Method for selective disruption of fatty tissue by controlled cooling
Abstract
A device (100) for selectively disrupting lipid-rich cells in a human subject other than a small child by cooling comprising: cooling means (110) for cooling a local region of the skin of a subject to selectively disturb lipid-rich cells of the region, while simultaneously keeping the subject's skin at a temperature at which they are not disturbed. lipid-rich cells, in which the cooling media is adapted to the cooling of lipid-rich cells at a temperature between about -10 ° C and about 25 ° C. a temperature control unit (105) for controlling the temperature of the cooling means, and temperature measuring means (120) that are adapted to measure the temperature of the subject's skin and / or the temperature on the skin of the subject and / or the surface temperature of the subject's skin; characterized in that the temperature control unit is further adapted to control the temperature of the cooling means such that the temperature of the subjects' skin and / or the temperature in the subject's skin and / or the temperature in the The subject's skin surface does not fall below a predetermined minimum temperature depending on the subject's skin temperature and / or the subject's skin temperature and / or the surface temperature of the subject. subject's skin

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Projected expiry passed 17 March 2023, 3.5 years ago.
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22 claims: 15 independent, 7 dependent
- 1ES 2 300 569 T3 IS 2 300 569 T3 CLAIMS REIVINDICACIONES 1. A device (100) for selectively disturbing lipid-rich cells in a human subject other than a young child by cooling comprising:1. Un dispositivo (100) para perturbar selectivamente las células ricas en lípidos en un sujeto humano que no sea un niño pequeño mediante enfriamiento que comprende: cooling means (110) for cooling a local region of a subject's skin to selectively disturb the lipid-rich cells of the region, while simultaneously maintaining the subject's skin at a temperature at which the cells are not disturbed. lipid-rich cells, wherein the cooling media is adapted to cooling the lipid-rich cells to a temperature between about -10 ° C and about 25 ° C. medios (110) de enfriamiento para refrigerar una región local de la piel de un sujeto para perturbar selectivamente las células ricas en lípidos de la región, mientras, simultáneamente con esto, mantener la piel del sujeto a una temperatura a la cual no se perturben las células ricas en lípidos, en la que los medios de enfriamiento se adapten al enfriamiento de las células ricas en lípidos a una temperatura entre aproximadamente -10°C y aproximadamente 25°C. a temperature control unit (105) for controlling the temperature of the cooling means, and temperature measuring means (120) that are adapted to measure the subject's skin temperature and / or the skin temperature of the subject and / or the temperature on the surface of the subject's skin;characterized in that the temperature control unit is further adapted to control the temperature of the cooling means such that the temperature of the skin of the subjects and / or the temperature in the skin of the subject and / or the temperature in the subject's skin surface does not drop below a predetermined minimum temperature as a function of the subject's skin temperature and / or the subject's skin temperature and / or the surface temperature of the subject's skin. una unidad (105) de control de temperatura para controlar la temperatura de los medios de enfriamiento, y medios (120) de medición de la temperatura que se adaptan para medir la temperatura de la piel del sujeto y/o la temperatura en la piel del sujeto y/o la temperatura en la superficie de la piel del sujeto;caracterizados porque la unidad de control de la temperatura se adapta adicionalmente para controlar la temperatura de los medios de enfriamiento de tal manera que la temperatura de la piel de los sujetos y/o la temperatura en la piel del sujeto y/o la temperatura en la superficie de la piel del sujeto no baja por debajo de una temperatura mínima predeterminada en función de la temperatura de la piel del sujeto y/o la temperatura en la piel del sujeto y/o la temperatura en la superficie de la piel del sujeto.
- 4El dispositivo de una cualquiera de las reivindicaciones 1 a 3, en el que la unidad de control de temperatura se adapta para mantener una temperatura promedio de los medios de enfriamiento entre aproximadamente -15 y 35°C, o entre aproximadamente -15 y 30°C, o entre aproximadamente -15 y 25°C, o entre aproximadamente -15 y 20°C, o entre aproximadamente -15 y 15°C, o entre aproximadamente -15 y 10°C, o entre aproximadamente -15 y 5°C, o entre aproximadamente -10 y 35°C, o entre aproximadamente -10 y 30°C, o entre aproximadamente -10 y 25°C, o entre aproximadamente -10 y 20°C, o entre aproximadamente -10 y 15°C, o entre aproximadamente -10 y 10°C, o entre aproximadamente -10 y 5°C, o entre aproximadamente -5 y 20°C, o entre aproximadamente -5 y 15°C, o entre aproximadamente -5 y 10°C, o entre aproximadamente -5 y 5°C. Four. The device of any one of claims 1 to 3, wherein the temperature control unit is adapted to maintain an average temperature of the cooling means between about -15 and 35 ° C, or between about -15 and 30 ° C, or between about -15 and 25 ° C, or between about -15 and 20 ° C, or between about -15 and 15 ° C, or between about -15 and 10 ° C, or between about -15 and 5 ° C, or between about -10 and 35 ° C, or between about -10 and 30 ° C, or between about -10 and 25 ° C, or between about -10 and 20 ° C, or between about -10 and 15 ° C, or between about -10 and 10 ° C, or between about -10 and 5 ° C, or between about -5 and 20 ° C, or between about -5 and 15 ° C, or between about -5 and 10 ° C, or between about -5 and 5 ° C.
- 6The device of any one of claims 4 or 5, wherein the predetermined minimum temperature is about -10 ° C or about -10 ° C or about -5 ° C, or about 0 ° C, or about 5 ° C , or about 10 ° C, or about 15 ° C, or about 20 ° C, or about 30 ° C. 6. El dispositivo de una cualquiera de las reivindicaciones 4 ó 5, en el que la temperatura mínima predeterminada es aproximadamente de -10°C o aproximadamente -10°C o aproximadamente -5°C, o aproximadamente 0°C, o aproximadamente 5°C, o aproximadamente 10°C, o aproximadamente 15°C, o aproximadamente 20°C, o aproximadamente 30°C.
- 9The device of any one of claims 1 to 8, wherein the cooling means has a skin contacting surface and / or a flat surface and / or a contoured surface. 9. El dispositivo de una cualquiera de las reivindicaciones 1 a 8, en el que los medios de enfriamiento tienen una superficie que contacta con la piel y/o una superficie plana y/o una superficie contorneada.
- 10The device of any one of claims 1 to 9, wherein the cooling means is adapted to apply to the skin of the subject with a pressure that is approximately equal to or greater than that of the systolic blood pressure in the dermis of the subject with in order to decrease blood flow within the dermis. 10. El dispositivo de una cualquiera de las reivindicaciones 1 a 9, en el que los medios de enfriamiento se adaptan para aplicarse a la piel del sujeto con una presión que es aproximadamente igual a o mayor que la de la presión sanguínea sistólica en la dermis del sujeto con el fin de disminuir el flujo sanguíneo dentro de la dermis.
- 11El dispositivo de una cualquiera de las reivindicaciones 1 a 9, en el que los medios de enfriamiento se adaptan para aplicarse a la piel del sujeto con una presión que es aproximadamente igual a o menor que la presión sanguínea sistólica en la dermis del sujeto con el fin de disminuir el flujo sanguíneo dentro de la dermis. eleven. The device of any one of claims 1 to 9, wherein the cooling means is adapted to apply to the subject's skin with a pressure that is approximately equal to or less than the systolic blood pressure in the subject's dermis in order to to decrease blood flow within the dermis. ES 2 300 569 T3 IS 2 300 569 T3
- 12The device of any one of claims 1 to 9, wherein the cooling means is adapted to apply to the subject's skin under pressure in an amount sufficient to decrease blood flow within the dermis. 12. El dispositivo de una cualquiera de las reivindicaciones 1 a 9, en el que los medios de enfriamiento se adaptan para aplicarse a la piel del sujeto con presión en una cantidad suficiente para disminuir el flujo sanguíneo dentro de la dermis.
- 14The device of any one of claims 1 to 13, further comprising at least one other cooling means, wherein the cooling means is adapted such that the fold is pressed into the subject's skin between the cooling means and a second cooling means when the device is applied. 14. El dispositivo de una cualquiera de las reivindicaciones 1 a 13, que comprende adicionalmente al menos otros medios de enfriamiento, en el que los medios de enfriamiento se adaptan de tal manera que se presiona el pliegue en la piel del sujeto entre los medios de enfriamiento y unos segundos medios de enfriamiento cuando se aplica el dispositivo.
- 15El dispositivo de una cualquiera de las reivindicaciones 1 a 14 que comprende adicionalmente:medios de detección de cristales para obtener retroalimentación acerca de si se han formado cristales en las células ricas en lípidos, dicha retroalimentación se usa por la unidad de control de la temperatura para controlar la temperatura de los medios de enfriamiento. fifteen. The device of any one of claims 1 to 14 further comprising: crystal detection means for obtaining feedback as to whether crystals have formed in the lipid-rich cells, said feedback being used by the temperature control unit to control the temperature of the cooling media.
- 18The device of any one of claims 1 to 16, further comprising:18. El dispositivo de una cualquiera de las reivindicaciones 1 a 16, que comprende adicionalmente: means for providing mechanical movement to the lipid-rich cells prior to, simultaneous with, or after application of the cooling means. medios para proporcionar un movimiento mecánico a las células ricas en lípidos antes de, simultáneo con, o después de la aplicación de los medios de enfriamiento.
- 20El dispositivo de una cualquiera de las reivindicaciones 1 a 19, en el que los medios de enfriamiento se adaptan para refrigerar las células ricas en lípidos a una temperatura de aproximadamente -10 y 20°C o a una temperatura entre aproximadamente -10 y 15°C, o a una temperatura entre aproximadamente -10 y 10°C, o a una temperatura entre aproximadamente -10 y 4°C, o a una temperatura entre aproximadamente -4 y 25°C, o a una temperatura entre aproximadamente -4 y 20°C, o a una temperatura entre aproximadamente -4 y 15°C, o a una temperatura entre aproximadamente -4 y 10°C, o a una temperatura entre aproximadamente -4 y 4°C, o a una temperatura entre aproximadamente -2 y 25°C, o a una temperatura entre aproximadamente -2 y 20°C, o a una temperatura entre aproximadamente -2 y 15°C, o a una temperatura entre aproximadamente -2 y 10°C, o a una temperatura entre aproximadamente -2 y 4°C. twenty. The device of any one of claims 1 to 19, wherein the cooling means is adapted to cool the lipid-rich cells at a temperature of about -10 and 20 ° C or at a temperature between about -10 and 15 ° C , or at a temperature between approximately -10 and 10 ° C, or at a temperature between approximately -10 and 4 ° C, or at a temperature between approximately -4 and 25 ° C, or at a temperature between approximately -4 and 20 ° C, or at a temperature between about -4 and 15 ° C, or at a temperature between about -4 and 10 ° C, or at a temperature between about -4 and 4 ° C, or at a temperature between about -2 and 25 ° C, or at a temperature between approximately -2 and 20 ° C, or at a temperature between approximately -2 and 15 ° C, or at a temperature between approximately -2 and 10 ° C, or at a temperature between approximately -2 and 4 ° C.
- 21El dispositivo de una cualquiera de las reivindicaciones 1 a 20, en el que las células ricas en lípidos son células adiposas dentro del tejido subcutáneo o celulitis. twenty-one. The device of any one of claims 1 to 20, wherein the lipid-rich cells are fat cells within the subcutaneous tissue or cellulite.
Independent claims15
221 paragraphs in 15 sections, as filed
IS 2 300 569 T3
DESCRIPTION
Devices for the selective disturbance of fat tissue by controlled cooling.
Field of the invention
The present invention relates to devices for use in the selective disruption of lipid-rich cells by controlled cooling. The present invention further relates to a device for use in performing procedures for the selective disruption of lipid-rich cells by controlled cooling. Other aspects of the invention are described in or are obvious from the following description (and within the scope of the invention).
Background
The subcutaneous fatty tissue of newborns is unusually sensitive to cold. In newborns, the intracellular lipid content of subcutaneous fat cells, or "adipocytes" comprises an increased index of highly saturated triglycerides. Even moderately cold temperatures can adversely affect cells that have a highly saturated lipid content, rendering the subcutaneous fat tissue of newborns vulnerable to adipocyte necrosis after exposure to cold. Hypothermia of the subcutaneous fatty tissue can result in associated inflammation of the dermis and / or epidermis. For example, in newborns, cold panniculitis disorders are known to cause painful lesions on the skin.
As newborns develop, the ratio of saturated to unsaturated fatty acids gradually decreases among the intracellular triglycerides of adipocytes. Having a higher content of unsaturated fatty acids is more protective against cold, and the incidence of cold panniculitis in young children gradually decreases. For detailed descriptions on the topic of cold panniculitis, see 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. (1968) Arch. Derm. 97: 372-380; Moschella, Samuel L. and Hurley, Harry J. (1985) Diseases of the Corium and Subcutaneous Tissue. In Dermatology (WB Saunders Company): 1169-1181; John C Maize (1998) Panniculitis in Cutaneous Pathology (Churchill Livingstone): 327-344; Bondey, Edward E. and Lazarus, Gerald S. (1993) Disorders of Subcutaneous Fat (Cold Panniculitis) In Dermatology in General Medicine (McGraw-Hill, Inc.): 1333-1334.
In adults, the intracellular lipid content varies between cell types. Dermal and epidermal cells, for example, are relatively low in unsaturated fatty acids compared to the underlying adipocytes that make up subcutaneous fatty tissue. For a detailed review of the composition of fatty tissue in mammals, see Renold, Albert E. and Cahill, Jr., George F (1965) Adipose Tissue. In the Handbook of Physiology (American Physiology Society): 170-176. As a result, different cell types, for example lipid-rich and non-lipid-rich cells, have varying degrees of susceptibility to cold. In general, non-lipid-rich cells can withstand lower temperatures than lipid-rich cells.
It would be highly desirable to selectively and non-invasively damage the adipocytes of the subcutaneous fatty tissue without causing injury to the surrounding dermal and epidermal tissue. Health and cosmetic benefits are known to occur as a result of the reduction of fatty tissue, however, current procedures, such as liposuction, involve invasive procedures with potentially life-threatening risks (e.g., excessive bleeding, shock septic, infection and swelling).
Current procedures for the non-invasive removal of subcutaneous fatty tissue include the use of radiant energy and cooling solutions. United States Patents N<sup>you</sup> 5,143,063, 5,507,790, and 5,769,879 describe procedures for using radiant energy to reduce subcutaneous fatty tissue, however, applied energy levels are difficult to control and collateral damage to the dermis and / or epidermis often occurs. . The cooling solutions proposed by WO 00/44346 do not stabilize the surface temperatures of the skin and therefore also fail to adequately protect the dermis and / or epidermis against collateral damage. GB228660 describes a skin cooling device.
A previous study carried out in guinea pigs describes the removal of subcutaneous fatty tissue by cryodamage. Burge, S. and Dawber, R. (1990) Cryobiology 27: 153-163. However, this result was achieved using relatively aggressive cooling modalities (eg, liquid nitrogen), which induced epidermal damage. Ideally, the removal of subcutaneous fatty tissue by cooling does not produce associated damage to the epidermis.
Temperature-controlled procedures and devices to selectively damage lipid-rich cells (eg, adipocytes comprising subcutaneous fatty tissue) without causing injury to non-lipid-rich cells (eg, dermis and / or epidermis) are hitherto unknown. .
Summary
It has now been shown that adipose tissue comprising lipid-rich cells can be selectively disturbed without causing injury to surrounding non-lipid-rich tissue (e.g. dermal and epidermal tissue) by controlling the temperature and / or pressure applied to the cells. respective tissues.
IS 2 300 569 T3
A cooling method is described for the selective disruption of lipid-rich cells in a human subject other than a young child which comprises applying a cooling element close to the subject's skin to create a temperature gradient within a sufficient local region. to disturb and therefore reduce the lipid-rich cells of said region, and, simultaneously with this, maintaining the subject's skin at a temperature at which non-lipid-rich cells in the vicinity of the cooling element are not disturbed.
Also described is a method of treating a region of the body of a subject to achieve a desired reduction in subcutaneous adipose tissue, comprising a) applying a cooling element close to the skin of the subject in the region in which reduction is desired. of subcutaneous adipose tissue to create a temperature gradient within said region sufficient to selectively disturb the lipid-rich cells of the former and, simultaneously with this maintaining the subject's skin at a temperature at which non-lipid-rich cells near the cooling element are not disturbed; b) repeating the application of the cooling element to the skin of the subject of step (a) a plurality of times until the desired reduction in the subcutaneous adipose tissue has been achieved.
The invention relates to a device for selectively disrupting lipid-rich cells in a human subject other than a young child as defined in claim 1 attached hereto. Preferred embodiments are defined in the dependent claims.
Equipment for locally reducing lipid-rich cells is disclosed, comprising a treatment device operable to house a cooling agent, a source of the cooling agent connected to the treatment device to supply said cooling agent; a control unit coupled to the treatment device and to the source of the cooling agent for controlling the cooling temperature of said cooling agent, which selectively induces damage to lipid-rich cells in said target tissue.
A kit for locally reducing lipid-rich cells is further described, comprising a means for setting a cooling agent to a predetermined temperature; and a means for applying said cooling agent to the target tissue, whereby the cooling agent selectively induces damage to lipid-rich cells in said target tissue.
In this description, "comprises", "comprising", "containing" and "having" and the like may have the meanings ascribed to them in United States patent law and may mean "includes", "including ”And the like; "Essentially constituted by" or "is essentially constituted" also have the meaning attributed to them in United States patent law and the term has no specific limits, allowing the presence of more than what is listed as long as the basic characteristics or novel of what is listed are not changed by the presence of more than what is listed, but exclude prior art embodiments.
These and other objects and embodiments are described in or are obvious and within the scope of the invention, from the following Detailed Description.
Description of the drawings fig. 1A illustrates a treatment system fig. 1B represents a diagram illustrating a configuration of the control unit.
fig. 1C represents a diagram showing the cooling / heating element.
fig. 1D represents a uniform cooling treatment system with a control probe.
fig. 2A illustrates a treatment system for cooling lipid-rich cells within a skin fold.
fig. 2B illustrates a treatment system for cooling lipid-rich cells within a skin fold with a control probe.
fig. 3A illustrates a treatment system that includes a suction unit.
fig. 4 illustrates a treatment system that is combined with a suction system to provide treatment of an isolated area.
figs. 5 A, B illustrate a treatment system that can perimeter surround a target tissue mass.
fig. 6 represents an image of the skin surface showing the cleft after 17 days in some areas that coincide with the cold exposure sites.
fig. 7 represents the histology of subcutaneous adipose tissue 17 after exposure to cold (guinea pig II, Site E): Fig. 7A shows the low magnification view and fig. 7B shows the view in high magnification.
ES 2 300 569 T3 figs. 8A, B represent site C; 8C, D represents site E; and 8E, F represents the F site; each of which shows the histology of the subcutaneous adipose tissue 17 days after exposure to cold (Guinea Pig II, Site C, E and F).
fig. 9 represents an image of the device used to administer the cooling to the Guinea Pig III) figs. 10A, B, C, D, E, F, G, H, I, and J represent the temperature plots of exposure sites 1, 2, 7, 11, 12, 13, 14, 15, 16 and 18 of Guinea Pig III at various depths of tissue.
fig. 11 depicts an ultrasound image of Test Site 11, 3.5 months after exposure.
figs. 12A, B represent the histology of Test Site 8, 6 days after exposure. Figs. 12C, D represent the histology of Test Site 9 (control).
figs. 13A, B, C, D and E represent the macroscopic sections along the center of Test Sites 1, 3, 11, 12 and 18, 3.5 months after exposure.
Detailed description
The present description relates to a method for locally reducing adipose tissue which comprises applying a cooling element to a subject at a temperature sufficient to selectively disturb lipid-rich cells, wherein the temperature does not produce unintended effects on the cells. not rich in lipids. Preferably, the cooling element is coupled to or contains a cooling agent.
A cooling procedure for the selective disruption of lipid-rich cells in a human subject other than a young child is described which comprises applying a cooling element close to the subject's skin to create a temperature gradient within a local region. sufficient to selectively disturb and therefore reduce the lipid-rich cells of said region, and simultaneously with this, maintaining the subject's skin at a temperature where non-lipid-rich cells in the vicinity of the cooling element are not disturbed.
Also described is a method of treating a region of the body of a subject to achieve a desired reduction in subcutaneous adipose tissue, comprising a) applying a cooling element close to the skin of the subject in the region in which reduction is desired. of the subcutaneous adipose tissue to create a temperature gradient within said region sufficient to selectively disturb the lipid-rich cells of the former, and, simultaneously with this, maintaining the subject's skin at a temperature where non-lipid-rich cells near the cooling element are not disturbed; b) repeating the application of the cooling element to the skin of the subject of step (a) a plurality of times until the desired reduction in subcutaneous adipose tissue has been achieved.
The cooling elements of the present invention can contain the cooling agents in the form of a solid, liquid or gas. Solid cooling agents can comprise, for example, thermally conductive materials, such as metals, metal plates, glasses, gels, and ice or ice suspensions. Liquid cooling agents can comprise, for example, saline, glycerol, alcohol, or water / alcohol mixtures. When the cooling element includes a circulating cooling agent, preferably, the temperature of the cooling agent is constant. The salts can be combined with liquid mixtures to obtain the desired temperatures. The gases can include, for example, cold air or liquid nitrogen.
In one embodiment, the cooling elements can be applied in such a way that direct contact with a subject is accomplished, by either agent or element. In another embodiment, direct contact is made solely by the agent. In yet another embodiment, direct contact is not made by the agent or element; Cooling is accomplished by close placement of the cooling element and / or agent.
Preferably, the temperature of the cooling agent is less than about 37 ° C, but not less than -196 ° C (ie, the temperature of liquid nitrogen).
Preferably, the temperature range of the administered cooling element is between about 40 ° C and -15 ° C, even more preferably between 4 ° C and -10 ° C if the cooling agent is a liquid or a solid. Generally, the cooling element is preferably maintained at an average temperature of between about -15 ° C and about 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C, or 5 ° C; about -10 ° C and about 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C or 5 ° C; about -15 ° C and about 20 ° C, 15 ° C, 10 ° C or 5 ° C.
The element and / or cooling agent can be applied up to two hours. Preferably, the cooling agent is applied between 1 and 30 minutes. The cooling element can be applied for at least a few hundred milliseconds (eg shorter durations are envisioned, eg with sprayers). It can be applied, for example, in very short intervals (for example, approximately 1 second), repeatedly (for example, approximately
ES 2 300 569 T3 10-100 times) and between applications, a temperature is maintained that does not cause epidermal damage (eg, approximately 0 ° C to -10 ° C, depending on the length of exposure). In a mild cooling regime, for example, liquid nitrogen can be sprayed from a distance (for example, from about 10 to 30 cm) where some portion of the liquid nitrogen droplets evaporate during spraying and / or spraying. mixes with the surrounding air.
The elements and / or cooling agents of the present invention are applied, for example, to the surface of the skin through direct or indirect contact. The skin of a subject comprises the epidermis, dermis, or a combination thereof. The cooling element and / or agent is a non-toxic cooling agent when applied directly to the surface of the skin.
The element and / or cooling agent can be applied more than once, for example, in repetitive cycles. The cooling agent can be applied in a pulsed or continuous manner. The cooling element and / or agent can be applied by all conventional procedures known in the art, including topical application by spraying if in liquid, gas or solid particulate form. Preferably, the application is by external means, however, the elements and / or cooling agents of the present invention can also be applied subcutaneously by injection or other conventional means. For example, the cooling agent can be applied directly to the subcutaneous tissue and then removed after contact or left in the subcutaneous tissue to achieve thermal equilibrium and thus the cooling of the lipid-rich tissue (for example, subcutaneous injection of an agent). cooling liquid or small cooling particles, such as granules or microbeads).
Preferably, the methods of the present disclosure are non-invasive (eg, superficial or topical laparoscopic procedures that do not require invasive surgical techniques).
The cooling element and / or agent can be applied to a defined zone or to multiple zones. The spatial distribution of the element and / or cooling agent can be controlled as needed. Generally, the dimension of the surface area (eg where the cooling agent is in contact with the skin) should be at least three times the depth of the subcutaneous fatty tissue that is the target of cooling. Preferably, the minimum diameter of the surface area is at least 1 cm<sup>2</sup>. Even more preferably, the diameter of the surface area is between 3 and 20 cm.<sup>2</sup>. Determination of the optimal surface zone will require routine variation of various parameters. For example, larger surface areas can be cooled, such as those exceeding 3500 cm<sup>2</sup>, according to the methods of the present invention if hypothermia is prevented with additional means. Hypothermia can be avoided by compensating for heat transfer away from the body to other sites (by applying, for example, warm water to one or more additional sites). Multiple elements and / or cooling agents can be used, for example, by bringing larger surface areas into contact (greater than, for example, 3500 cm<sup>2</sup>).
The cooling element and / or agent can follow the contour of the zone to which it is applied. For example, flexible equipment can be used to follow the contour of the surface area where cooling is applied. The equipment can also modify the shape of the contacted surface such that the surface is contoured around or within the cooling agent or equipment containing the cooling agent upon contact. The element and / or cooling agent may come into contact with more than one surface at a time, for example, when the surface is folded and contacted on each side with the element and / or cooling agent. Preferably, a skin fold is contacted on both faces with the cooling element and / or agent to increase cooling efficiency.
Preferably, the solid cooling element and / or agent is shaped to improve the thermodynamics of heat exchange ("heat exchange") at the contacted surface (eg, the surface of the skin). In order to improve conduction, a liquid can be used at the interface between the solid cooling agent and the contacted surface.
When necessary, the application of the cooling element and / or agent can be coupled with the use of a pain management agent, such as an anesthetic or analgesic (cooling alone has analgesic properties, thus the use of additional pain management agents is optional). For example, local anesthetics can be applied topically to the point of contact before, after or during the application of the cooling agent. When necessary, systemic administration of an anesthetic can be provided by conventional procedures, such as injection or oral administration. The temperature of the cooling agent can be changed during the treatment, for example, in such a way that the cooling rate is decreased in order to provide a less discomforting treatment. Additionally, the methods of the present invention can be performed in combination with other fat reduction procedures known in the art, such as liposuction.
Preferably, the lipid-rich cells of the present invention are adipocytes within the subcutaneous fatty tissue or cellulite. Thus, the lipid-rich cells that comprise the subcutaneous adipose tissue are the target of the disturbance according to the methods of the present invention. Additionally, it is within the scope of the invention to direct the disturbance to lipid-rich cells comprising surrounding adventitious organs or other internal anatomical structures.
IS 2 300 569 T3
The intracellular lipids of adipocytes are confined within the paraplasmic vacuole. There are univacular and plurivacular adipocytes within the subcutaneous fatty tissue. Most are univacular, and larger than about 100 µm in diameter. This size can increase dramatically in obese subjects due to an increase in intracellular lipid content.
Preferably, the lipid-rich cells of the present invention have a total intracellular lipid content of between 20-99%. Preferably, the lipid-rich cells of the present invention have an intracellular lipid content comprised of 20-50% saturated triglycerides, and even more preferably about 30-40% saturated triglycerides. Intracellular triglycerides include, but are not limited to, saturated fatty acids, eg, myristic, palmitic, and stearic acid; monounsaturated fatty acids, for example palmitoleic and oleic acids; and polyunsaturated fatty acids, for example linoleic and linolenic acid.
Preferably, the lipid-rich cells of the present invention are located within the subcutaneous adipose tissue. The saturated fatty acid composition of subcutaneous adipose tissue varies according to the different anatomical positions in the human body. For example, human subcutaneous adipose tissue in the abdomen may have the following saturated fatty acid composition: myristic acid (2.6%), palmitic (23.8%), palmitoleic (4.9%), stearic (6, 5%), oleic (45.6%), linoleic (15.4%) and linolenic (0.6%). The subcutaneous adipose tissue in the abdominal area can comprise approximately 35% saturated fatty acids. This is comparatively higher than in the buttock area, which can comprise about 32% saturated fatty acids. At room temperature, the saturated fatty acids in the abdominal area are in a semi-solid state as a result of the higher fatty acid content. The buttock area is not similarly affected. Malcom G. et al., (1989) Am. J. Clin. Nutr. 50 (2): 288-91. One skilled in the art can modify temperature ranges or application times as necessary to account for anatomical differences in response to the cooling procedures of the present invention.
Preferably, the non-lipid-rich cells of the present invention have a total intracellular lipid content of less than 20%, and / are not disturbed by the cooling methods of the present invention. Preferably, the non-lipid-rich cells of the present invention include cells that have an intracellular lipid content that comprises less than about 20% highly saturated triglycerides, even more preferably less than about 7-10% highly saturated triglycerides. Non-lipid-rich cells include, but are not limited to, those surrounding subcutaneous fatty tissue, such as cells of the vasculature, peripheral nervous system, epidermis eg, melanocytes), and dermis (eg, fibrocytes).
Damage to the dermis and / or epidermis that is avoided by the methods of the present invention may involve, for example, inflammation, irritation, swelling, lesion formation, and hyper- or hypopigmentation of melanocytes.
Without wishing to be bound by theory, it is believed that selective disruption of lipid-rich cells is the result of localized crystallization of highly saturated fatty acids upon cooling to temperatures that do not induce crystallization of highly saturated fatty acids in cells not rich in lipids. The crystals break the bilayer membrane of lipid-rich cells, producing necrosis. This prevents damage to non-lipid-rich cells, such as dermal cells, at temperatures that induce crystal formation in lipid-rich cells. Cooling is also believed to induce lipolysis (eg, metabolism) of lipid-rich cells, further enhancing reduction in subcutaneous adipose tissue. Lipolysis can be enhanced by local exposure to cold which induces stimulation of the sympathetic nervous system.
In one embodiment, the temperature of the lipid-rich cells is not less than about 10 ° C. Preferably, the temperature of the lipid-rich cells is between -10 ° C and 37 ° C. More preferably, the temperature of the lipid-rich cells is between -4 ° C and 20 ° C. Even more preferably, the temperature of the lipid-rich cells is between -2 ° C and 15 ° C. Preferably, the lipid-rich cells are cooled to less than 37 ° C, for up to two hours. Generally, lipid-rich cells are preferably kept at an average temperature of between about -10 ° C and about 37 ° C, 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C , or 4 ° C; about -4 ° C and about 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C, or 4 ° C; approximately -2 ° C and approximately 35 ° C, 30 ° C, 25 ° C, 20 ° C, 15 ° C, 10 ° C, or 5 ° C.
In yet another embodiment, the temperature range of lipid-rich cells is between 37 ° C and -10 ° C. Pulse cooling procedures followed by brief warm-up periods can be used to minimize collateral damage to non-lipid-rich cells. More preferably, the temperature range of the lipid-rich cells is between -8 ° C and 33 ° C. Even more preferably, the temperature range of lipid-rich cells is between -2 ° C and 15 ° C. The temporal profile of skin cooling can be carried out in a continuous cooling action or in multiple cooling cycles or indeed in a combination of cooling cycles with active heating.
The cooling methods of the present invention advantageously eliminate unwanted effects on the epidermis. In one embodiment, the temperature of the epidermis is not less than less than about 15 ° C. Preferably, the temperature of the epidermis is between about -10 ° C and 35 ° C. More preferably, the temperature of the epidermis is between about -5 ° C and 10 ° C. Even more preferably, the temperature of the epidermis is between about -5 ° C and 5 ° C.
IS 2 300 569 T3
The cooling procedures of the present disclosure advantageously eliminate unwanted effects on the dermis. In one embodiment, the dermis temperature is not less than about -15 ° C. Preferably, the dermis temperature is between about -10 ° C and 20 ° C. More preferably, the dermis temperature is between about -8 ° C and 15 ° C. Even more preferably, the dermis temperature is between about -5 ° C and 10 ° C. In a preferred embodiment, the lipid-rich cells are cooled to about -5 ° C to 5 ° C for up to two hours and the dermal and epidermal cells maintain an average temperature of about 0 °. In the most preferred embodiment, the lipid-rich cells are cooled to about -5 to 15 ° C for times ranging from about one minute to about two hours.
The methods of the present disclosure can be applied in short intervals (for example, time intervals of 1 minute, 5 minutes, 15 minutes, 30 minutes and 60 minutes) or long intervals (for example, time intervals of 12 hours and 24 hours). Preferably the intervals are between 5 and 20 minutes. Heat can optionally be applied between cooling intervals.
Feedback mechanisms can be employed to monitor and control temperatures in the subcutaneous adipose tissue of the skin (ie, the dermis, epidermis, or a combination thereof). A feedback mechanism can monitor a subject's skin temperature to ensure that the skin temperature does not drop below a predetermined minimum temperature, eg, about -10 ° C to about 30 ° C. A non-invasive device can be applied externally to measure the surface temperature at the point of contact and / or the surrounding region. An invasive device, such as a thermocouple, can be used to measure internal temperatures.
Feedback mechanisms can include anything known in the art for monitoring temperature and / or crystal formation. Crystal formation can be measured, for example, by ultrasound or with acoustic, optical, and mechanical measurements. Mechanical measurements can include, for example, tensile strength measurements.
In one embodiment, a multilayer model can be used to estimate temperature profiles over time and at different depths. Temperature profiles are designed to produce a temperature gradient within the tissue, with the lowest temperature at the surface. In a preferred embodiment, the temperature profiles are designed to minimize blood flow during cooling. Feedback mechanisms may be employed, including, for example, thermocouples, ultrasound (for example, to detect phase changes in subcutaneous adipose tissue), or shock wave propagation (for example, shock wave propagation is alters if a phase transition occurs) to achieve optimal temperature gradients.
Substantial cooling of the subcutaneous fat layer, for example, to a target temperature between about -5 ° C and 15 ° C, by cooling the skin surface, has various requirements. The heat extracted from the skin's surface establishes a temperature gradient within the skin, which cools first the epidermis, dermis, and finally the subcutaneous fat layer. Dermal blood flow carries heat from inside the body to the dermis. Dermal blood flow can therefore severely limit the cooling of the deep dermis and the subcutaneous fat layer. Therefore, it is strongly preferred to temporarily limit or eliminate cutaneous blood flow, for example by locally applying pressure to the skin in excess of systolic blood pressure, while cooling as a treatment to achieve reduction in the subcutaneous fat layer. A general requirement is that the cooling time at the skin surface must be long enough to allow heat to flow from the dermis and subcutaneous fat layers in order to achieve the desired temperature for skin treatment. When the subcutaneous fat layer is cooled to a temperature below that of the crystallization of its lipids, the latent heat of freezing of these lipids must also be removed by diffusion. The skin surface cooling temperature and the cooling time can be adjusted to control the depth of treatment, for example the anatomical depth at which the subcutaneous fat layer is affected. The diffusion of heat is a passive process, and the temperature inside the body is almost always close to 37 ° C. Therefore, another general requirement is that the temperature of the skin surface during cooling must be below that of the desired target temperature (for example, adipocytes) for the treatment of the region, for at least part of the time during the one that the cooling is carried out.
When a skin diameter greater than about 2 cm is cooled, and without blood flow, one-dimensional heat diffusion offers a good approximation to estimate the temperature profiles in the skin during the cooling time. Heat diffusion is governed by the general diffusion equation, δΤ / δΐ = kó<sup>2</sup>T / oz<sup>2</sup>, where T (z, t) is the skin temperature as a function of depth z and time t, and κ is the thermal diffusivity, which is approximately 1.3 x 10 <sup>3</sup> cm<sup>2</sup>s<sup>-1</sup> for skin tissue. Approximate solutions and solutions for the heat diffusion equation have been formulated for the plane geometry of a semi-infinite sheet, roughly the location of the skin. When the surface of the skin (z = 0) is kept at a given low temperature, a useful approximation is that the flow of heat from a depth z requires a time of approximately t = z<sup>2</sup> to achieve a temperature difference that is half the initial difference, where t is in seconds and z is in millimeters. In this way, z can be considered<sup>2</sup> an approximate value for a temporary thermal constant. For example, if the initial skin temperature is 30 ° C, and 0 ° C ice is placed firmly against the surface of the skin, it takes about 1 second for the temperature at a depth of 1 millimeter to reach about 15 ° C. The subcutaneous fat layer normally begins at about 3 mm and is from millimeters to several centimeters thick. The temporary thermal constant for heat transfer from the top of the fat layer
ES 2 300 569 T3 subcutaneous is therefore approximately 10 seconds. To achieve substantial cooling of the subcutaneous fat layer, at least several and preferably more than 10 temporary cooling time thermal constants are required. Therefore, cooling must be maintained for approximately 30-100 seconds on the surface of the skin, and in the absence of dermal blood flow, so that the temperature of the uppermost portion of the subcutaneous fat layer approaches that of the surface of the skin. cool skin. The latent heat of crystallization of lipids, mentioned above, must also be removed when the temperature of the fat falls below that of crystallization. Thus, cooling times greater than 1 minute are generally desired, and cooling times greater than about 1 minute can be used to adjust the depth of the affected adipocytes, for times up to more than one hour.
Accordingly, in yet another embodiment, the dermis is cooled at a rate sufficient to induce vasoconstriction. Blood circulation within the dermis stabilizes the dermis temperature close to body temperature. Blood flow can be minimized in order to cool subcutaneous adipose tissue to temperatures below body temperature. Rapid cooling of the epidermal surface can achieve reflective vasoconstriction that limits blood circulation in an appropriate way.
In yet another embodiment, a vasoconstrictor drug is administered to induce vasoconstriction. Vasoconstrictor drugs can be applied, for example topically, at the point of contact before, after or during the application of the cooling agent. Administration of the vasoconstrictor drug through conventional procedures, such as injection or oral administration, can be provided when necessary. The vasoconstrictor drug can be any of those known in the art. Preferably, the vasoconstrictor drug is EMLA cream or epinephrine.
In yet another embodiment, pressure is applied to a surface, either at the point of contact with the cooling agent or in the vicinity of the former, in such a way as to limit lateral blood flow. Pressure can be applied, for example, to a skin surface by compressing the skin surface in a one-time or multiple-time skin compression. The pressure can also be applied under vacuum either at the point of contact with the cooling agent or in the vicinity of the former.
Without wishing to be bound by theory, it is believed that the rate of crystal formation in lipid-rich cells can be altered by applying pressure during the cooling process. Sudden crystallization, rather than the slow accumulation of crystals, would cause greater damage to lipid-rich cells. It is also believed that the application of pressure can force the movement of crystals within lipid-rich cells, increasing damage to the bilayer membrane. Furthermore, the different compartments of the subcutaneous adipose tissue have different viscosities. In general, the viscosity increases at lower temperatures (eg, those particularly close to the point of phase change). Because the phase change for lipid-rich cells occurs at higher temperatures than for non-lipid-rich cells, non-uniform lines of tension are formed within the subcutaneous adipose tissue upon application of pressure. Pronounced damage is believed to occur within these power lines.
In yet another aspect, the temperature of the dermis and / or epidermis ranges between 35 ° C and -15 ° C. More preferably, the temperature of the dermis and / or epidermis ranges from -10 ° C to 10 ° C. Even more preferably, the temperature of the dermis and / or epidermis ranges from -8 ° C to 8 ° C. Oscillating temperatures on the surface of the skin can provide intermittent heating to counteract the potential side effects of the cooling process (eg, crystal formation in dermal or epidermal cells).
In yet another aspect, the application of the cooling agent is coupled with the application of electric or acoustic fields, constant or oscillating in time, located in the dermis and / or epidermis, to reduce or eliminate the formation of crystals in the previous ones. .
Fig. 1A illustrates a treatment system 100 for cooling a target zone in accordance with one embodiment of the invention. As shown in fig. 1A, the treatment system 100 includes a control unit 105 and a treatment unit 107, which may include a cooling / heating element 110 and a treatment interface 115.
The control unit 105 may include a power supply, for example, the control unit may be coupled to a power source to supply power to the treatment unit 107. Control unit 105 may also include a computing device having control hardware and software to control, based on properties and / or input parameters, cooling / heating element 110 and treatment interface 115. Treatment interface 115 includes a detector 120.
Fig. 1B is a diagram illustrating a configuration of the control unit 105 according to an embodiment of the invention. As shown in fig. 1B, the control unit 105 may comprise a computing device, which may be a desktop computer (such as a PC), a workstation, a central computer system, and so on. The computing device 125 may include a processor device 130 (or central processing unit "CPU"), a memory device 135, a storage device 140, a user interface 145, a system bus 150, and a communication interface 155. CPU 130 can be any type of processing device that supports instructions, processing data, and so on. The device
IS 2 300 569 T3
135 Memory can be any type of memory device that includes one or more random access memory ("RAM"), read-only memory ("ROM"), Flash memory, electrically erasable programmable read-only memory ("EEPROM "), and so on. Storage device 140 may be any data storage device for read / write to / from any removable and / or integrated optical, magnetic and / or magneto-optical storage media, and the like (e.g., an optical disk, a read-only memory compact disc “CD-ROM”, CD rewritable “CD-RW”, digital versatile disc-ROM “DVD-ROM”, DVD-RW, and so on). System device 140 may also include a controller / interface (not shown) for connecting to system bus 150. In this way, memory device 135 and storage device 140 are suitable for storing data as well as process instructions scheduled for execution in CPU 130. User interface 145 may include a touch screen, control panel, keyboard, tablet, display, or any other type of interface that can be connected to the system bus 150 through a corresponding input / output adapter / interface device (not it shows). Communication interface 155 can be adapted to communicate with any type of external device, including treatment unit 107. Communication interface 155 can be further adapted to communicate with any system or network (not shown), such as one or more computing devices on a local area network ("LAN"), wide area network ("WAN"). , internet, and so on. Interface 155 can be connected directly to system bus 150, or it can be connected through a suitable interface (not shown). The control unit 105 may thus provide the execution of processes, by itself and / or in cooperation with one or more additional devices, which may include algorithms for controlling the processing unit 107 according to the present invention. The control unit 105 can be programmed or instructed to carry out these processes according to any communication protocol, programming language on any platform. In this way, processes can be embedded in data as well as instructions stored in memory device 135 and / or storage device 140 or received at interface 155 and / or user interface 145 for execution on CPU 130. .
Referring back to FIG. 1A, the processing unit 107 may be an electronic diary type device, automated equipment, and the like. Cooling / heating element 110 can include any type of cooling / heating component, such as a thermoelectric cooler and the like.
Fig. 1C is a diagram showing the cooling / heating element 110 according to an embodiment with the present invention. As shown in fig. 1C, cooling / heating element 110 may include a network of passageways through which a plug flow cooling / heating liquid flows. The passages can be formed by any conductive heat pipes and the like. Cooling / heating fluid can be directed into element 110 through an inlet 175 and expelled through an outlet 180. The cooling / heating fluid can be any fluid that has a controlled temperature, such as air / gas. or chilled liquid. For example, a chilled acetone or salt water bath can be used using ice or frozen carbon dioxide as the source of chilled liquid pumped through element 110. In this way, a circulation system can be formed in which the fluid expelled at the inlet 180 is re-cooled at the fluid source and redirected to the inlet 175. The temperature can be monitored and controlled by the control unit 105. fluid source and / or element 110, which may include the rate at which cooling fluid is pumped through element 110. As further shown in FIG. 1C, there may be a temperature difference, AT, between the regions of element 110. For example, heat can be transferred from the target tissue to the cooling fluid during treatment by causing the fluid near the outlet 180 to have a temperature greater than that of the cooling fluid near the inlet 175. This AT can be reduced by reducing the size of the element 110. In accordance with one embodiment of the invention, the configuration of the steps in element 110 and the corresponding application of element 110 to a target tissue can be adjusted to any temperature difference necessary to treat various target tissues. For example, the region of element 110 near outlet 180 can be applied to treating areas that require a higher treatment temperature, and so on. The passageways of element 110 can thus be configured according to the size, shape, formation, and so on, of the target tissue requiring the various treatment temperatures. Cooling / heating fluid can also be pumped through element 11 in a pulsating manner.
Referring back to FIG. 1A, treatment interface 115 can be any type of interface between cooling / heating element 110 and epidermis 160 to effect treatment on epidermis 160, dermis 165, and fat cells 170. For example, treatment interface 115 may include a (conductive) cooling plate, a container filled with cooling fluid, a free-forming membrane (for a complementary interface with an irregular epidermis), a convex cooling element (e.g. , as shown in Fig. 3), and the like. Preferably, treatment interface 115 comprises a heat conductive material that complements epidermis 160 for maximum heat transfer between cooling / heating element 110 and epidermis 160, dermis 165, and / or fat cells 170. For example, the treatment interface 115 can be a fluid-filled container or a membrane such that the pressure change in the cooling element 110 produced by a pulsating flow of the cooling fluid can be transferred to the target tissue .: Furthermore, the treatment interface 115 can simply be a chamber in which the cooling / heating fluid can be applied directly to the target tissue (epidermis 160, dermis and fat cells 170), for example, using a spray device and the like.
The detector 120 is a temperature monitor, eg, a thermocouple, a thermistor, and the like. Detector 120 can include any type of thermocouple, including types T, E, J, K, G, C, D, R, S, B, to monitor tissue cooling. Detector 120 may also include a thermistor, which may comprise thermally sensitive resistors.
ES 2 300 569 T3 whose resistances change with the change of temperature. The use of thermistors can be particularly advantageous due to their sensitivity. According to an embodiment of the invention, a thermistor with a large negative coefficient of resistance to temperature ("NTC") can be used. Preferably, a thermistor used as detector 120 may have a working temperature range of from about -15 ° C to 40 ° C inclusive. In addition, detector 120 may include a thermistor with active polymer or ceramic elements. A ceramic thermistor may be more preferable as it can have the most reproducible temperature measurements. A thermistor used as detector 120 can be encapsulated in a protective material such as glass. Various other temperature monitoring devices can of course also be used as dictated by the size, geometry and resolution of the desired temperature. The detector 120 may also comprise an electrode that can be used to measure the electrical resistance of the surface area of the skin. The formation of ice within the superficial structures of the skin similar to the epidermis or the dermis produces an increase in electrical resistance. This effect can be used to monitor ice formation within the dermis. Detector 120 may additionally be comprised of a combination of various measurement procedures.
The detector 120 can thus extract, among others, information on the temperature of the epidermis 160, the dermis 165 and / or the fat cells 170 as feedback to the control unit. Information on the sensed temperature can be analyzed by the control unit 105 based on the properties and / or input parameters. For example, the temperature of the fat cells 170 can be determined by calculating based on the temperature of the epidermis 160 detected by the detector 120. In this way, the treatment system 100 can non-invasively measure the temperature of the cells 170 fats. The control unit 105 then uses this information to control the continuous feedback from the treatment unit 107, adjusting, for example, the energy / temperature of the cooling / heating element 110 and the treatment interface 115, thereby maintaining the optimal treatment temperature of the target fat cells 170 while leaving the surrounding epidermis 160 and dermis 165 intact. As described above, the cooling / heating element 110 can provide adjustable temperatures in the range of about -10 ° C to 42 ° C. The automated temperature measurement and control sequence can be repeated to maintain these temperature ranges until a procedure is completed.
It should be noted that reduction of adipose tissue by cooling lipid-rich cells can be even more effective when tissue cooling is accompanied by physical manipulation, eg, massage, of the target tissue. In accordance with one embodiment of the present invention, the treatment unit 107 may include a tissue massage device, such as a vibrator device and the like. Alternatively, a piezoelectric transducer may be used within the treatment unit 107 in order to provide oscillation or mechanical movement of the cooling / heating element 107 (or better the treatment unit?). The detector 120 may include feedback devices to detect changes in the viscosity of the skin in order to monitor the effectiveness of the treatment and / or avoid any damage to the surrounding tissue. For example, a vibration sensing device can be used to detect any change in the resonance frequency of the target tissue (or surrounding tissue), which may indicate a change in the viscosity of the tissue, being mechanically moved or vibrated. by means of a vibration device contained in the treatment unit 107.
To further ensure that the epidermis 160 and / or the dermis 165 are not damaged by the cooling treatment, an optical sensing / feedback device can be used to monitor the change in the optical properties of the epidermis (diffusion enhancement if produce ice formations); An electrical feedback device can be used to monitor the change in electrical impedance of the epidermis caused by ice formation on the epidermis; and / or an ultrasound feedback device can be used to monitor for ice formation (actually to prevent it) on the skin. Any such device may include a signaling control unit 105 to stop or adjust treatment to prevent damage to the skin.
In accordance with one embodiment of the invention, the treatment system 100 can include numerous configurations and equipment. Algorithms that are designed for different types of procedures, settings, and / or equipment can be included for the control unit 105.
As shown in fig. 1D, the treatment system 100 may include a probe controller 175 and a probe 180 for minimally invasive measurement of the temperature of fat cells 170. Advantageously, the probe 180 may be able to measure a more accurate temperature of the fat cells, thereby improving the control of the treatment unit 170 and the effectiveness of the treatment.
It should be noted that the treatment system 100 can be controlled remotely. For example, the link between the control unit 105 and the treatment unit 107 may be a remote link (wired or wireless) providing the control unit 105 with remote control of the cooling / heating element 110, of the interface 115. treatment, controller probe 175, and probe 180.
While the exemplary treatment system 100 is illustrative of the basic components of a system suitable for use with the present invention, the architecture shown should not be considered limiting as many variations of the hardware configuration are possible without departing from the present invention.
Fig. 2A illustrates a treatment system 200 for cooling fat cells 170 by folding the target tissue in accordance with one embodiment of the invention. As shown in fig. 2A, the 200 system of
ES 2 300 569 T3 treatment may include corresponding control units 105 and two-sided treatment units 107 coupled to a compression unit 205. Unit 205 can be adapted to drive treatment units 107 together, thereby folding (or "pinching") target tissue (epidermis 160, dermis 165, and fat cells 170) between treatment units 107. The treatment interface 115 of the respective treatment units 107 on either face of the target tissue can thus cool the fat cells 170 on the multiple faces more effectively, as described above. Detectors 120 are included to measure and monitor the temperature of the target tissue. As shown in fig. 2A, the control units 105 can be connected to form an integrated system. In accordance with one embodiment of the present invention, the various components of system 200 can be controlled using any number of control unit (s).
As described above, physical manipulation of the target tissue can improve the effectiveness of the cooling treatment. According to one embodiment of the present invention, the compression unit 205 can vary the force with which the treatment units 107 are simultaneously propelled around the target tissue (epidermis 160, dermis 165 and fat cells 170). For example, compression unit 205 may apply a pulsating force for alternate tensioning and loosening of the fold (or "pinch") of the target tissue. The tensile strength can be further monitored to detect any changes in the properties (eg, the viscosity) of the target tissue, thereby ensuring the effectiveness and safety of the treatment.
Fig. 2B illustrates system 200 with a probe 180 similar to that of system 100 shown in FIG. 1C for minimally invasive fat cell temperature measurement. As described above, probe 180 may be able to more accurately measure a temperature of fat cells 170, thereby improving control of treatment unit 107 and effectiveness of treatment.
Figs. 3A and 3B are diagrams showing a treatment system 300 according to an embodiment of the present invention. As shown in fig. 3A, the system 300 may include a suction unit 305, and the treatment unit 107 may include the treatment interface 115 having a curved surface, forming, for example, a dome, to form and contain a chamber 310 above. epidermis 160. As shown in FIG. 3B, the suction unit 305 can be activated to draw the air out of the chamber 310 such that the target tissue (epidermis 160, dermis 165 and fat cells 170) is brought into contact with the treatment interface 115. Advantageously, treatment interface 115 can surround target fat cells 170 for more effective cooling. Treatment interface 115 may be made of a solid, rigid or flexible material that is in contact with the skin or a thermal coupling agent between the skin surface and the treatment unit. Interface surface 115 may also have multiple openings connected to suction unit 305. The skin is partially embedded within these multiple openings, which can increase the total surface area of the epidermis 160 in thermal contact with the treatment interface (eg, stretching of the skin). Skin tightening reduces the thickness of the epidermis and dermis, facilitating the cooling of fat 170. Numerous detectors 120 and / or probes 180 may be included in treatment system 300 to monitor tissue temperature during treatment, as described above with reference to FIGS. 1A, 1C, 2A and 2B, the detailed description of which will not be repeated here.
Fig. 4 illustrates a treatment system 400 according to an embodiment of the invention. As shown in fig. 4, the suction unit 305 can be connected to an aperture ring around the treatment interface 115 such that, when activated, a suction seal 410 is formed with the epidermis 160 around the treatment interface 115. As a result, treatment at the treatment interface 115 can be carried out in an isolated area of the target tissue.
Advantageously, the subject or body part may be immersed in a hot bath and the treatment at interface 115 may not be affected. Consequently, the treatment area can be enlarged while the surrounding warm environment can prevent general hypothermia.
Figs. 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 may form a band (or cylinder) around the mass 515 of the target tissue. Treatment system 500 can comprise any rigid or flexible material. Cooling / heating fluid can be pumped through treatment system 500 via inlet 175 and outlet 180, as shown in FIG. 5B. The cooling / heating element 110 can be formed by an internal container of a network of passageways, such as a pipe and the like. Heat transfer with target tissue mass 515 can be effected via treatment interface 115, which can include any heat conductive material. Treatment system 500 may further include a closure mechanism 510, such as a hook and loop closure and the like, for closure and wrapping around tissue mass 515. For example, referring to FIG. 5A, treatment system 500 can apply internal pressure to target tissue mass 515. Target tissue mass 515 can be any section, body part, or limb of a subject. For example, the target tissue mass can be an arm, upper or lower leg, waist, and so on, of a subject. The pressure and flow of the cooling fluid in the system 500 can be controlled by the control unit 105 to an optimal treatment temperature and / or pressure. A tight fit around tissue mass 515 and increased internal pressure may also allow the subject to be immersed in a hot bath. As described above, the fluid flow can be a pulsating flow.
The present invention is further described by way of the following non-limiting illustrative Examples, which provide a better understanding of the present invention and its many advantages.
IS 2 300 569 T3
Examples
Example 1
Selective damage to fat tissue by selective cooling in vivo
The procedures of the present disclosure were carried out on a 6-month-old white Hanford miniature guinea pig female ("Guinea Pig I") and a 6-month-old black female Yucatán miniature guinea pig ( "Guinea Pig II"). Guinea pigs were anesthetized using Telazol / Xylazine (4.4 mg / kg im + 2.2 mg / kg im). Inhaled anesthesia (Halothane or Isoflurane (1.5-3.0%) with oxygen (3.0 L / min) was dosed by mask and filtered with an F-air canister only if injectable anesthesia did not provide sufficient somatic analgesia. Various test sites were marked with micro tattoos by applying Indian Ink to the corners of each test site. After mapping the test sites, the cold exposures were carried out using a cooling device as described in fig. 1A. The treatment interface area was a flat area the size of 2 x 4 cm<sup>2</sup> with a built-in temperature sensor. The interface was in thermal contact with a thermoelectric heater, which was electronically regulated by a control unit such that the temperature at the interface surface was kept constant at a preset temperature. During cold exposure, the cooling device was applied to the skin with less to moderate pressure that did not produce significant mechanical compression of blood flow. The cooling element was applied to the skin without any manipulation of the surface profile.
Various combinations of pre-set cooling interface temperatures and exposure times were tested. In some locations, a heat conductive lotion was applied between the skin and the cooling interface. This heat-conducting lotion consisted mainly of glycerol. Guinea pig I was observed for 61 days until excision biopsies were obtained from all test sites and the guinea pig was sacrificed. An additional puncture biopsy obtained on day 2 was taken from test site C.
Biopsies were processed for routine light microscopy and stained with Hematoxylin and Eosin. The indicated temperature is that of the applied cooling element. Table 1 represents the parameters of the cooling application and the results obtained at various sites in Guinea Pig I:
TABLE I
<td>Site</td><td>Temperature</td><td>Weather</td><td>Lotion</td><td>Results</td>
<td rowspan="2">TO</td><td rowspan="2">-6 ° C</td><td rowspan="2">1 minute</td><td rowspan="2"> +</td><td>At 61 days:</td>
<td>No epidermal damage. No dermal damage. No slit evident. Without modifications obvious histological.</td>
<td rowspan="2">B</td><td rowspan="2">-6C</td><td rowspan="2">1 minute</td><td rowspan="2"></td><td>At 61 days:</td>
<td>No epidermal damage. No dermal damage No slit evident. Without modifications obvious histological.</td>
<td rowspan="2">C</td><td rowspan="2">-6 ° C</td><td rowspan="2">5 minutes</td><td rowspan="2"> +</td><td>At 61 days:</td>
<td>No epidermal damage. No dermal damage. Cleft due to tissue loss</td>
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<td></td><td></td><td></td><td></td><td>subcutaneous adipose (1 week to 61 days). Decrease in average size of adipocytes to a depth of between approximately 3-6 mm. Histological damage evident in adipose tissue. After 2 days: Inflammation of the tissue and panniculitis.</td>
<td>D</td><td>-3.5 ° C</td><td>5 minutes</td><td> +</td><td>At 61 days: No damage epidermal. No dermal damage. No slit evident. Histological damage bordering the adipose tissue. Decrease in average size of adipocytes.</td>
<td>AND</td><td>Control</td><td></td><td></td><td>Normal - no changes within the epidermis, dermis, and subcutaneous adipose tissue</td>
IS 2 300 569 T3
Guinea pig II was observed for 50 days until excision biopsies were obtained from all test sites and the guinea pigs were sacrificed. An additional biopsy was obtained from test site E on day 17. Biopsies were processed for routine light microscopy and stained with Hematoxylin and Eosin as described above. Table 2 represents the parameters of the cooling application and the results obtained at various sites in Cobaya II:
<td>Location- I lie</td><td>Temperature</td><td>Weather</td><td>Lotion</td><td>Results</td>
<td>C</td><td>-6C</td><td>5 minutes</td><td></td><td>At 50 days: Pronounced cleft (2- 3 mm) due to loss of subcutaneous adipose tissue. No epidermal damage. No dermal damage. Without pigmentary changes, however, the size of adipocytes and histological damage in adipose tissue decreased,</td>
<td>D</td><td>-8 'C</td><td>5 minutes</td><td></td><td>After 50 days: Pronounced cleft (23 mm) due to loss of subcutaneous adipose tissue. No epidermal damage. No dermal damage. Without pigmentary changes, however, there was damage to the adipocytes to a depth of approximately 6 mm. Decreased size of adipocytes and damage</td>
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<td></td><td></td><td></td><td></td><td>histological to adipose tissue.</td>
<td>AND</td><td>-9 ° C</td><td>5 minutes</td><td></td><td>At 50 days: Pronounced cleft (23 mm) due to loss of subcutaneous adipose tissue. No epidermal damage. No dermal damage. Without pigmentary changes, however, there was damage to the fat cells at a depth of approximately 6 mm. The size of adipocytes and histological damage to adipose tissue decreased. At 17 days: Signs of panniculitis.</td>
<td>F</td><td>-22 C</td><td>5 minutes</td><td></td><td>At 50 days: Pronounced epidermal damage with pronounced hypopigmentation. Scar formation with dermal contraction and complete ablation of subcutaneous adipose tissue.</td>
Fig. 6 depicts an image of the skin surface from Guinea Pig II test sites D, E and F, 17 days after challenge. A cleft can be seen at 1 that coincides with the cold exposure site, which coincides with test site D and 2, which coincides with test site E. No abnormal epidermal changes can be observed at these test sites . In 3, which coincides with test site F, where aggressive cooling procedures were applied, the damage to the epidermis is pronounced (eg, loss of pigmentation and formation of a central cortex).
Fig. 7 depicts the histology of Test Site E (Guinea Pig II), 17 days after cold exposure at -9 ° C for 5 minutes, in samples taken from an area below the cold exposure site. Fig. 7A represents a small increase in energy (1.25x) and FIG. 7B represents a close-up with mean power magnification (5x) of the same specimen. Epidermis 701, dermis 702, subcutaneous fat layer shown
IS 2 300 569 T3
703 and muscle layer 704. Histology reveals signs of lobular and septal panniculitis within subcutaneous fat layer 703, which is an inflammation of adipose tissue. The average size of fat cells decreased compared to the sample from the unexposed area. No evidence of tissue alterations was observed in the epidermis, dermis, or muscle layer.
A decrease in subcutaneous adipose tissue was demonstrated by clinical observation of the cleft within the skin surface at the precise location of cooling, as well as by histology (Hematoxylin and Eosin staining). Fig. 8A, B, C, D, E and F represent the histology 50 days after exposure with a low energy increase of 2.5x (Figs. 8A, 8C and 8E) and a mean energy increase of 5x (Figs. 8B, 8D and 8F) from test site C (figs. 8A and 8B), test site E (Figures 8C and 8D) and test site F (Figures (E and 8F). Epidermis 801 and dermis 802 are not damaged at test sites C and E while the more aggressive cooling regimen applied to test site F resulted in damage to the epidermis and dermis (eg, crust formation and inflammation can be observed). The subcutaneous fat layer 803 shows decreased adipocyte size and structural changes (eg, apparent condensation of the fat cell layer with fibrous septa that are embedded in the condensed fat layer). As a result of the aggressive cooling regime applied to test site F, almost the entire layer was removed, leaving only a few groups of residual fat cells. Thus, when an aggressive cooling regimen was applied (test site F), pronounced non-selective damage to the epidermis and dermis was observed.
Taken together, the results demonstrate that selective disruption of subcutaneous adipose tissue was achieved using the cooling procedures of the present disclosure without causing damage to the epidermis and dermis.
Temperature measurement was carried out during surface cooling of the skin to -7 ° C applied with pressure sufficient to stop the blood flow of the skin to illustrate the time and depth dependence of cooling, in a live guinea pig. Thermocouples inserted at depths of 0, 2, 4 and 8 millimeters were used to record the temperature. Although the conditions of this experiment were not ideal (the skin cooler was not strictly maintained at -7 ° C on the surface), it was clear that cooling of the dermis (2 mm) and fat (4 mm 8mm) generally as expected (see eg Fig. 10).
Example 2
Temperature profile measurements at various tissue depths
This study was conducted using 6-month-old, black, hairless female Yucatán minicobayas (Sinclair Research center, Columbia, MO). The guinea pig was anesthetized using Telazol / Xylazine (4.4 mg / kg im + 2.2 mg / kg im). Inhaled anesthesia (Halothane or Isoflurane (1.5-3.0%) with Oxygen (3.0 L / min) was dosed by mask and filtered with an F-air canister only if the injected anesthesia did not provide sufficient somatic analgesia. Micro-tattoo test sites were marked by applying Indian Ink to the corners of each test site and inserting hypodermic needles into the corners of those test sites. Cold exposure was carried out with a round bottom convex copper plate attached to a heat exchanger, which was cooled by a circulating cooling agent tempered to -7 ° C. the exposure time ranged from 600 to 1200 s. Table 3 represents the parameters of the cooling application and the results obtained at various sites in Guinea Pig III. The cold plate had three central openings of approximately 1mm in diameter through which thermocouples were placed to monitor the temperature profile at different depths of the tissue during cold exposure. The cold exposure device, shown in fig. 9, was firmly held at the test site during exposure to cold. Cold exposures were carried out on two different experimental days, one week apart. On the first experimental day, the thermocouples were occasionally displaced during cold exposure leading to a 0.5 mm variability of the thermocouple depth measurement. An additional set of thermocouple exposures were carried out on the second experimental day at well defined depths with minimal to none variability in thermocouple depths. The location of the thermocouples on the first experimental day at test sites 1, 2, 3, 7, 11 and 12 was 2.5, 4.5 and 10 mm deep (+/- 0.5 mm). Test sites 14, 15, 16 and 18 were treated on the second experimental day at a thermocouple depth of 2.4 and 8 mm, with displacement from minimal to none. Some thermocouple depth variability may still be present due to tissue compression during cold exposure. A solution containing glycol was used to ensure good thermal contact on the skin surface. The guinea pig was observed for 3 * / 2 months after treatment, until it was sacrificed and tissue was harvested from the test sites for analysis. Table 3 represents the parameters of the cooling application and the results obtained in various sites of Cobaya III:
IS 2 300 569 T3
<td>β</td><td>r — 1</td><td>Φ</td><td rowspan="3">Φ Ό</td><td>3Ü</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> '0</td><td>Φ</td><td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>• Η</td><td>• Η</td><td></td><td>ΓΟ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>υ</td><td>υ</td><td>Φ</td><td rowspan="5">Φ Λ Φ U</td><td></td><td> 0)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>ό</td><td>• Η</td><td> ></td><td> ©</td><td>φ</td><td>ο \ ο</td><td></td><td rowspan="3">ο \ ο σ></td><td></td><td></td><td>ο \ ®</td><td>ο \ ο</td><td></td><td></td><td></td><td></td><td>ο \ ®</td>
<td>β</td><td> 9-1</td><td>• Η</td><td></td><td>ω</td><td></td><td></td><td></td><td></td><td>σ \</td><td>Ο</td><td></td><td></td><td></td><td></td><td>L0</td>
<td>• Η</td><td>ρ</td><td>Ρ</td><td>φ</td><td>Φ</td><td> <0</td><td></td><td></td><td></td><td> |></td><td>LD</td><td></td><td></td><td></td><td></td><td> <0</td>
<td>Ε</td><td>φ</td><td>Φ</td><td>ω</td><td>Ε</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>ω</td><td>ÍL</td><td> 1—1</td><td rowspan="2">Φ</td><td>Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Η</td><td>β</td><td>φ</td><td>μ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Q</td><td>ω</td><td>Μ</td><td></td><td>Οι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>β</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> '0</td><td>ω</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>• Η</td><td>φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>υ</td><td>ω</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Φ 4J β</td><td>Φ Ε</td><td></td><td></td><td></td><td></td><td> +</td><td> +</td><td> 1</td><td> +</td><td></td><td> + +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> + +</td><td> +</td>
<td>φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>β</td><td>ΓΩ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Η</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> ©</td><td>ι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td></td><td>β</td><td>Ό</td><td></td><td></td><td></td><td>Ε</td><td>Ε</td><td></td><td>Ε</td><td></td><td>Ε</td><td>Ε</td><td></td><td></td><td></td><td></td><td></td>
<td></td><td> 3</td><td>ίδ</td><td></td><td></td><td></td><td>ε</td><td>Ε</td><td></td><td>Ε</td><td></td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td>
<td rowspan="2">Ε Λ</td><td> 44</td><td>Ό</td><td></td><td></td><td></td><td>ο</td><td>ο</td><td></td><td>ο</td><td></td><td>ο</td><td>ο</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td>
<td>η</td><td></td><td></td><td></td><td></td><td>rd</td><td>rd</td><td></td><td>rd</td><td></td><td>rd</td><td>rd</td><td>ο</td><td> 00</td><td>C0</td><td> 00</td><td> 00</td>
<td>Η</td><td></td><td rowspan="2">Ό</td><td></td><td></td><td></td><td> ©</td><td> ©</td><td></td><td> ©</td><td></td><td> ©</td><td> ©</td><td>rd</td><td> ©</td><td> ©</td><td> ©</td><td> ©</td>
<td rowspan="2">0) Η</td><td>Η</td><td></td><td></td><td></td><td>Ο</td><td>Ο</td><td></td><td>OR</td><td></td><td>υ</td><td>υ</td><td> ©</td><td>Ο</td><td>Ο</td><td>Ο</td><td>υ</td>
<td>Λ</td><td></td><td></td><td></td><td></td><td><sup>0</sup></td><td><sup>0</sup></td><td></td><td><sup>0</sup></td><td></td><td> °</td><td> 0</td><td>Ο</td><td><sup>0</sup></td><td><sup>0</sup></td><td><sup>0</sup></td><td></td>
<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td></td><td>σι</td><td></td><td>σι</td><td>m</td><td></td><td>σι</td><td>σι</td><td>Μ *</td><td>ιη</td>
<td></td><td></td><td></td><td></td><td></td><td></td><td>Ο]</td><td>CN</td><td></td><td>rd</td><td></td><td>rd</td><td>rd</td><td>Γ *</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>
<td> ©</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>π</td><td>β</td><td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>• Η</td><td>β</td><td>Φ</td><td></td><td></td><td></td><td>Ε</td><td></td><td></td><td>Ε</td><td></td><td></td><td></td><td></td><td>Ε</td><td>ε</td><td>Ε</td><td></td>
<td rowspan="3">ε Λ Ε <1></td><td> 44</td><td>Ό</td><td></td><td></td><td></td><td>Ε</td><td></td><td></td><td>Ε</td><td></td><td></td><td></td><td></td><td>Ε</td><td>Ε</td><td>Ε</td><td></td>
<td> 0</td><td>• Η</td><td></td><td></td><td></td><td>LD</td><td></td><td></td><td>LP</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Ρ</td><td></td><td></td><td></td><td></td><td>© υ</td><td></td><td></td><td>© U</td><td></td><td></td><td> <¡</td><td></td><td>© Ο</td><td>© ο</td><td>© U</td><td> <</td>
<td>Ε-ι</td><td></td><td></td><td></td><td></td><td></td><td> °</td><td></td><td></td><td><sup>0</sup></td><td></td><td></td><td></td><td></td><td><sup>0</sup></td><td> 0</td><td><sup>0</sup></td><td></td>
<td></td><td></td><td></td><td></td><td></td><td></td><td>r-</td><td>to</td><td></td><td>Γ-</td><td></td><td> 5</td><td>to</td><td>to</td><td>η</td><td>rd</td><td>ο</td><td> ¡5</td>
<td></td><td></td><td></td><td></td><td></td><td></td><td>Ε</td><td>ιη</td><td></td><td>ε</td><td></td><td></td><td>Ε</td><td></td><td></td><td></td><td></td><td></td>
<td>C</td><td></td><td></td><td rowspan="2">Ό</td><td></td><td></td><td>Ε</td><td> *</td><td></td><td>Ε</td><td></td><td></td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td></td>
<td>• Η</td><td></td><td>ά</td><td></td><td></td><td></td><td>οι</td><td></td><td></td><td></td><td></td><td></td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td>
<td>Ε Λ</td><td> ©</td><td>β 44</td><td>Φ Ό</td><td></td><td></td><td>LD (Μ</td><td>© υ</td><td></td><td>ιη 04</td><td></td><td></td><td>LT CN</td><td>σι ©</td><td>σι ©</td><td>σι ©</td><td>σι ©</td><td>Ε</td>
<td>Have</td><td></td><td>pro</td><td>Η τι</td><td></td><td></td><td>© Ο ο</td><td>οι Ε 1 Ε</td><td></td><td>© υ η</td><td></td><td>Ν / Α</td><td>© u Μ *</td><td>Ο</td><td>OR Ί *</td><td>Ο</td><td>Ο 'Τ I</td><td>© OR η</td>
<td>Ν</td><td></td><td></td><td></td><td></td><td></td><td> 0</td><td> 0</td><td> 0</td><td>β</td><td>β</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0</td>
<td>• Η</td><td>β</td><td></td><td></td><td></td><td></td><td>Ό</td><td>Ό</td><td>Ό</td><td>φ</td><td>φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td>Ό</td>
<td>γ * Η</td><td> '0</td><td></td><td></td><td></td><td></td><td>Φ</td><td>Φ</td><td>Φ</td><td>Ε</td><td>Ε</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td>
<td>(ΰ</td><td>• Η</td><td></td><td></td><td></td><td></td><td>OR</td><td>Ρ</td><td>4J</td><td>Ο</td><td> 0</td><td>οι</td><td>Οι</td><td>Cn</td><td>Cn</td><td>Οι</td><td> 01</td><td>Ρ</td>
<td>υ</td><td>Ο</td><td></td><td></td><td></td><td></td><td>ω</td><td>ω</td><td>ω</td><td>τι</td><td>τΐ</td><td>Rh</td><td>ι — 1</td><td>Γ — 1</td><td>ι — 1</td><td> 1</td><td>ι — 1</td><td>ω</td>
<td> 0</td><td>Φ</td><td></td><td></td><td></td><td></td><td> 0</td><td> 0</td><td> 0</td><td>Λ</td><td>Λ</td><td>φ</td><td>φ</td><td>φ</td><td>Φ</td><td>φ</td><td>Φ</td><td> 0</td>
<td>h-3</td><td></td><td></td><td></td><td></td><td></td><td>υ</td><td>Ο</td><td>OR</td><td>ϊ?</td><td> 3</td><td>to</td><td> 15</td><td> !5</td><td> 5</td><td></td><td> ¡5</td><td>OR</td>
<td> 0)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ω</td><td></td><td>ω</td><td>Φ</td><td>U1</td><td>ω</td><td>ω</td><td>ω</td><td>φ</td>
<td rowspan="2">Ό</td><td></td><td></td><td></td><td></td><td></td><td>σ></td><td>CQ</td><td></td><td> 0</td><td></td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>
<td></td><td></td><td></td><td></td><td></td><td> 0</td><td> 0</td><td></td><td>4J</td><td></td><td>4J</td><td>Ρ</td><td>Ρ</td><td>-Ο</td><td>Ρ</td><td>-Ρ</td><td>4J</td>
<td> 0</td><td>ω</td><td>β</td><td></td><td></td><td></td><td>4J</td><td>4J</td><td></td><td>β</td><td></td><td>β</td><td>β</td><td>β</td><td>β</td><td>β</td><td>β</td><td>β</td>
<td>α</td><td> 0</td><td>Ό</td><td></td><td></td><td></td><td>β</td><td>β</td><td></td><td>β</td><td></td><td>β</td><td>β</td><td>β</td><td>β</td><td>β</td><td>β</td><td>β</td>
<td>g</td><td>Λ</td><td>-Η</td><td></td><td></td><td></td><td>β</td><td>β</td><td></td><td>• Η</td><td></td><td>· Γ |</td><td>• Η</td><td>-Η</td><td>• Η</td><td>Ή</td><td>• Η</td><td>-Η</td>
<td>Φ</td><td>X</td><td>OR</td><td></td><td></td><td></td><td>• Η</td><td>Η</td><td></td><td>Ε</td><td></td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td><td>Ε</td>
<td>-Η</td><td>φ</td><td></td><td></td><td></td><td></td><td>Ε</td><td>Ε</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Εη</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Ο</td><td></td><td>Ο</td><td>ο</td><td>Ο</td><td>Rh</td><td> —1</td><td>Ο</td><td>U1</td>
<td></td><td></td><td></td><td></td><td></td><td></td><td>ιη</td><td>LD</td><td></td><td>γΗ</td><td></td><td> (—1</td><td>γΗ</td><td>γΗ</td><td>C4</td><td>γ-1</td><td>Γ — 1</td><td>γΗ</td>
<td>05 Ρ β</td><td>of</td><td>I</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Ρ></td><td rowspan="2">ω 4J</td><td>Φ</td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td> 05</td><td>• Η</td><td>Ρ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>ρ</td><td>β</td><td>ρ</td><td>β</td><td></td><td></td><td></td><td></td><td> 0</td><td></td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>φ</td><td> 0)</td><td> 9-1</td><td>φ</td><td></td><td></td><td>Ο</td><td>ο</td><td>Μ</td><td>ο</td><td>μ</td><td>Ο</td><td>υ</td><td>OR</td><td>Ο</td><td>ο</td><td>ο</td><td>ο</td>
<td></td><td>1Π</td><td>β</td><td>• Η</td><td></td><td></td><td> 0</td><td> 0</td><td>4J</td><td> 0</td><td>-Ρ</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>
<td>ε</td><td>π3</td><td>φ</td><td>Ε</td><td></td><td></td><td></td><td></td><td>β</td><td></td><td>β</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Q)</td><td></td><td></td><td></td><td></td><td></td><td>Γ-</td><td></td><td>ο</td><td></td><td>ο</td><td>ι></td><td>Γ **</td><td>Ι></td><td>Ο</td><td>Γ</td><td>Γ-</td><td> [></td>
<td>Η</td><td></td><td></td><td></td><td></td><td></td><td>I</td><td> 1</td><td>ο</td><td> 1</td><td>υ</td><td> 1</td><td> 1</td><td> 1</td><td>I</td><td> 1</td><td>I</td><td> 1</td>
<td>Φ</td><td></td><td> 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Rh</td><td></td><td>β</td><td> .</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Λ</td><td>Φ</td><td>φ</td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Ε</td><td>Ν</td><td>• Η</td><td>4J</td><td></td><td></td><td></td><td></td><td></td><td></td><td colspan="2">1 Η</td><td>C4</td><td>ΓΏ</td><td></td><td>L0</td><td>Κ0</td><td> 00</td>
<td>W</td><td></td><td>Ε</td><td></td><td></td><td></td><td>γΗ</td><td>(Μ</td><td>η</td><td></td><td>σ></td><td>1 Η</td><td>Rh</td><td>Γ — 1</td><td>Rh</td><td>γ — 1</td><td>Rh</td><td>Rh</td>
IS 2 300 569 T3
The test sites were exposed to the device, adjusted to a refrigerant temperature of -7 ° C, and exposed for 600 s and 1200 s. The dermis hardened immediately after exposure to cold, as determined by palpation, and became viscous as it returned to its normal temperature, approximately one minute after exposure. There was no evident epidermal damage or alteration on examination of healing with polarized magnifying lenses minutes after exposure. There was no bubble formation and the Nikolsky signs were negative. During the entire survival period there was no major damage to the epidermis. No crusts, bubbles or pronounced pigmentary changes were observed. Some test sites have a minor increase in epidermal pigmentation. This mild hyperpigmentation could be removed after a few months by gently rubbing the epidermis.
The temperature measurements of the thermocouples depended on the depth, body location, and the pressure with which the cooling was applied. They are shown in figs. 10 AJ the graphs of temperature at different depths of the tissue during cold exposure for various test sites and are also summarized in Table 3. For some test sites, it was observed that the temperature oscillations could be related to a glass nearby blood. Some temperature graphs were not considered due to movement or misplacement of the thermocouple (marked as 'error' in table 3). The temperature within the deep dermis or superficial fat layer is within the range of -2 ° C to -4 ° C. The temperature within 4-5 mm of depth is within the range of approximately 0 ° C to 7 ° C depending on variations in contact pressure and anatomical area. This location showed a high variability of the different temperature graphs. The temperature within the 8-10 mm depth, which corresponds to a depth within the subcutaneous fat layer had a temperature in the range of 7-24 ° C.
Histology was obtained from a control (site 9) and a cold-exposed site (site 8) (-7 ° C, 600 s) 6 days after challenge and analyzed by a dermatopathologist. The following were described at the control and cold site:
The epidermis of both samples is normal and presents basket-woven stratum corneum with normal thickness, normal interpapillary ridges compared to the control. Mild perivascular lymphocytic infiltration is present within the cold-exposed site. However, there are no clear signs of vasculitis present in both samples.
Control subcutaneous fat has normal morphology. The subcutaneous fat at the cold site shows clear signs of lobular and septal panniculitis. Most adipocytes are surrounded by lymphocytes infiltrated with occasional lipids that contain macrophages. The thickness of the subcutaneous septa is increased. Mild vascular changes do not show overt signs of vasculitis. Three and a half months after exposure to cold, the guinea pig was sacrificed and tissue from the exposure sites was harvested by full thickness excision, after which 20 MHz ultrasound was performed at the sites of selected essays. In vivo ultrasound clearly demonstrated the loss of fatty tissue in the treatment area by cooling the skin against surrounding tissue exposed without cold. In fig. eleven An in vivo ultrasound is shown 3 * / 2 months after cold exposure.
Harvested tissue was cut microscopically along the test sites and macroscopic tissue cross-sections were imaged. In fig. 13 AE shows the macroscopic cross sections of sites 1, 3, 11, 12 and 18. A decrease in the thickness of the subcutaneous fat layer was observed at all sites exposed to cold versus the adjacent layer of fat not exposed to cold. cold. Gross cross-sections match well with ultrasound. Two different compartments could be identified within the subcutaneous fat layer, a superficial fat layer and a deep fat layer. The thickness of the surface fat layer was drastically reduced at cold treatment sites, while the depth of the fat layer did not change significantly. The percentage of reduction of the superficial fat layer in the interior of the test zone compared to the exterior is listed for some test sites in Table 3. A subcutaneous fat layer change was observed for cold exposed sites 1, 11, 12 and 18. The average decrease in surface fat layer thickness within the tested test sites was 47%. For the unexposed control face, no significant decrease in thickness was found in any fat layer.
These examples confirm that it is possible in a guinea pig model to achieve selective damage to the subcutaneous adipose tissue by external cooling within a specific range of external cooling temperature and exposure time, without significant damage to the epidermis and dermis. Removal of subcutaneous fat was also demonstrated by an obvious indentation in the surface of the treated skin, which exactly coincided with the exposure to cooling, and with measurements of the fat layer in relation to the site of exposure to cold and the macroscopic cross sections after sacrifice. Pronounced histological changes, which were selective in subcutaneous adipose tissue, were observed 6 days after cold exposure. Histologically, a panniculitis with a decrease in fat cell size was observed. There was evidence that the cold response of different sites may vary and that the more superficial fat layer is more affected by tissue loss than the deeper fat layer. The Guinea Pig III results however imply that there is an improvement in fat removal in the superficial fat layer versus the deeper layer. The explanation for this is a) the surface fat layer is exposed to lower temperatures due to the gradient and / or b) the deeper fat layer in guinea pigs may be less susceptible to selective cold damage.
IS 2 300 569 T3
Fig. 9 represents an image of the device for exposure to cold of Guinea Pig III. The cold copper plate 91 is brought into contact with the skin. The temperature profile within the skin during cold exposure was measured by thermocouples 29 inserted into the tissue at different depths. The device is spring loaded 93 to provide pressure during cold exposure.
Fig. 10 represents the temperature profile at various depths during cold exposure of Guinea Pig III for 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 (Site 15), 10I ( site 16) and 10J (site 18). The temperature was marked at various depths with T3-E (surface), T0-B (2-2.5 mm), T1-C84-5 mm) and T2-D (8-10 mm).
Fig. 11 represents an ultrasound of test site 11 taken 3 * / 2 months after exposure. The section below 1105 is external to the section of the cold exposed area below 1106. You can clearly distinguish the dermis 1102 from the fat layer 1103 and the muscle layer 1104. Within the fat layer 1103, two distinct layers can be distinguished; the surface fat layer 1103a and the deep fat layer 1103b. The ultrasound matches well with the macroscopic cross section of the same tissue in fig. 13c.
Fig. 12 depicts the histology of Test Site 8 (Fig. 12A and 12B) six days after cold exposure (-7 ° C, 600 s) and Test Site 9, which is an unexposed control (Fig. 12C and 12D). The micrographs show a low power magnification image (1.25x) in Figs. 12A and 12C and an average increase in energy (5x) in FIG. 12B and 12D. The images show epidermis 701, dermis 702 and subcutaneous fat 703.
While the unexposed control shows normal tissue morphology, the cold-exposed tissue shows clear signs of panniculitis in the subcutaneous fat. Inflammatory cells have migrated into this area and the average fat cell size has decreased.
Figs. 13 AE represent macroscopic sections along the center of the different test sites after the guinea pig was sacrificed, 3 * / 2 months after cold exposure: 13A (site 1), 13B (site 3); fig. 13C (location 11), fig. 13D (location 12) and fig. 13E (site 18). Each figure is 1300 scale, having 1cm units and 1mm subunits. The epidermis 1301, the dermis 1302, the superficial fat layer 1303 and the deep fat layer 1304. For the unexposed control of fig. 13B no thickness changes were observed in the different layers. Figs. 13A, 13C, 13D and 13E show the cross-section of the cold exposed areas, which coincide with the central 4-5 cm of tissue and the surrounding non-cold areas. A decrease in thickness within the surface fat layer of cold-exposed versus non-cold-exposed areas can be observed in all cold-exposed samples. In Table 3, the change in% of the thickness for each sample is listed.
Numerous embodiments of the invention have been described. However, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
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Numbers
- Publication
- 2300569
- Publication, DOCDB
- 2300569
- Publication, EPODOC
- ES2300569T
- Application
- 3716609
- Application, DOCDB
- 03716609
- Application, EPODOC
- ES20030716609T
Titles2
- English
- DEVICES FOR SELECTIVE PERTURBATION OF FAT FABRIC THROUGH CONTROLLED COOLING.
- Spanish
- DISPOSITIVOS PARA LA PERTURBACION SELECTIVA DE TEJIDO GRASO MEDIANTE ENFRIAMIENTO CONTROLADO.
Classification
- CPC, 16
- A61F7/00
- A61B5/415
- A61B18/02
- A61B5/6804
- A61F7/10
- A61B2018/0237
- A61F2007/0056
- A61B2018/0262
- A61F2007/0075
- A61F2007/0094
- A61F2007/0054
- A61F2007/0096
- A61F2007/029
- A61F2007/0082
- A61F2007/0239
- A61H23/00
- IPC, 6
- A61F7 00
- A61B18 02
- A61F7 10
- A61H23 02
- C12N5 07
- C12N5 077