Method for selective disruption of fatty tissue by controlled cooling

Detailed description of the invention

(Related application / patent and transfer by reference) This application claims the priority of US Application No. 60 / 6,365,662 filed on March 15, 2002, the content of which is explicitly incorporated into the text by this reference.

Each application and patent cited in the text includes each document or cited document cited in each of the above applications and patents (including the "application cited document" at the time of litigation of each issued patent), PCT application and foreign application. And the corresponding patents, the prioritization claims of these applications and patents, and the documents cited in the application citations, which are clearly incorporated into the text by this citation. Generally, the document or document is described in the cited reference list or in the text prior to "Claims". Each of these documents or documents (references cited herein), as well as the documents or documents described in the references cited herein above (including manufacturer's specifications, instructions, etc.), is the text of this citation. Is clearly incorporated into.

(Invention titles created under federal-sponsored investigation) Not applicable

(Technical field of invention) This invention<u style="single">Fat</u>Selective fat-rich cells<u style="single">Na</u>Used for destruction<u style="single">Control medical equipment</u>About the method<u style="single">.. Book</u>Other aspects of the invention are evident from the following disclosure (within the scope of the invention).

(Background of invention) The subcutaneous adipose tissue of newborns is very sensitive to cold. In newborns, the intracellular lipid content of subcutaneous adipocytes, or "fat-containing cells," contains highly saturated triglycerides in increased proportions. Even at moderately cold temperatures, it adversely affects cells with highly saturated triglycerides, weakening the neoplastic subcutaneous adipose tissue and causing continued cold exposure to necrosis of adipocytes. Hypothermia of the subcutaneous adipose tissue causes inflammation of the epidermis and dermis. For example, a disease called cold subcutaneous adipose tissue inflammation in newborns is known to cause painful skin damage.

As the newborn matures, the ratio of saturated fatty acids to unsaturated fatty acids in the intracellular triglycerides (triglycerides) of adipocytes gradually decreases. The higher the content of unsaturated fatty acids, the more protective it is against the cold, and the less likely it is that infants will develop cold subcutaneous adipose tissue inflammation. For a detailed commentary on the issue of cold lipolithiasis, please refer to the following literature. Epstein et al. (1970) New England J. of Med.282 (17): 966-67, Duncan et al. (1966) Arch. Derm. 94: 722-724, Kellum et al. (1966) 1968) Arch. Derm. 97: 372-380, Moschella, Samuel L., Hurley, Harry J. (1985) Diseases of Corium and Subcotaneous Tissue in Dermatology (WB) Saunders Company) 1169-1181, John C Maize (1998) Panniculitis in Cutaneous Pathology (Churchill Livingstone) 327-344, Bondei, Edward E and Lazarus, Gerald S. (1993) Disorder of Subcutaneous Fat (Cold Panniculitis) in Dermatology in General Medicine (MacGraw-Hill, Inc.) 1333-1334.

In adults, the intracellular lipid content depends on the cell type. For example, dermal cells and epidermal cells are relatively low in unsaturated fatty acids compared to the underlying adipocytes that form the subcutaneous adipose tissue. For a detailed review of the components of mammalian adipose tissue, see Renold, Albert E. and Cahill, Jr., George F. (1965) Adipose Tissue in Handbook of Physiology (American Physiology Society) 170-176. As a result, depending on the different cell types, for example, lipid-rich cells and non-lipid-rich cells have different degrees of sensitivity to cold. In general, non-lipid cells can withstand colder temperatures than non-lipid cells.

It is highly desirable to selectively and non-invasively damage the adipocytes of the panniculus adipos without causing damage to the epidermal and dermal tissues. Although both health and cosmetological benefits due to adipocyte depletion are known, current methods such as liposuction are potentially life-threatening (eg, heavy bleeding, distress, septic shock, infection, etc.) Includes infringing procedures with swelling).

Current methods of non-invasively removing subcutaneous adipose tissue include the use of radiant energy and cooling solutions. U.S. Pat. Nos. 5,143,063, 5,507,790, and 5,769,879 describe the use of radiant energy to reduce panniculus adipos. However, the applied energy levels are difficult to control and often result in incidental damage to the dermis and epidermis. The cooling solution proposed by WO 00/44346 does not stabilize the surface temperature of the skin. Therefore, incidental damage to the dermis and epidermis cannot be sufficiently protected.

Previous studies conducted in guinea pigs have described the removal of subcutaneous adipose tissue by cold injury. Burge, S and Dawber, R. (1990) Cryobiology 27: 153-163. However, this result was obtained using a relatively aggressive cooling mode (eg, liquid nitrogen) and caused epidermal damage. Ideally, the removal of subcutaneous adipose tissue by cooling does not cause incidental damage to the epidermis.

Temperature-controlled methods and devices that selectively damage lipid-rich cells (eg, adipocytes with subcutaneous adiposium) without damaging non-lipid-rich cells (dermis and epidermis) have been known to date. Absent.

(Overview) By controlling the temperature and pressure applied to each of the above-mentioned receiving tissues, the adipose tissue containing the lipid-rich cells selectively does not destroy the non-lipid-rich tissues (for example, dermal tissue and epidermal tissue) around the adipose tissue. It turned out to be destroyed.

In one aspect, the invention selectively selects lipid-rich cells of a non-infant subject.<u style="single">Decrease</u>Let cool<u style="single">Control a medical device that contains elements</u>Regarding the method, the above person<u style="single">The law is above</u>Adjacent to the subject's skin<u style="single">In preparation for activating the cooling elements</u>,the above<u style="single">Topical with hyperlipidic cells</u>Area lipid-rich cells<u style="single">Selectively</u>Reduce<u style="single">As much as possible, reduce the temperature in the above local area between about -10 ° C and about 20 ° C.</u>At the same time, non-lipid-rich cells near the cooling element<u style="single">Damaged</u>Keep the subject's skin at no temperature.<u style="single">In one aspect, with respect to a method of controlling a medical device comprising a cooling element that selectively reduces lipid-rich cells of a non-infant subject, the method comprises activating the cooling element adjacent to the subject's skin. In order to selectively reduce the lipid-rich cells in the local region containing the lipid-rich cells, the temperature in the local region is reduced, and at the same time, the non-lipid-rich cells in the vicinity of the cooling element are damaged. The temperature of the subject's panniculus adiposum is provided as feedback to keep the subject's skin at an unacceptable temperature and to ensure that the subject's dermal tissue temperature does not cool below a predetermined minimum temperature. There is.</u><u style="single">In one aspect, with respect to a method of controlling a medical device comprising a cooling element that selectively reduces lipid-rich cells of a non-infant subject, the method comprises activating the cooling element adjacent to the subject's skin. In order to selectively reduce the lipid-rich cells in the local region containing the lipid-rich cells, the temperature in the local region is reduced, and at the same time, the non-lipid-rich cells in the vicinity of the cooling element are damaged. The subject's skin is maintained at a temperature that is not received, and the folds in the subject's skin are pressed between the cooling element and another cooling element.</u><u style="single">In one aspect, with respect to a method of controlling a medical device comprising a cooling element that selectively reduces lipid-rich cells of a non-infant subject, the method comprises activating the cooling element adjacent to the subject's skin. In order to selectively reduce the lipid-rich cells in the local region containing the lipid-rich cells, the temperature in the local region is reduced, and at the same time, the non-lipid-rich cells in the vicinity of the cooling element are damaged. The subject's skin is maintained at unacceptable temperatures and at least one pulsation is given to the lipid-rich cells prior to, at the same time as, or after application of the cooling element.</u><u style="single">In one aspect, with respect to a method of controlling a medical device comprising a cooling element that selectively reduces lipid-rich cells of a non-infant subject, the method comprises activating the cooling element adjacent to the subject's skin. In order to selectively reduce the lipid-rich cells in the local region containing the lipid-rich cells, the temperature in the local region is reduced, and at the same time, the non-lipid-rich cells in the vicinity of the cooling element are damaged. A material having high thermal conductivity is applied to the subject's skin before the subject's skin is maintained at a temperature not to be received and the cooling element is actuated on the subject's skin.</u>

In one aspect, the invention treats an area of the subject's body to reduce subcutaneous adipose tissue as desired.<u style="single">Control medical equipment that includes cooling elements</u>Regarding the method, the above person<u style="single">The law is</u>, A)<u style="single">By activating the cooling element adjacent to the subject's skin in areas where reduction of subcutaneous adipose tissue is desired.</u>Selectively select lipid-rich cells in the above region<u style="single">The temperature of the cooling element is controlled by electrically adjusting at least one thermoelectric element contained in the cooling element in order to reduce the temperature, and the circulation of the coolant through the cooling element is controlled.</u>sufficient<u style="single">To reduce the temperature in the above area</u>At the same time, non-lipid-rich cells in the vicinity of the cooling element<u style="single">Damaged</u>Keeping the subject's skin at no temperature, b) to the subject's skin in a) above until the desired reduction in subcutaneous adipose tissue is achieved.<u style="single">Operation of the above cooling element</u>Is repeated multiple times.

In another aspect, the invention<u style="single">With respect to a method of controlling a medical device containing a cooling element that treats an area of the subject's body to reduce the subcutaneous adiposium as desired, the above methods: a) the area where the reduction of the subcutaneous adiposium is desired. The temperature in the region is sufficiently reduced in order to selectively reduce the lipid-rich cells in the region by activating the cooling element adjacent to the skin of the subject, and at the same time, the cooling element of the region. The subject's skin is maintained at a temperature at which nearby non-lipid excess cells are not damaged, and b) the cooling element to the subject's skin in a) above until the desired reduction in subcutaneous adiposium is achieved. The cooling element is applied to the folds on the subject's skin, and the folds on the subject's skin are pressed between the cooling element and another cooling element.</u>。

In one embodiment, the present invention<u style="single">With respect to a method of controlling a medical device containing a cooling element that treats an area of the subject's body to reduce the subcutaneous adiposium as desired, the above methods: a) the area where the reduction of the subcutaneous adiposium is desired. The temperature in the region is sufficiently reduced in order to selectively reduce the lipid-rich cells in the region by activating the cooling element adjacent to the skin of the subject, and at the same time, the cooling element of the region. The subject's skin is maintained at a temperature at which nearby non-lipid hyperrich cells are not damaged, and b) the cooling element to the subject's skin in a) above until the desired reduction in subcutaneous adiposium is achieved. The operation of the above is repeated a plurality of times, further comprising applying a highly thermally conductive material to the skin of the subject before activating the cooling element.</u>。<u style="single">In one embodiment, with respect to a method of controlling a medical device comprising a cooling element that selectively reduces lipid-rich cells of a non-infant subject, the method comprises activating the cooling element adjacent to the subject's skin. In order to selectively reduce the lipid-rich cells in the local region containing the lipid-rich cells, the temperature in the local region is reduced, and at the same time, the non-lipid-rich cells in the vicinity of the cooling element are damaged. The subject's skin is maintained at an unacceptable temperature, and vibration is applied to the lipid-rich cells prior to, at the same time as, or after the activation of the cooling element.</u>

<u style="single">In one embodiment, with respect to a method of controlling a medical device comprising a cooling element that treats an area of the subject's body to reduce the subcutaneous fat tissue as desired, the above methods: a) Reduction of the subcutaneous fat tissue. Sufficiently reduce the temperature in the region to selectively reduce the lipid-rich cells in the region, with the action of a cooling element adjacent to the subject's skin in the desired region. At the same time, the subject's skin is maintained at a temperature at which the non-lipid excess cells in the vicinity of the cooling element are not damaged, and b) the subject's skin in the above a) until the desired reduction in subcutaneous adiposium is achieved. The action of the cooling element on the skin is repeated a plurality of times, and vibration is applied to the lipid-rich cells prior to, at the same time as, or after the action of the cooling element.</u> In another embodiment, the present invention<u style="single">With respect to a method of controlling a medical device containing a cooling element that selectively treats hyperlipidocytes, the above method involves placing the cooling element on the skin surface of a subject in an area where reduction of subcutaneous adiposium is desired. Activating the cooling element that cools the subcutaneous fat tissue and cooling the subcutaneous fat tissue so that the subcutaneous fat tissue in the region is selectively reduced and vasoconstriction occurs, but the above. Non-lipid excess cells in contact with the cooling element comprise maintaining the subject's skin at an undamaged temperature.</u>。

In this disclosure, "comprises," "comprising," "containing," "having," etc. have the meaning given by 35 USC. , "Includes" or "includes" and so on. "Consisting essentially of" and "consisting essentially of" also have the meaning given by 35 USC. In addition, there are no restrictions on the terms, and as long as the basic and new features of the described ones are not changed by the existence of more than the described ones and the embodiments of the prior art are excluded, the above-mentioned ones described above. Take into account the above existence.

These and other objectives and embodiments are described or are apparent from the claims of the invention and the detailed description below.

(Detailed explanation) The present invention relates to a method of locally reducing adipose tissue, wherein the method is at a temperature sufficient to selectively destroy lipid-rich cells and at a temperature that does not adversely affect non-lipid-rich cells. It is equipped with the application of cooling elements to. Preferably, the cooling element is bound to or comprises a coolant.

The present invention, in one aspect, is cooling to selectively destroy lipid-rich cells in a non-infant subject.<u style="single">Control a medical device that contains elements</u>Regarding the method, the above method puts a cooling element near the skin of the subject.<u style="single">Activate</u>To create a sufficient temperature gradient for selective fracture in the local area. This reduces the lipid-rich cells in the region and at the same time maintains the subject's skin at a temperature that does not destroy the non-lipid-rich cells in the vicinity of the cooling element.

The present invention, in one embodiment, is for treating a body area of a subject in order to reduce subcutaneous adipose tissue as desired.<u style="single">Control medical equipment</u>Regarding the method. The methods a) cool the subject's skin adjacent to the subject's skin in the area where subcutaneous adiposium is desired to be reduced in order to create a temperature gradient sufficient to selectively destroy the lipid-rich cells in the area. Element<u style="single">Activate</u>At the same time, the subject's skin is maintained at a temperature at which the non-lipid excess cells in the vicinity of the cooling element are not destroyed, and b) the subject's skin is subjected to the cooling element until the subcutaneous adiposium is reduced as desired. To<u style="single">Activate</u>It is provided that the step a) is repeated multiple times.

The cooling elements of the present invention include coolants in the form of liquids, solids or gases. Solid coolants consist of, for example, heat conductive materials such as metals, metal plates, glass, gels, ice and ice suspensions. The liquid coolant comprises, for example, salt water, glycerol, alcohol, a mixture of alcohol and water, and the like. When the cooling element contains a circulating cold agent, the temperature of the cold agent is preferably constant. The salt is combined with the liquid mixture to obtain the desired temperature. The gas includes, for example, cooling air and liquid nitrogen.

In one embodiment, the cooling element is applied in direct contact with the subject via a drug or element. In other embodiments, direct contact is made only through the drug. In yet another embodiment, no direct contact is made through the drug or element. Cooling is performed by arranging cooling elements and coolants in close proximity.

Preferably, the coolant temperature is less than about 37 ° C and above -196 ° C (ie, the temperature of liquid nitrogen).

Preferably, the temperature range of the controlled cooling element is between about 40 ° C and -15 ° C, more preferably 4 ° C and -10 ° C, when the coolant is a liquid or solid. Between. In general, the cooling element is preferably an average temperature between about -15 ° C and about 35 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C, 5 ° C, or about-. Average temperature between 10 ° C and about 35 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C, 5 ° C, or about -15 ° C and about 20 ° C, 15 Maintained an average temperature between ° C, 10 ° C and 5 ° C.

The above cooling elements and agents can be applied for up to 2 hours. The cooling element is preferably applied between 1 and 30 minutes. The cooling elements can be applied for at least 100 ms (eg using a spray for a shorter period). For example, liquid nitrogen can be applied repeatedly (eg, 10-100 times) for a very short period of time (eg, about 1 second). Then, during application, a temperature that does not cause epidermal damage is maintained (depending on the exposure time, for example, from about 0 ° C to -10 ° C). In a gradual cooling mode, for example, liquid nitrogen is sprayed from a distance (eg, about 10-30 cm). Some of the liquid nitrogen droplets evaporate during spraying or mix with the surrounding air.

The cooling elements and coolants of the present invention are applied to the skin surface, for example, by direct or indirect contact. The subject's skin consists of the dermis or epidermis or a combination thereof. Coolants and coolants are non-toxic coolants when applied directly to the skin surface.

The cooling element or coolant is applied more than once, eg in a repeating cycle. The coolant can be applied intermittently or continuously. As for the cooling element and the coolant, all the conventional methods known in the art can be applied, and if it is a liquid, gas or granular solid substance, it includes local application by spraying. Preferably, the application is by external means. However, the cooling elements and coolants of the present invention can also be applied subcutaneously by injection or other conventional means. For example, the coolant is applied directly to the subcutaneous tissue so that thermal equilibrium is reached and the lipid-rich tissue is cooled, and then the coolant is either removed after contact or left in the subcutaneous tissue (eg, liquid cooling). Subcutaneous injection of the drug or subcutaneous injection of fine cooling particles such as pellets or microbeads).

Preferably, the methods of the invention are non-invasive (eg, superficial or topical or laparoscopic procedures do not require invasive surgical techniques).

The cooling elements and coolants can be applied to one limited area or many areas. The spatial distribution of cooling elements and coolants is controlled as needed. In general, the size of the surface area (eg, where the coolant contacts the skin) is at least three times the depth of the subcutaneous adipose tissue to be cooled. Preferably, the minimum diameter of the surface area is at least 1 cm.²belongs to. More preferably, the diameter of the surface area is 3 cm²From 20 cm²It is between. Several parametric variables (parameters) that change on a daily basis are required to determine the optimum surface area. For example, 3500 cm²Large surface areas beyond are cooled according to the methods of the invention if hypothermia is prevented by other means. Hypothermia can be prevented by compensating for heat conduction that escapes from the body elsewhere (eg, by applying warm water in one or several places). Numerous cooling elements and coolants (eg 3500 cm)²Used when in contact with a larger (larger) surface area.

The cooling element or coolant can follow the contour of the area to which it is applied. For example, a flexible device is used to follow the outer shape of the surface area to be cooled. The device may also change the shape of the contact surface so that at the time of contact, the coolant or the device containing the coolant forms a contact surface around or inside. The cooling element or coolant can come into contact with more than one surface at the same time. For example, it is a case where the surface is folded and a cooling element or a coolant is brought into contact with both sides thereof. Preferably, the folds of the skin increase the efficiency of cooling by contacting the cooling elements and coolants on both sides.

Preferably, the solid cooling element or coolant is shaped to increase thermodynamic heat exchange (thermal exchange) at its contact surface (eg, skin surface). A liquid is used at the interface between the solid coolant and the contact surface to increase heat conduction.

If necessary, cooling elements and coolants are used with pain treatments such as anesthetics or analgesics (cooling alone has a pain-relieving effect, so the use of additional pain treatments is optional. is there). The local anesthetic is typically applied to the contact point before, after or during application of the coolant, for example. If necessary, systemic administration of the anesthetic is performed by conventional methods such as injection or oral administration. The temperature of the coolant can be changed during treatment, for example, the cooling rate is reduced to reduce discomfort. Further, the method of the present invention is carried out in combination with other fat reduction techniques well known in the art such as liposuction.

Preferably, the lipid-rich cells of the present invention are adipocytes in subcutaneous adipose tissue or cellulite. Therefore, lipid-rich cells, including subcutaneous adipose tissue, are subject to destruction by the methods of the invention. Furthermore, it is within the scope of the present invention to target the destruction of lipid-rich cells with an adventitia that surrounds organs and other internal structures.

The intracellular lipids of adipocytes are confined within the accessory vacuoles. Within the panniculus adipos, there are single or multiple vacuole adipocytes. Most are single vacuoles, larger than about 100 μm in diameter. This size increases dramatically in obese subjects due to the increased amount of intracellular lipids.

Preferably, the lipid-rich cells of the invention have a total intracellular lipid content between 20 and 99%. Preferably, the lipid-rich cells of the invention have an endocellular lipid content consisting of about 20-50% saturated triglycerides. And more preferably, it has an amount of endocellular lipid consisting of about 30-40% saturated triglyceride. Intracellular triglycerides are, but are not limited to, for example saturated fatty acids such as myristic acid, palmitic acid and stearic acid, and for example monounsaturated fatty acids such as palmitoleic acid and oleic acid. , Contains polyunsaturated fatty acids such as linoleic acid and linoleic acid.

Preferably, the lipid-rich cells of the invention are in the subcutaneous adipose tissue. The components of saturated fatty acids in the subcutaneous adipose tissue change in different parts of the human body. For example, the subcutaneous adipose tissue of the human abdomen has the following components of saturated fatty acids. That is, myristic acid (2.6%), palmitic acid (23.8%), palmitoleic acid (4.9%), stearic acid (6.5%), oleic acid (45.6%), linoleic acid (15.4%), linoleic acid (0.6%). .. The abdominal subcutaneous adipose tissue consists of about 35% saturated fatty acids. This is higher than the buttocks, which consist of about 32% saturated fatty acids. At room temperature, the saturated fatty acids in the abdominal region are in a semi-solid state as a result of the high fatty acid content. The buttock area is not affected in the same way. Malcom G. et al. (1989) Am. J. Clin. Nutr. 50 (2): 288-91. Experts in the art may change the temperature range or the number of applications if it is necessary to compensate for the physical differences corresponding to the cooling method of the present invention.

Preferably, the non-lipid-rich cells of the present invention have a total intracellular lipid content of 20% or less and are not destroyed by the cooling method of the present invention. Preferably, the non-lipid-rich cells of the present invention are cells having an intracellular lipid amount of less than about 20% highly saturated triglyceride, more preferably less than about 7-10% of highly saturated triglyceride. Including. The non-lipid hypercells are, but are not limited to, non-lipid hypercells around the panniculus adipos, such as vasculature, peripheral nervous system, epidermis (eg, melanocytes), dermis (eg, fibers). Cell) is a cell.

Damage to the dermis and epidermis avoided by the methods of the invention includes, for example, inflammation, swelling, formation of damage, hypopigmentation and hyperpigmentation of melanocytes.

Although not constrained by theory, selective disruption of hyperlipid cells is a highly saturated fatty acid in non-lipid hypercells when cooled at a temperature that does not induce crystallization of hypersaturated fatty acids in non-lipid hypercells. Is believed to be due to local crystallization. Crystals disrupt the double-structured membrane of hyperlipidic cells, causing cell necrosis. In this way, damage to non-lipid-rich cells, such as dermal cells, is avoided at temperatures that cause crystal formation of the lipid-rich cells. Cooling is also thought to induce lipolysis (eg, metabolism) of hyperlipidic cells, further promoting the loss of subcutaneous adipose tissue. Lipolysis is promoted by stimulation of the sympathetic nervous system and local cold exposure.

In one embodiment, the temperature of the lipid-rich cells is about 10 ° C. or less. Preferably, the temperature of the hyperlipidic cells is between -10 ° C and 37 ° C. More preferably, the temperature of the hyperlipidic cells is between -4 ° C and 20 ° C. More preferably, the temperature of the hyperlipidic cells is between -2 ° C and 15 ° C. Preferably, the hyperlipidic cells are cooled to a temperature below 37 ° C for up to 2 hours. In general, hyperlipidic cells are preferably about -10 ° C and about 37 ° C, 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C or 4 ° C. Is maintained at an average temperature between about -4 ° C and between 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C or 4 ° C. Is maintained at an average temperature of about 2 ° C and between 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C or 5 ° C. Maintained about average temperature.

In yet another embodiment, the temperature range of hyperlipidic cells fluctuates between 37 ° C and -10 ° C. To minimize involuntary damage to non-lipid-rich cells, a method of pulse cooling with short-term heating is used. More preferably, the temperature range of hyperlipidic cells fluctuates between -8 ° C and 33 ° C. Even more preferably, the temperature range of lipid-rich cells fluctuates between -2 ° C and 15 ° C. The temporal profile of skin cooling is one continuous cooling, multiple cooling cycles, or a practical combination of cooling and active heating cycles.

The cooling method of the present invention advantageously eliminates unwanted effects on the epidermis. In one embodiment, the temperature of the epidermis is about -15 ° C or higher. Preferably, the temperature of the epidermis is between about -10 ° C and 35 ° C. More preferably, the temperature of the epidermis lies between about -5 ° C and 10 ° C. More preferably, the temperature of the epidermis is between about -5 ° C and 5 ° C.

The cooling method of the present invention advantageously eliminates unwanted effects on the dermis. In one embodiment, the temperature of the dermis is about -15 ° C or higher. Preferably, the temperature of the dermis is between about -10 ° C and 20 ° C. More preferably, the temperature of the dermis is between about -8 ° C and 15 ° C. More preferably, the temperature of the dermis is between about -5 ° C and 10 ° C. In a preferred embodiment, the hyperlipidic cells are cooled to about 5 ° C to 5 ° C for up to 2 hours and the dermal and epidermal cells are maintained at an average temperature of about 0 ° C. In the most preferred embodiment, the hyperlipidic cells are cooled to about -5 ° C to 15 ° C within a time range of about 1 minute to a maximum of about 2 hours.

The method of the present invention is applied for a short period of time (eg, 1 minute, 5 minutes, 15 minutes, 30 minutes, 60 minutes) or for a long time (eg, 12 hours, 24 hours). Preferably, the period is between 5 and 20 minutes. Heating is performed between coolings, depending on the situation.

Feedback mechanisms are used to monitor and control the temperature of the subcutaneous adipose tissue of the skin (ie, the dermis, epidermis, or a combination thereof). The feedback mechanism monitors the subject's skin temperature to prevent the temperature from dropping below a predetermined minimum temperature, eg, below the minimum temperature between about -10 ° C and about 30 ° C. be able to. Non-infringing devices are applied externally to measure the surface temperature of the contact point and the surrounding area. Non-intrusive devices such as thermocouples are used to measure the internal temperature.

The feedback mechanism includes everything well known in the art for monitoring temperature and crystal formation. Crystal formation is measured, for example, by ultrasonic imaging measurement, acoustic measurement, optical measurement, or mechanical measurement. Mechanical measurements include measurement of tensile strength.

In one embodiment, a multi-layer model is used to estimate temperature profiles at different depths over time. The temperature profile is designed to create a temperature gradient within the tissue and exhibits a low temperature at the surface. In a preferred embodiment, the temperature profile is designed to minimize blood flow during cooling. For a suitable temperature gradient, for example, a thermocouple or an ultrasonic device (eg, discovering changes in the layers of the subcutaneous adiposium) or a shock wave propagation (eg, the shock wave propagation changes when layer transformation occurs). A feedback mechanism with a device is used.

For example, to cool the subcutaneous fat layer to a target temperature of substantially between about -5 ° C and 15 ° C, some requirements need to be met. The heat extracted from the surface of the skin creates a temperature gradient inside the skin, cooling the epidermis, dermis, and finally the subcutaneous fat layer in that order. Blood flow in the dermis transfers heat from the center of the body to the dermis. For this reason, dermal blood flow significantly limits the cooling of deep dermis and subcutaneous fat. Therefore, it is strongly desired to temporarily limit or stop subcutaneous blood flow by locally applying a pressure larger than the maximum blood pressure to the skin while cooling as a treatment for reducing subcutaneous fat. What is generally required is that the time to cool the skin surface must be long enough for heat to escape from the dermis and subcutaneous fat layer in order to bring the subcutaneous fat layer to the desired therapeutic temperature. .. When the subcutaneous fat is cooled below the lipid crystallization temperature, the latent heat that freezes the lipid must also be removed by diffusion. The cooling temperature and cooling time of the skin surface are adjusted to control, for example, the therapeutic depth, which is the body depth at which subcutaneous fat is affected. Thermophoresis is a passive process and the temperature in the center of the body is almost always around 37 ° C. Therefore, another general requirement is that the skin surface temperature during cooling is below the desired target (eg, adipocyte) therapeutic region temperature during at least some of the cooling period. That is what you have to do.

When cooling skin diameters larger than about 2 cm, and in the absence of blood flow, one-dimensional heat diffusion provides a good approximation for estimating the long-term skin temperature profile during cooling. Thermal diffusion is a general diffusion equation, δT / δt = κδ²T / δz²Determined by. Here, T (z, t) is the skin temperature as a function of depth z and time t, and κ is the thermal diffusivity, which is about 1.3 × 10 for skin tissue.^―3cm²s^―1Is. The solution of the thermal diffusion equation and the approximate solution are obtained for the semi-infinite thick plate plane shape close to the state of the skin. When the skin surface (z = 0) is kept at a certain low temperature, a useful approximation is that the heat flowing out of depth z is half the initial temperature difference. To, t = about z²It takes time. Where t is seconds and z is millimeters. Therefore, z²Is considered to be an approximation of the thermal time constant. For example, if the initial skin temperature is 30 ° C and 0 ° C ice is fixedly placed on the surface of the skin, then the temperature at a depth of 1 mm can reach about 15 ° C. It takes about 1 second. Typically, the subcutaneous fat layer starts at z = about 3 mm and extends from a few millimeters up to a few centimeters. The heat time constant for heat conduction from the top of the subcutaneous fat layer is about 10 seconds. In order to substantially cool the subcutaneous fat, a heat time constant of at least 5,6, preferably greater than 10, is required for the cooling time. Therefore, in the absence of dermal blood flow, cooling must be maintained on the skin surface for approximately 30-100 seconds in order for the temperature of the apex of subcutaneous fat to approach the cooled skin surface. When the temperature of the fat drops below the crystallization temperature, the latent heat of lipid crystallization must be removed, as described above. Therefore, it is generally desirable that the cooling time is 1 minute or more, and the cooling time of about 1 minute or more and up to 1 hour or more is used to adjust the depth of adipocytes.

Therefore, in other embodiments, the dermis is cooled at a rate sufficient to cause vasoconstriction. Blood circulation in the dermis stabilizes the dermis temperature to a temperature near body temperature. Blood flow is minimized to cool the panniculus adipos to below body temperature. Rapid cooling of the epidermal surface results in vasoconstriction that adequately restricts blood circulation.

In other embodiments, a vasoconstrictor is administered to cause vasoconstriction. The vasoconstrictor is typically applied topically to the point of contact before, after or during application of the coolant, for example. If necessary, the vasoconstrictor is systematically administered by conventional methods such as injection or oral administration. The vasoconstrictor may be anything known in the art. Preferably, the vasoconstrictor is EMLA cream or epinephrine.

In other embodiments, pressure is applied to the surface at or near the point of contact with the coolant so that lateral blood flow is restricted. For example, pressure is applied to the skin surface by pressing the skin surface into a skin fold consisting of single or multiple folds. The pressure may be due to evacuating the contact point with the coolant or its vicinity.

Although not constrained by theory, the rate of crystal formation of hyperlipidic cells is altered by applying pressure during the cooling process. Sudden crystallization rather than slow formation of crystals causes significant damage to lipid-rich cells. The application of pressure is thought to generate the force to move crystals into lipid-rich cells and increase damage to the bilayer membrane. In addition, different compartments of subcutaneous adipose tissue have different viscosities. In general, the viscosity is high at low temperatures (eg, at temperatures particularly close to the phase change point). Since the phase change of lipid-rich cells occurs at a higher temperature than non-lipid-rich cells, non-uniform tension lines are formed in the subcutaneous adipos tissue when pressure is applied. It is believed that these tension lines will be significantly damaged.

In other embodiments, the dermis and epidermis temperatures fluctuate between 35 ° C and -15 ° C. More preferably, the dermis temperature and epidermis temperature fluctuate between 10 ° C and -10 ° C. More preferably, the dermis temperature and epidermis temperature fluctuate between 8 ° C and -8 ° C. The fluctuating skin surface temperature provides intermittent warming and prevents potential side effects of the cooling process (eg, the formation of intracellular crystals in the dermis or epidermis).

In other embodiments, a coolant is applied in place of the dermis or epidermis and a constant or oscillating electric or sound field is applied to reduce or prevent the formation of crystals in the dermis or epidermis. To.

FIG. 1A shows a treatment system 100 for cooling a target area according to an embodiment of the present invention. As shown in FIG. 1A, the treatment system 100 includes a control unit 105 and a treatment unit 107, which treatment unit 107 includes a heating / cooling element 110 and a treatment interface 115.

The control unit 105 includes a power source, for example, the control unit is coupled with a power source to supply electricity to the treatment unit 107. The control unit 105 also includes a computer device having control software and hardware based on input characteristic values and parameters, a cooling / heating element 110, and a therapeutic interface 115. The treatment interface 115 includes a detector 120.

FIG. 1B shows the configuration of the control unit 105 according to the embodiment of the present invention. As shown in FIG. 1B, control unit 105 includes computer device 125. The computer device 125 may be a general purpose computer (such as a personal computer), a workstation, a mainframe computer system, or the like. The computer device 125 includes a processor device (central processing unit "CPU") 130, a memory element 135, a storage device (storage device) 140, a user interface 145, a system bus 150, and a communication interface 155. including. The CPU 130 is a processing device for executing instructions and processing data. The memory element 135 is a memory element including at least one random access memory (RAM), read-only memory (ROM), flash memory, electrically erasable ROM (EEPROM), and the like. The storage device 140 can be used as a removable integrated optical, magnetic, optical magnetic storage means, etc. (for example, a hard disk, a compact disk read-only memory "CD-ROM", a rewritable CD "CD-RW". , CD-BD ROM "DVD-ROM", DVD-RW, etc.), a data storage device for reading and writing. The storage device 140 also includes a control / interface (not shown) for connecting to the system bus 150. As described above, the memory element 135 and the storage device 140 are suitable for storing data other than storing the instructions of the programmed process to be executed by the CPU 130. The user interface 145 includes a touch screen, a control panel, a keyboard, a keypad, a display, or some other type of interface. The interface is connected to system bus 150 via a corresponding input / output device interface / adapter (not shown). community The nication interface 155 is designed to communicate with an external device that includes the treatment unit 107. The communication interface 155 is also designed to communicate with some system or network (not shown), such as one or more on a local area network (LAN), wide area network (WAN), or the Internet. Computer device. In this way, the control unit 105 carries out the process alone or in collaboration with one or more additional devices. The additional device may include an algorithm for controlling the treatment unit 107 according to the present invention. The control unit 105 is programmed or instructed to perform these processes according to the communication protocol or programming language on the platform. Thus, the process is materialized in the data and instructions stored in the memory element 135 and storage device 140, or in the data and instructions received in interface 155 and user interface 145, to run on CPU 130. ing.

Returning to FIG. 1A and referring to it, the treatment unit 107 may be a portable device, an automatic device, or the like. The cooling / heating element 110 includes a cooling / heating component such as a thermoelectric cooler.

FIG. 1C is a diagram showing a cooling / heating element 110 according to an embodiment of the present invention. As shown in FIG. 1C, the cooling / heating element 110 includes a network of passages through which the cooling / heating fluid flows. The passage is formed by a heat conduction tube or the like. The cooling and heating fluid is oriented to be discharged from the outlet 180 through the inlet 175 within the element 110. The cooling and heating fluid is a temperature controlled fluid such as cooled air, gas or liquid. For example, a salt water bath or an acetone bath is used as a source of cooling liquid that is cooled with ice or dry ice and delivered to element 110. In this way, the circulation system is formed and the fluid discharged from the outlet 180 is recooled at the source of the fluid and enters the inlet 175. The temperature of the source of the fluid and the element 110 and the ratio of the cooling fluid sent to the element 110 are monitored and controlled by the control unit 105. Therefore, the temperature of the cooling heating element 110 is controlled or programmed using the control unit 105. Further, as shown in FIG. 1C, there is a temperature difference ΔT between the regions of element 110. For example, the heat emitted from the target tissue is transferred to the cooling fluid during treatment, which causes the temperature of the fluid near the outlet 180 to be higher than the temperature of the cooling fluid near the inlet 175. Such ΔT becomes smaller by reducing the size of element 110. According to one embodiment of the invention, the structure of the passageway of element 110 and the corresponding application of element 110 to the target tissue are the temperature differences required to treat various tissue targets. For example, the element 110 region near the exit 180 can be applied to a treatment region that requires a high treatment temperature. Therefore, the passage of element 110 is created by the size, shape, composition, etc. of the target tissue that requires various treatment temperatures. The cooling and heating fluid can be pumped into the element 110 in a pulsating manner.

Returning to 1A above, the therapeutic interface 115 is the interface between the cooling and heating element 110 and the epidermis 160, affecting the treatment of the epidermis 160, the dermis 165 and the adipocytes 170. For example, the therapeutic interface 115 includes a cooling (conducting) plate, a cooling fluid filling vessel, a free-form membrane (for a complementary interface of non-flat epidermis), a convex cooling element (eg, shown in FIG. 3), and the like. Preferably, the treatment interface 115 comprises a thermally conductive material that complements the epidermis, which maximizes heat transfer between the epidermis 160, the dermis 165, the adipocytes 170 and the cooling and heating element 110. .. For example, the treatment interface 115 is a fluid-filled container or membrane so that the pressure change from the cooling element 110 caused by pulsing the flow of cooling fluid can be transferred to the target tissue. In addition, the treatment interface 115 may simply be a chamber, where the cooling and heating fluid is applied directly to the target tissue (epidermis 160, dermis and adipocytes 170), for example by using a spraying device.

The detector 120 is a temperature monitor, for example, a thermocouple or a thermistor. The detector 120 includes thermocouples of type T, E, J, K, G, C, D, R, S, B for monitoring tissue cooling. The detector 120 includes a thermistor with a thermal sense resistor whose resistance changes with temperature changes. The use of thermistors is advantageous, especially because of their excellent sensitivity. According to one embodiment of the invention, a thermistor with a large negative temperature coefficient of resistance (NTC) is used. Preferably, the thermistor used in the detector 120 has an operating temperature range of about -15 ° C to 40 ° C. In addition, the detector 120 includes a polymer or ceramic thermistor with active elements. Ceramic thermistors are most preferred because they have the best measurement temperature reproducibility. The ceramic thermistor used in the detector 120 is covered with a protective material such as glass. Of course, various other temperature monitoring devices are used, determined by the desired size, structure and temperature accuracy. The detector 120 comprises electrodes, which are used to measure the electrical resistance of the skin surface area. Freezing within superficial skin structures such as the epidermis or dermis causes increased electrical resistance. This effect is used to monitor freezing in the epidermis. The detector 120 is further composed of a combination of several measurement methods.

As described above, the detector 120 extracts temperature information from the epidermis 160, the dermis 165, and the adipocyte 170 as feedback to the control unit 105. The detected information is analyzed by the control unit 105 based on the input physical properties and parameters. For example, the temperature of adipocytes 170 is determined by calculations based on the temperature of epidermis 160 detected by detector 120. Therefore, the treatment system 100 can measure the temperature of adipocytes 170 without invading. This information is then used by the control unit 105 to continuously control the treatment unit 107. The continuous control of the treatment unit 107 is performed, for example, by adjusting the energy and temperature of the cooling and heating element 110 and the treatment interface 115. In this way, the target adipocytes 170 are maintained at a suitable therapeutic temperature while leaving the surrounding epidermis 160 and dermis 165 intact. As mentioned above, the cooling and heating element 110 can be adjusted to a temperature range from about -10 ° C to a maximum of 42 ° C. To maintain such a temperature range, automatic temperature measurements and control sequences are repeated until the procedure is complete.

It should be noted that when tissue cooling involves physical manipulations such as massaging target cells, the reduction of adipose tissue by cooling the lipid-rich cells is more effective. According to one embodiment of the invention, the treatment unit 107 includes a tissue massage device such as a vibrating device. Instead, a piezoelectric transducer is used within the treatment unit 107 to give the cooling and heating element 107 (or even better treatment unit) mechanical rocking and motion. The detector 120 includes a feedback device that detects changes in skin viscosity to monitor the effectiveness of treatment and prevent damage to surrounding tissues. For example, a vibration detector is used to detect a change in the resonance frequency of a target tissue (or surrounding tissue). The change in the resonance frequency is a change in the viscosity of the tissue, and the target tissue (or surrounding tissue) is mechanically moved or vibrated by the vibrating device included in the treatment unit 107.

To further ensure that the epidermis 160 and dermis 165 are not damaged by cryotherapy, optical detectors and feedback devices are used to monitor changes in the optical properties of the epidermis (scattering if freezing occurs). Promoted). Electrical feedback devices are used to monitor changes in epidermal electrical resistance caused by freezing in the epidermis. Ultrasonic feedback devices are used to monitor (actually avoid) freezing in the skin. Such a device may include a signal control unit 105 that stops or adjusts treatment to prevent skin damage.

In one embodiment of the invention, the treatment system 100 includes several device configurations and devices. Algorithms designed for different types of treatments and structures and equipment are included for control unit 105.

As shown in FIG. 1D, the treatment system 100 includes a probe controller 175 and a probe 180 for measuring the non-noxious minimum temperature of adipocytes 170. Advantageously, the probe 180 can more accurately measure the temperature of adipocytes 170. Thereby, the probe 180 improves the control of the treatment unit 107 and the effectiveness of the treatment.

It is noteworthy that the treatment system 100 can be remotely controlled. For example, the link (communication) between the control unit 105 and the treatment unit 107 is a remote link (wired or wireless). The control unit 105 remotely controls the cooling and heating element 110, the treatment interface 115, the probe controller 175, and the probe 180.

The typical treatment system 100 described above illustrates the basic components of a system suitable for use with the present invention, but the structures illustrated are not limiting. The reason is that many hardware forms can be modified without departing from the present invention.

FIG. 2A shows a therapeutic system 200 that cools adipocytes 170 by folding target cells according to one embodiment of the invention. As shown in FIG. 2A, the treatment system 200 includes a corresponding control unit 105 and a bilateral treatment unit 107 coupled to the compression unit 205. The compression unit 205 is designed to pull the two treatment units 107 together, thereby folding the target tissue (epidermis 160, dermis 165, adipocyte 170) between the treatment units 107. As described above, in this way, the therapeutic interface 115 of the therapeutic units 107 on both sides of the target tissue effectively cools the adipocytes 170 from multiple sides. As shown in FIG. 2A, control units 105 are connected to form an integrated system. According to one embodiment of the present invention, various components of the system 200 are controlled using a large number of control units.

As mentioned above, physical manipulation of the target tissue enhances the effectiveness of cryotherapy. According to one embodiment of the invention, the compression unit 205 changes the force that pulls the treatment unit 107 together around the target tissue (epidermis 160, dermis 165, adipocyte 170). For example, the compression unit 205 can be pulsed to alternately tension and relax the folds of the target tissue (ie, the "picked up portion"). In addition, resistance to tension in the target tissue is monitored to detect changes in the properties of the target tissue (eg, viscosity), thereby ensuring the effectiveness and safety of the treatment.

Figure 2B shows the system 200 with probe 180. This system 200 is similar to the system 100 for measuring the non-noxious minimum temperature of adipocytes 170 shown in FIG. 1D. As mentioned above, the probe 180 can more accurately measure the temperature of adipocytes, thereby improving the control of the treatment unit 107 and the effectiveness of the treatment.

3A and 3B are diagrams showing a treatment system 300 according to an embodiment of the present invention. As shown in FIG. 3A, system 300 includes a drinking unit 305 and treatment unit 107 includes a curved treatment interface 115. The curved surface forms, for example, a dome for forming and accommodating the chamber 310 on the epidermis 160. As shown in FIG. 3B, the suction unit 305 is activated to draw air out of the chamber 310 and the target tissues (epidermis 160, dermis 165, adipocytes 170) are sucked into contact with the treatment interface 115. The therapeutic interface 115 advantageously surrounds the target adipocytes 170 and cools the target adipocytes 170 more effectively. The treatment interface 115 is made of solid or flexible material and is in direct contact with the skin surface or in contact with the thermal binder between the skin surface and the treatment unit. The surface of the interface 115 may have a large number of openings connected to the suction unit 305. The skin partially penetrates these numerous openings, which increases the total surface area of the epidermis 160 in thermal contact with the therapeutic interface (eg, skin stretch). Skin elongation reduces the thickness of the epidermis and dermis. The fat 170 can be easily cooled. Several detectors 120 and probes 180 are included in the treatment system 300 to monitor tissue temperature during treatment, but are detailed here as mentioned above with reference to Figures 1A, 1C, 2A, 2B. The explanation will not be repeated.

FIG. 4 shows a treatment system 400 according to an embodiment of the present invention. As shown in FIG. 4, the suction unit 305 is connected to a ring-shaped opening around the treatment interface 115 to form a suction seal 410 by the dermis 160 around the treatment interface 115 during operation. As a result, treatment is delivered to the isolated target tissue area at the treatment interface 115. Advantageously, treatment at interface 115 is unaffected when the subject, or part of the body, is immersed in a warm bath. Therefore, the warm surroundings can increase the therapeutic area while generally preventing hypothermia.

5A and 5B are diagrams showing a treatment system 500 according to an embodiment of the present invention. As shown in FIGS. 5A and 5B, the treatment system 500 forms a band (or cylinder) around the target tissue mass 515. The treatment system 500 consists of a flexible material or a solid material. As shown in FIG. 5B, the cooling and heating fluid is pumped through the treatment system 500 via inlet 175 and outlet 180. The cooling / heating element 110 is formed by an internal container such as a pipe or a passage network. Heat transfer to the target tissue mass 515 is via a therapeutic interface 115 containing a heat conductive material. The treatment system 500 further includes a fixation mechanism 510 such as a hook or loop fastener to secure and embrace the tissue mass 515. The treatment system 500 further includes a flexible material so that the pressure of the cooling fluid delivered to the treatment system 500 is transmitted to the target tissue 515. For example, referring to FIG. 5A, the treatment system 500 can apply inward pressure to the target tissue mass 515. The target tissue mass 515 may be the subject's site, body part or limb. The target tissue mass 515 is, for example, the subject's arm or upper leg or lower leg or hip. The pressure and flow rate of the cooling fluid of the system 500 is controlled by the control unit 105 so as to have a suitable treatment temperature and treatment pressure. The close contact around the tissue mass 515 and the large inward pressure allow the subject to be immersed in a warm bath. The fluid flow may be a pulsatile flow, as described above.

The invention is additionally illustrated by the following exemplary and non-limiting examples, which provide a better understanding of the invention and many of its advantages.

Example 1: Selective damage to adipose tissue due to controlled cooling of the body The method of the present invention was performed on a 6-month-old female white Hanford mini-pig (pig I) and a 6-month-old female black Yucatan mini-pig (pig II). These pigs were anesthetized with terrazole / xylazine (4.4 mg / kg im + 2.2 mg / kg im). Inhalational anesthetics (halothane or isoflurene (1.5-3.0%) and oxygen (3.0 liters / minute)) are supplied by the mask and fluorine air absorption canals only if injection anesthesia does not sufficiently soothe the body. Was filtered using. Several test sites were marked with a small tattoo (tattoo) by applying ink to the corners of each test site. After mapping the test site, cold exposure was performed using the cooling device shown in FIG. 1A. The area of the treatment interface is 2 x 4 cm with a built-in temperature sensor²It was a flat area of the size of. The interface was thermally contacted with the thermoelectric cooling device. The thermoelectric cooling device is electrically adjusted by a control unit so that the surface temperature of the interface is maintained at a preset constant temperature. The cooling device was lightly applied to the skin during cold exposure so that no significant mechanical pressure was applied to the bloodstream. The cooling element was applied to the skin without manipulating the surface shape.

Various combinations were tested for preset cooling interface temperatures and exposure times. For some sites, a heat conductive lotion was applied between the skin and the cooling interface. This heat conductive lotion consists mainly of glycerol. Pig I was observed for 61 days until a biopsy of excision of the test site was obtained or until the pig was killed. From test site C, there was an additional punch biopsy obtained on day 2.

The biopsy was processed for a conventional light microscope and stained with hematoxylin and eosin. The indicated temperature is the temperature of the applied cooling element. Table 1 shows the parameters of the cooling application and the results obtained at various sites in Pig I. table 1 Site temperature time lotion result A -6 ° C 1 minute + 61 days No epidermis damage No dermis damage Clear concave No clear organizational structure change B -6 ° C 1 minute-in 61 days No epidermis damage No dermis damage Clear concave No clear organizational structure change C -6 ° C 5 minutes + 61 days No epidermis damage No dermis damage Concave due to lack of subcutaneous adipose tissue (1 week to 61 days) At a depth between about 3-6 mm Decrease in average size of adipocytes In 2 days Tissue inflammation and panniculitis D -3.5 ° C 5 minutes + 61 days No epidermis damage No dermis damage Clear concave Structural damage to the border in adipose tissue Decrease in average size of adipocytes E Control Normal-In the epidermis, dermis and subcutaneous adipose tissue No change

Pig II was observed for 50 days until excision biopsy was secured from all test sites and the pig was sacrificed. An additional biopsy was secured on day 17 from test site E. The biopsy was processed for a conventional light microscope and stained with hematoxylin and eosin, as described above. The indicated temperature is the temperature of the applied cooling element. Table 2 shows the parameters of the cooling application and the results obtained at various sites in Pig II. Table 2 Site temperature time lotion result C -6 ° C 5 minutes-in 50 days Conspicuous depression due to lack of subcutaneous adipose tissue (2 ~ 3mm) No display damage No dermis damage, No change in pigment, reduced size of adipocytes, Tissue structure damage of adipose tissue D -8 ° C 5 minutes-in 50 days Conspicuous depression due to lack of subcutaneous adipose tissue (2 ~ 3mm) No display damage No dermis damage No pigment change, Adipocyte damage to a depth of about 6 mm, Reduced adipocyte size, Tissue structure damage of adipose tissue E -9 ° C 5 minutes-in 50 days Conspicuous depression due to lack of subcutaneous adipose tissue (2 ~ 3mm) No display damage No dermis damage No pigment change, Adipocyte damage to a depth of about 6 mm, Reduced adipocyte size, Tissue structure damage of adipose tissue In 17 days Signs of panniculitis F -22 ° C 5 minutes-in 50 days Significant subcutaneous pigmentation And significant skin damage Scratch formation associated with dermis contraction And complete resection of subcutaneous adipose tissue

FIG. 6 shows skin surface images of test sites D, E, and F of Pig II 17 days after exposure. In 1 and 2, there are dents that match the site of cold exposure. The above 1 corresponds to the test site D, and the above 2 corresponds to the test site E. No abnormal epidermal changes were observed at these test sites. 3 matched test site F and cooling was actively applied. In 3 above, the damage to the epidermis is significant (eg, disappearance of pigmentation and formation of a central hard exodermis).

FIG. 7 shows the tissue structure of test site E (pig II) 17 days after cold exposure at 9 ° C for 5 minutes, which is a sample taken from the area below the cold exposure site. FIG. 7A shows the sample at low magnification (1.25x), and FIG. 7B shows the sample magnified at medium magnification (5x). Epidermis 701, dermis 702, subcutaneous fat 703 and muscle layer 704 are shown. The tissue structure presents with signs of lobular and septal adipose tissue inflammation within the subcutaneous fat 703, the adipose tissue inflammation being inflammation of the adipose tissue. The average size of adipocytes is small compared to samples obtained from unexposed areas. No evidence of tissue change is found in the epidermis, dermis and muscle layer.

The decrease in panniculus adiposum was demonstrated not only by tissue structure (staining of hematoxylin and eosin), but also by clinical observation of dents on the surface of the skin. Figures 8A, B, C, D, E, F show 50 days post-exposure for test sites C (Figures 8A and 8B), test sites E (Figures 8C and 8D) and test sites F (Figures 8E and 8F). The tissue structure is shown at a low magnification of 2.5 times (Fig. 8A, 8C, 8E) and a medium magnification of 5 times (Fig. 8B, 8D, 8F). Epidermis 801 and dermis 802 are undamaged at test sites C and E. On the other hand, test site F uses a more aggressive cooling mode, causing damage to the epidermis and dermis (eg, scar formation and inflammation). Subcutaneous fat 803 exhibits reduced size and structural changes of adipocyte-containing cells (eg, a clear condensation of fibrous septum and adipocyte layer is contained within the condensed adipocyte layer. ). As a result of applying an aggressive cooling mode to test site F, almost all layers are removed, leaving only the residual adipocyte population. Thus, when aggressive cooling modalities are applied, non-selective and significant damage is seen in the epidermis and dermis.

That is, the above results illustrate that the use of the cooling method of the present invention results in the selective destruction of the panniculus adipos without damaging the epidermis or dermis.

When cooling the skin surface at -7 ° C, temperature measurements live while applying sufficient pressure to stop blood flow in the skin to demonstrate the time and depth dependence of cooling. It was done with a pig. Thermocouples were used inserted to a depth of 0,2,4,8 mm to record the temperature. Although this experimental condition was not ideal (skin cooling device could not maintain the skin surface exactly at -7 ° C), cooling of the epidermis (2mm) and fat (4mm, 8mm) went as expected. It is clear that it was broken (see, for example, Figure 10).

Example 2: Measurement of temperature profile at various tissue depths. The study was conducted using 6-month-old black female hairless Yucatan mini pigs (Sinclair Lisaly Center, Missouri, Columbia). This pig has tetherazole / xylazine (4.4mg / kg im + 2.2mg / kg) It was anesthetized using im). Inhalational anesthetics (halothane or isoflurene (1.5-3.0%) and oxygen (3.0 liters / min)) are supplied by the mask and fluorinated air absorption canal only if injection anesthesia does not sufficiently soothe the body. Filtered using. Some test sites were marked with a tiny tattoo (tattoo) with ink applied to the corners of each test site. Then, it was subcutaneously injected into the corner of the test site. Cold exposure was performed using a round convex copper plate attached to the heat exchanger. The heat exchanger was cooled by a circulating coolant adjusted to -7 ° C. Exposure time ranged from 600 to 1200 seconds. Table 3 shows the cooling application parameters and the results obtained at various sites in Pig III. The cooling plate had three central openings with a diameter of about 1 mm. Thermocouples were placed through the openings to monitor the temperature profile of tissues at different depths during cold exposure. The cold exposure device shown in FIG. 9 was securely fixed to the test site during cold exposure. Cold exposure was performed on two different experimental days, one week apart. On the first experimental day, the thermocouples moved occasionally during cold exposure, changing the thermocouple measurement depth by 0.5 mm. On the second experimental day, additional exposure with thermocouples was performed with minimal changes in thermocouple depth and clarification of depth. The positions of the thermocouples with respect to the test sites 1,2,3,7,11,12 on the first experiment day were 2.5 mm, 4.5 mm, 10 mm (± 0.5 mm) deep. Test sites 14, 15, 16 and 18 were treated on the second experimental day with thermocouple depths of 2 mm, 4 mm and 8 mm with minimal depth displacement. Nevertheless, due to tissue compression during cold exposure, the thermocouple depth varies. A solution containing glycol was used for good thermal contact with the skin surface. Pigs were observed for three and a half months after treatment and then sacrificed and tissue from the test site was harvested for analysis. Table 3 shows the parameters of the cooling application and the results obtained from various parts of Pig III. Table 3 Site temperature (coolant) Exposure time Position temperature and depth Temperature and depth 1 -7 ° C 5 minutes flank 0 ° C, 2.5mm 7 ° C, 5mm 2 -7 ° C 5 minutes flank -2 ° C, 2.5 mm Not available 3 Control flank 7 -7 ° C 10 minutes Abdominal 3 ° C, 2.5mm 7 ° C, 5mm 9 Control abdomen 11 -7 ° C 10 minutes Buttocks Not available Not available 12 -7 ° C 10 minutes Buttocks 4 ° C, 2.5mm Not available 13 -7 ° C 21 minutes Buttocks -4 ° C, 2mm Not available 14 -7 ° C 21 minutes Buttocks -4 ° C, 2mm 3 ° C, 4mm 15 -7 ° C 11 minutes Buttocks -4 ° C, 2mm 1 ° C, 4mm 16 -7 ° C 10 minutes Buttocks -4 ° C, 2mm 0 ° C, 4mm 18 -7 ° C 15 minutes flank -3 ° C, 2mm Not available Site temperature and depth Concave after 3.5 months Relative decrease in surface fat layer after 3.5 months 1 24 ° C, 10mm + 66% 2 21 ° C, 10mm + 3-9% 7 19 ° C, 10mm + 9 11 12 ° C, 10mm ++ 79% 12 13 ° C, 10mm + 57% 13 7 ° C, 10 mm 14 12 ° C, 8mm + 15 12 ° C, 8mm + 16 14 ° C, 8mm ++ 18 15 ° C, 8mm + 66%

The test site was exposed to a device set to a coolant temperature of -7 ° C for 600-1200 seconds. As can be seen by palpation, the dermis solidified immediately after cold exposure and became viscose when it returned to normal temperature about 1 minute after exposure. Close-up studies with polarized magnifying lenses minutes after exposure showed no evidence of epidermal damage or changes. No blisters were formed and no Nikolsky phenomenon was observed. There was no significant damage to the epidermis during survival. No crusting, swelling or significant pigment changes were observed. At some test sites, epidermal pigmentation was slightly increased. This slight hyperpigmentation can be removed in a few months by gently rubbing the epidermis.

Thermocouple temperature measurements depend on depth, body position and cooling pressure. Temperature plots at different tissue depths during cold exposure for various test sites are shown in Figures 10A-J and summarized in Table 3. Temperature fluctuations were observed at some test sites. This oscillation is considered to be related to nearby blood vessels. Some temperature plots were not considered to be due to thermocouple movement or misalignment (labeled with "error" in Table 3). The temperature of the deep dermis or superficial fat layer is in the range of -2 ° C to -4 ° C. Temperatures at depths of 4-5 mm are in the range of about 0 ° C-7 ° C and depend on contact pressure and changes in the anatomical region. This position presented a variety of temperature plots with large variability. The temperature at a depth of 8-10 mm, corresponding to the depth within the subcutaneous fat layer, was in the range of 7-24 ° C.

Controlled tissue (site 9) and cold exposed site (site 8) (-7 ° C, 600 s) were obtained 6 days after exposure and analyzed by a cutaneous pathologist. At the site of control and cold exposure, the following is stated:

The epidermis of both samples exhibits a normal, basket-knitted stratum corneum with normal thickness. Compared to the control unit, it exhibits a ridge of normal reticular tissue. There is a small amount of lymphocyte infiltration around the blood vessels in the cold-exposed site. However, there are no clear signs of vasculitis in both samples.

The subcutaneous fat of the control part has a normal morphology. Subcutaneous fat at the site of cold exposure clearly shows signs of lobular adipose tissue inflammation and septal adipose tissue inflammation. Many adipocytes are surrounded by lymphocyte infiltration with secondary lipids, including macrophages. The thickness of the subcutaneous septum is increasing. However, soft blood vessels are a clear sign of vasculitis. Three and a half months after cold exposure, after performing 20 MHz ultrasound imaging of the selective test site, the pig was sacrificed and tissue from the exposed site was harvested by full-thickness resection. Ultrasound images in vivo showed that adipose tissue had disappeared in the area treated by skin cooling compared to the surrounding tissue that had not been exposed to cold. A biological ultrasound image three and a half months after cold exposure is shown in FIG.

The collected macroscopic tissue was excised from the test site. The photographed image was obtained from a macroscopic tissue section. Macroscopic tissue cross-sections of sites 1,3,11,12,18 are shown in Figures 13A-E. All cold-exposed sites show an increase in the thickness of the subcutaneous fat layer compared to the surrounding non-cold-exposed fat layer. The macroscopic cross section is in good agreement with the ultrasound image. Two different compartments within the subcutaneous fat could be distinguished into a superficial fat layer and a deep fat layer. The thickness of the surface fat layer is dramatically reduced at the site of cold treatment. On the other hand, the deep fat layer has not changed much. Percentage reductions in the surface fat layer inside and outside the test area are listed in Table 3 for several test sites. Changes in the subcutaneous fat layer can be seen at cold-exposed sites 1,11,12,18. The reduction in superficial subcutaneous fat layer thickness within the evaluated test site averaged 47%. No reduction in thickness was observed in any of the fat layers for unexposed control sites.

These examples confirm in a pig model that external cooling at a specific range of cooling temperatures and exposure times can selectively damage the panniculus adipos without serious damage to the epidermis or dermis. It was. Subcutaneous fat removal was also demonstrated by obvious dents on the treated skin surface. The dents exactly matched the cold exposure and also exactly matched the post-sacrifice ultrasound microscopic cross-section fat layer measurements for the cold exposed site. Significant changes in tissue structure limited to subcutaneous adipose tissue were observed 6 days after cold exposure. In terms of tissue structure, adipocyte size decreased and panniculitis was observed. The responsiveness to cold changed at different sites, and there were signs that the surface fat layer was more susceptible to tissue loss than the deep fat layer. The results of Pig III suggest that the surface fat layer promotes fat removal more than the deep layer. The explanation for this is that a) the surface fat layer is exposed to colder temperatures due to the temperature gradient, and b) the deep fat layer of the pig is less sensitive to selective cold damage.

FIG. 9 shows an image of a device for cold exposure of Pig III. The cold copper plate 91 is in contact with the skin. The temperature profile in the skin during cold exposure is measured by thermocouples 92 inserted at different depths. The device is loaded with a spring for applying pressure during cold exposure.

Figure 10 shows the different test sites 10A (site 1), 10B (site 2), 10C (site 7), 10D (site 11), 10E (site 12), 10F (site 13), 10G (site 14), 10H. For (Site 15), 10I (Site 16), and 10J (Site 18), the temperature profile of Pig III during cold exposure is shown. Temperatures of various depths are marked using T3-E (surface), T0-B (2-2.5 mm), T1-C (4-5 mm) and T2-D (8-10 mm). There is.

FIG. 11 is an ultrasound image of test site 11 taken three and a half months after exposure. The lower part of 1105 is outside the cold exposed area and the lower part of 1106 is inside the cold exposed area. The dermis 1102 is clearly distinguished from the fat layer 1103 and the muscle layer 1104. Within the adipose layer 1103, two different layers, a surface adipose layer 1103a and a deep adipose layer 1103b, can be identified. The ultrasound image is in good agreement with the macroscopic cross section of the same tissue in Figure 13C.

FIG. 12 shows the tissue structure of test site 8 (FIGS. 12A and 12B) 6 days after cold exposure (-7 ° C, 600 seconds) and the tissue of test site 9 (FIGS. 12C and 12D), which is a non-exposure control unit. Show the structure. These micrographs show a low magnification (1.25x) image in FIGS. 12A and 12C and a medium magnification (5x) image in FIGS. 12B and 12D. The above image shows the epidermis 701, the dermis 702, and the subcutaneous fat 703. Cold-exposed tissues exhibit panniculitis in subcutaneous fat, whereas unexposed controls exhibit normal tissue morphology.

13A-E show macroscopic cross-sections of the central part of different test sites after sacrificing pigs three and a half months after cold exposure, FIGS. 13A (site 1), 13B (site 3), 13C. (Site 11), Fig. 13D (Site 12), Fig. 13E (Site 18). Each figure shows epidermis 1301, dermis 1302, surface fat layer 1303 and deep fat layer 1304, along with scale 1300 with 1 cm and 1 mm units. There is no change in the thickness of the different layers for the unexposed controls in Figure 13B. Figures 13A, 13C, 13D and 13E show cross sections of cold-exposed areas. The cold-exposed area corresponds to the central part of the tissue, 4 to 5 mm, and is surrounded by a non-cold-exposed area. It can be seen that the thickness of the surface fat layer in the cold-exposed region is reduced in all the cold-exposed samples as compared with the non-cold-exposed region. In Table 3, the change in thickness of each sample is shown in%.

Several embodiments of the present invention have been described. Nevertheless, it will be understood that various changes can be made without departing from the spirit and scope of the invention. Therefore, other embodiments are also within the scope of the claims.

<figref num="1A">Figure 1A shows the treatment system.</figref><figref num="1B">FIG. 1B shows a diagram showing the structure of the control unit.</figref><figref num="1C">FIG. 1C shows a diagram showing cooling and heating elements.</figref><figref num="1D">Figure 1D shows a planar cryotherapy system.</figref><figref num="2A">FIG. 2A shows a therapeutic system that cools hyperlipidocytes in the skin folds.</figref><figref num="2B">FIG. 2B shows a cryotherapy system that cools hyperlipidocytes in skin folds with probe controls.</figref><figref num="3A">FIG. 3A shows a treatment system that includes a drinking unit.</figref><figref num="3B">FIG. 3B shows a treatment system that includes a drinking unit.</figref><figref num="4">FIG. 4 shows a treatment system combined with a drinking unit to treat isolated areas.</figref><figref num="5A">FIG. 5A shows a therapeutic system that can surround the target tissue mass from the outer circumference.</figref><figref num="5B">FIG. 5B shows a therapeutic system that can surround the target tissue mass from the outer circumference.</figref><figref num="6">FIG. 6 shows a skin surface image after 17 days in the area corresponding to the cold exposure site.</figref><figref num="7A">The tissue structure of the subcutaneous tissue 17 days after cold exposure is shown (Pig II, site E), and FIG. 7A shows a low-magnification image.</figref><figref num="7B">The tissue structure of the subcutaneous tissue 17 days after cold exposure is shown (Pig II, site E), and FIG. 7B shows a high-magnification image.</figref><figref num="8A">The tissue structure of the subcutaneous adipose tissue 17 days after cold exposure is shown (Pig II, sites C, E, F), and FIG. 8A shows the site C.</figref><figref num="8B">The tissue structure of the subcutaneous adipose tissue 17 days after cold exposure is shown (Pig II, sites C, E, F), and FIG. 8B shows the site C.</figref><figref num="8C">The tissue structure of the subcutaneous adipose tissue 17 days after cold exposure is shown (Pig II, sites C, E, F), and FIG. 8C shows the site E.</figref><figref num="8D">The tissue structure of the subcutaneous adipose tissue 17 days after cold exposure is shown (Pig II, sites C, E, F), and FIG. 8D represents site E.</figref><figref num="8E">The tissue structure of the subcutaneous adipose tissue 17 days after cold exposure is shown (Pig II, sites C, E, F), and FIG. 8E shows the site F.</figref><figref num="8F">The tissue structure of the subcutaneous adipose tissue 17 days after cold exposure is shown (Pig II, sites C, E, F), and FIG. 8F shows the site F.</figref><figref num="9">Figure 9 shows an image of the equipment used to control cooling for Pig III.</figref><figref num="10A">FIG. 10A represents temperature plots at various tissue depths at exposure site 1 of Pig III.</figref><figref num="10B">FIG. 10B represents temperature plots at various tissue depths at exposure site 2 of Pig III.</figref><figref num="10C">Figure 10C shows temperature plots at various tissue depths at Pig III exposure site 7.</figref><figref num="10D">Figure 10D represents temperature plots at various tissue depths at Pig III exposure site 11.</figref><figref num="10E">Figure 10E represents temperature plots at various tissue depths at Pig III exposure site 12.</figref><figref num="10F">Figure 10F represents temperature plots at various tissue depths at Pig III exposure site 13.</figref><figref num="10G">Figure 10G represents temperature plots at various tissue depths at Pig III exposure site 14.</figref><figref num="10H">Figure 10H represents temperature plots at various tissue depths at Pig III exposure site 15.</figref><figref num="10I">FIG. 10I represents temperature plots at various tissue depths at the exposed site 16 of Pig III.</figref><figref num="10J">Figure 10J shows temperature plots at various tissue depths at Pig III exposure site 18.</figref><figref num="11">FIG. 11 shows an ultrasound image of test site 11 3.5 months after exposure.</figref><figref num="12A">FIG. 12A shows the tissue structure of test site 8 6 days after exposure.</figref><figref num="12B">FIG. 12B shows the tissue structure of test site 8 6 days after exposure.</figref><figref num="12C">FIG. 12C shows the tissue structure of test site 9 (control unit) 6 days after exposure.</figref><figref num="12D">FIG. 12D shows the tissue structure of test site 9 (control unit) 6 days after exposure.</figref><figref num="13A">FIG. 13A shows a macrocross section through the center of test site 1 3.5 months after exposure.</figref><figref num="13B">FIG. 13B shows a macrocross section through the center of test site 3 3.5 months after exposure.</figref><figref num="13C">FIG. 13C shows a macrocross section through the center of test site 11 3.5 months after exposure.</figref><figref num="13D">FIG. 13D shows a macrocross section through the center of test site 12 3.5 months after exposure.</figref><figref num="13E">FIG. 13E shows a macrocross section through the center of test site 18 3.5 months after exposure.</figref>