Medical, Inc.|Method of enhanced removal of heat from subcutaneous lipid-rich cells and treatment apparatus having an actuator|

---

US8523927B2|2007-07-13|2013-09-03|Zeltiq Aesthetics, Inc.|System for treating lipid-rich regions|

---

US20090018624A1|2007-07-13|2009-01-15|Juniper Medical, Inc.|Limiting use of disposable system patient protection devices|

---

US20090018625A1|2007-07-13|2009-01-15|Juniper Medical, Inc.|Managing system temperature to remove heat from lipid-rich regions|

---

US20090018627A1|2007-07-13|2009-01-15|Juniper Medical, Inc.|Secure systems for removing heat from lipid-rich regions|

---

US20090018626A1|2007-07-13|2009-01-15|Juniper Medical, Inc.|User interfaces for a system that removes heat from lipid-rich regions|

---

US8285390B2|2007-08-21|2012-10-09|Zeltiq Aesthetics, Inc.|Monitoring the cooling of subcutaneous lipid-rich cells, such as the cooling of adipose tissue|

---

US20090111736A1|2007-10-29|2009-04-30|Sri International|Orally-Absorbed Solid Dose Formulation for Vancomycin|

---

JP2011530349A|2008-08-07|2011-12-22|ザジェネラルホスピタルコーポレーション|Method and apparatus for skin hypopigmentation|

---

WO2010036732A1|2008-09-25|2010-04-01|Zeltiq Aesthetics, Inc.|Treatment planning systems and methods for body contouring applications|

---

US8603073B2|2008-12-17|2013-12-10|Zeltiq Aesthetics, Inc.|Systems and methods with interrupt/resume capabilities for treating subcutaneous lipid-rich cells|

---

EP2769703A3|2009-04-30|2014-09-24|Zeltiq Aesthetics, Inc.|Device and system for removing heat from subcutaneous lipid-rich cells|

---

US20110040361A1|2009-08-12|2011-02-17|Elizabeth Joyce Levy|Cosmetic and Dermatological Cryotherapy Device|

---

BR112012018521A2|2010-01-25|2019-09-24|Zeltiq Aesthetics Inc|household applicators for non-invasively removing heat from lipid-rich subcutaneous cells by phase change refrigerants, and associated devices, systems and methods|

---

US8676338B2|2010-07-20|2014-03-18|Zeltiq Aesthetics, Inc.|Combined modality treatment systems, methods and apparatus for body contouring applications|

---

WO2012103242A1|2011-01-25|2012-08-02|Zeltiq Aesthetics, Inc.|Devices, application systems and methods with localized heat flux zones for removing heat from subcutaneous lipid-rich cells|

---

KR102087894B1|2011-11-16|2020-03-12|더 제너럴 하스피탈 코포레이션|Method and apparatus for cryogenic treatment of skin tissue|

---

EP2779970B1|2011-11-16|2020-09-02|The General Hospital Corporation|Method and apparatus for cryogenic treatment of skin tissue|

---

EP2606845B1|2011-12-23|2016-10-26|Lina Medical ApS|Pulse generator|

---

US9844460B2|2013-03-14|2017-12-19|Zeltiq Aesthetics, Inc.|Treatment systems with fluid mixing systems and fluid-cooled applicators and methods of using the same|

---

US9545523B2|2013-03-14|2017-01-17|Zeltiq Aesthetics, Inc.|Multi-modality treatment systems, methods and apparatus for altering subcutaneous lipid-rich tissue|

---

KR101487850B1|2013-08-08|2015-02-02|클래시스| apparatus for treating obesity by freezing fat cell |

---

US10201380B2|2014-01-31|2019-02-12|Zeltiq Aesthetics, Inc.|Treatment systems, methods, and apparatuses for improving the appearance of skin and providing other treatments|

---

WO2015117005A1|2014-01-31|2015-08-06|The General Hospital Corporation|Cooling device to disrupt function sebaceous glands|

---

EP3104796B1|2014-02-12|2019-04-10|The General Hospital Corporation|Method and apparatus for affecting pigmentation of tissue|

---

US10935174B2|2014-08-19|2021-03-02|Zeltiq Aesthetics, Inc.|Stress relief couplings for cryotherapy apparatuses|

---

US9752856B2|2014-08-21|2017-09-05|Michael Blake Rashad|Protective collapsible shield|

---

US20160089550A1|2014-09-25|2016-03-31|Zeltiq Aesthetics, Inc.|Treatment systems, methods, and apparatuses for altering the appearance of skin|

---

US20160317346A1|2015-04-28|2016-11-03|Zeltiq Aesthetics, Inc.|Systems and methods for monitoring cooling of skin and tissue to identify freeze events|US10471269B1|2015-07-01|2019-11-12|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US10709895B2|2016-05-10|2020-07-14|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US11253717B2|2015-10-29|2022-02-22|Btl Healthcare Technologies A.S.|Aesthetic method of biological structure treatment by magnetic field|

---

US10695576B2|2015-07-01|2020-06-30|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US10478633B2|2015-07-01|2019-11-19|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US10821295B1|2015-07-01|2020-11-03|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US10695575B1|2016-05-10|2020-06-30|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US10709894B2|2015-07-01|2020-07-14|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

US11266850B2|2015-07-01|2022-03-08|Btl Healthcare Technologies A.S.|High power time varying magnetic field therapy|

---

US11247039B2|2016-05-03|2022-02-15|Btl Healthcare Technologies A.S.|Device including RF source of energy and vacuum system|

---

US10583287B2|2016-05-23|2020-03-10|Btl Medical Technologies S.R.O.|Systems and methods for tissue treatment|

---

WO2017210619A1|2016-06-03|2017-12-07|R2 Dermatology, Inc.|Cooling systems and methods for skin treatment|

---

WO2018005802A1|2016-06-29|2018-01-04|The General Hospital Corporation|Ice nucleation formulations for cryopreservation and stabilization of biologics|

---

US20180001107A1|2016-07-01|2018-01-04|Btl Holdings Limited|Aesthetic method of biological structure treatment by magnetic field|

---

US10556122B1|2016-07-01|2020-02-11|Btl Medical Technologies S.R.O.|Aesthetic method of biological structure treatment by magnetic field|

---

WO2018085212A1|2016-11-02|2018-05-11|Velis Christopher J P|Devices and methods for slurry generation|

---

US10500342B2|2017-08-21|2019-12-10|Miraki Innovation Think Tank Llc|Cold slurry syringe|

---

EP3952984A1|2019-04-11|2022-02-16|BTL Healthcare Technologies a.s.|Methods and devices for aesthetic treatment of biological structures by radiofrequency and magnetic energy|

法律状态:
2021-09-08| B350| Update of information on the portal [chapter 15.35 patent gazette]|

---

2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

---

2022-01-25| B06W| Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette]|

优先权:

---

申请号 | 申请日 | 专利标题

---

US201662334317P| true| 2016-05-10|2016-05-10|

---

US201662334213P| true| 2016-05-10|2016-05-10|

---

US201662334330P| true| 2016-05-10|2016-05-10|

---

US201662334337P| true| 2016-05-10|2016-05-10|

---

US62/334,330|2016-05-10|

---

US62/334,213|2016-05-10|

---

US62/334,317|2016-05-10|

---

US62/334,337|2016-05-10|

---

PCT/US2017/029887|WO2017196548A1|2016-05-10|2017-04-27|Skin freezing systems for treating acne and skin conditions|

---