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`EP 1 917 935 B1
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`EUROPEAN PATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`12.01.2011 Bulletin 2011/02
`
`(21) Application number: 07117532.7
`
`(22) Date of filing: 17.03.2003
`
`(51) Int Cl.:
`A61F 7/00‘2‘705'm)
`
`(54) Method for selective disruption oi Iatty tissue by controlled cooling
`
`Verfahren zur selektiven Spaltung von Fettgewebe durch gesteuerte KUthng
`
`Procédé pour la dislocation sélective d’un tissu gras par refroidissement controlé
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
`HU IE IT LI LU MC NL PT RO SE SI SK TR
`
`(30) Priority: 15.03.2002 US 365662 P
`
`(43) Date of publication of application:
`07.05.2008 Bulletin 2008/19
`
`(60) Divisional application:
`10167756.5 [2 241 295
`10181697.3 / 2 260 801
`
`(62) Document number(s) of the earlier application(s) in
`accordance with Art. 76 EPC:
`03716609.? /1 490 005
`
`(73) Proprietor: The General Hospital Corporation
`Boston, MA 02114 (US)
`
`(72) Inventors:
`0 Anderson, Richard, Rox
`Massachusetts General Hospitals
`275 Cambridge Street
`Ste. 501
`Boston, MA 02114-3130 (US)
`0 Manstein, Dieter
`Massachusetts General Hospitals
`275 Cambridge Street
`Ste. 501
`Boston, MA 02114-3130 (US)
`
`(74) Representative: Hansen, Norbert
`Maiwald Patentanwalts GmbH
`Elisenhof
`ElisenstraBe 3
`
`80335 Miinchen (DE)
`
`(56) References cited:
`WO-A1-97/24088
`US-A- 4 869 250
`US-A- 6 017 337
`
`GB-A- 2 286 660
`US-A- 5 339 541
`US-A1- 2001 023 364
`
`EP1917935B1
`
`
`
`Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
`Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
`Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`

`

`EP1917 935 B1
`
`Description
`
`FIELD OF THE INVENTION
`
`[0001] The present invention relates to methods for use in the selective disruption of lipid-rich cells by controlled
`cooling. The present invention further relates to a device for use in carrying out the methods for selective disruption of
`lipid-rich cells by controlled cooling. Other aspects of the invention are described in or are obvious from the following
`disclosure (and within the ambit of the invention).
`
`BACKGROUND
`
`[0002] The subcutaneous fatty tissue of newborns is unusually sensitive to the cold. In newborns, the intracellular lipid
`content of the subcutaneous fat cells, or "adipocytes," comprises increased ratios of highly saturated triglycerides. Even
`moderately cold temperatures can adversely affect cells having a highly saturated lipid content, rendering newborn
`subcutaneous fatty tissue vulnerable to adipocyte necrosis following exposure to the cold. Hypothermia of subcutaneous
`fatty tissue can result in associated inflammation of the dermis and/or epidermis. For example, disorders of cold pan-
`niculitis in newborns are known to produce painful skin lesions.
`[0003] As newborns mature, the ratio of saturated to unsaturated fatty acids among intracellular triglycerides of adi-
`pocytes gradually decreases. Having a higher content of unsaturated fatty acids is more protective against the cold, and
`the occurrence of cold panniculitis in infants gradually subsides. For detailed reviews on the subject of cold panniculitis,
`see Epstein et al. (1970) New England J. of Med. 282(17):966-67; Duncan et al. (1 966) Arch, Den’n. 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 (W.B. Saunders Company):1169 —1181; John C Maize (1998) Panniculitis In
`Cutaneous Pathology (Churchill Livingstone): 327—344; Bondei, Edward E. and Lazarus, Gerald S. (1993) Disorders of
`Subcutaneous Fat (Cold Panniculitis). In Dermatology in General Medicine (McGraw—Hill, Inc.): 1333—1334
`[0004]
`In adults, the intracellular lipid content varies among cell types. Dermal and epidermal cells, for instance, are
`relatively low in unsaturated fatty acids compared to the underlying adipocytes that form the 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 Handbook of Physiology (American Physiology Society): 170-176. As a result, the different
`cell types, e.g., lipid-rich and non-lipid-rich cells, have varying degrees of susceptibility to the cold. In general, non-lipid-
`rich cells can withstand colder temperatures than lipid-rich cells.
`[0005]
`It would be highly desirable to selectively and non-invasively damage adipocytes of the subcutaneous fatty
`tissue without causing injury to the surrounding dermal and epidermal tissue. Both health and cosmetic benefits are
`known to result from reduction of fattytissue, however, current methods, such as liposuction, involve invasive procedures
`with potentially life threatening risks (e.g., excessive bleeding, pain, septic shock, infection and swelling).
`[0006] Current methods for non—invasive removal of subcutaneous fatty tissue include the use of radiant energy and
`cooling solutions. U.S. Patent No.s 5,143,063, 5,507,790 and 5,769,879 describe methods for using radiant energy to
`reduce subcutaneous fatty tissue, however, the applied energy levels are difficult to control and often there is collateral
`damage to the dermis and/or epidermis. Cooling solutions proposed by WO 00/44346 do not stabilize skin surface
`temperatures and therefore, also fail to adequately protect against collateral damage to the dermis and/or epidermis.
`[0007] A previous study conducted in Guinea Pigs described the removal of subcutaneousfatty tissue by cryo-damage.
`Burge, S. and Dawber, R. (1990)Cryobiology 27:153-163. Howeverthis result was achieved using relatively aggressive
`cooling modalities (e.g., liquid nitrogen), which induced epidermal damage. Ideally, removal ofsubcutaneous fatty tissue
`by cooling would not cause associated damage to the epidermis. Reference is made to US 6 017 337.
`[0008] Temperature controlled methods and devices for selectively damaging lipid-rich cells (e.g., adipocytes com-
`prising the subcutaneous fatty tissue) without causing injury to non lipid-rich cells (e.g., dermis and/or epidermis) were
`heretofore unknown.
`
`SUMMARY
`
`It has now been shown that adipose tissue comprising lipid-rich cells can be selectively disrupted without
`[0009]
`causing injury to the surrounding non lipid-rich tissue (e.g., dermal and epidermal tissue) by controlling the temperature
`and/or pressure applied to the respective tissues.
`[0010] The invention relates to a cosmetic treatment method as defined in appended claim 1. Preferred embodiments
`are described in the dependant claims.
`comprising,
`[0011]
`In this disclosure, "comprises,
`containing" and "having" and the like can have the meaning
`ascribed to them in U.S. Patent law and can mean " includes," "including," and the like; "consisting essentially of" or
`"consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing forthe
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`EP1917 935 B1
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`presence of more than thatwhich is recited so long as basic or novel characteristics of that which is recited is not changed
`by the presence of more than that which is recited, but excludes prior art embodiments.
`[0012] These and other objects and embodiments are described in or are obvious from and within the scope of the
`invention, from the following Detailed Description.
`
`DESCRIPTION OF THE DRAWINGS
`
`[0013]
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`Figure 1A illustrates a treatment system.
`Figure 1B depicts a diagram illustrating a configuration of control unit.
`Figure 1C depicts a diagram showing cooling/heating element.
`Figure 1D illustrates a flat cooling treatment system with a probe controller.
`Figure 2A illustrates a treatment system for cooling lipid-rich cells within a skin fold.
`Figure 28 illustrates a treatment system for cooling lipid-rich cells within a skin fold with a probe controller.
`Figure 3A illustrates a treatment system that includes a suction unit.
`Figure 4 illustrates a treatment system that is combined with suction system to provide treatment of an isolated area.
`Figure 5A, B illustrate a treatment system which can enclose circumferentially a target tissue mass.
`Figure 6 depicts an image of the skin surface showing indentation after 17 days at some areas matching cold
`exposure sites.
`Figure 7 depicts histology of the subcutaneous adipose tissue 17 days after cold exposure (Pig ll, Site E). Figure
`7A shows the low magnification view and Figure 7B shows the high magnification view.
`Figure 8A, B depicts Site C; 8 C, D depicts Site E; and 8 E, F depicts Site F; each of which show histology of the
`subcutaneous adipose tissue 17 days after cold exposure (Pig ll, Site C, E and F).
`Figure 9 depicts an image of the device used to administer cooling to Pig I”.
`Figure 10A, B, C, D, E, F, G, H,
`l, and J depicts temperature plots ofthe exposure sites 1, 2, 7, 11, 12, 13,14, 15,
`16 and 18 of Pig III in various tissue depths.
`Figure 11 depicts an ultrasound image of test Site 11, 3.5 months after exposure.
`Figure 12A, B depicts histology of test Site 8, 6 days after exposure. Figure 120, D depicts histology of test Site 9
`(control).
`Figure 13A, B, C, D, and E depicts macroscopic sections through the center of test Sites 1,3, 11, 12 and 18, 3.5
`months after exposure.
`
`DETAILED DESCRIPTION
`
`[0014] The present invention relates to a method for locally reducing adipose tissue comprising applying a cooling
`element to a subject at a temperature sufficient to selectively disrupt lipid—rich cells, wherein the temperature does not
`produce unwanted effects in non lipid-rich cells. Preferably, the cooling element is coupled to orcontains a cooling agent.
`[0015]
`In one aspect, the invention relates to a cooling method for selective disruption of lipid-rich cells in a non-infant
`human subject comprising applying a cooling element proximal to the subject’s skin to create a temperature gradient
`within a local region sufficient to selectively disrupt and thereby reducethe lipid-rich cells of said region, and, concurrently
`therewith maintain the subject’s skin at a temperature wherein non lipid-rich cells proximate to the cooling element are
`not disrupted.
`[0016]
`In one embodiment, the invention relates to a method for treating a region of a subject’s body to achieve a
`desired reduction in subcutaneous adipose tissue, comprising a) applying a cooling element proximal to the subject’s
`skin in the region where subcutaneous adipose tissue reduction is desired to create a temperature gradient within said
`region sufficient to selectively disrupt lipid—rich cells therein, and, simultaneously therewith maintain the subject’s skin
`atatemperaturewherein non lipid—rich cells proximateto the cooling clement are not disrupted; b) repeatingthe application
`of the cooling element to the subject’s skin of step (a) a plurality of times until the desired reduction in subcutaneous
`adipose tissue has been achieved.
`liquid or gas. Solid cooling agents can
`[0017] Cooling elements can contain cooling agents in the form of a solid,
`comprise, for example thermal conductive materials, such as metals, metal plates, glasses, gels and ice or ice slurries.
`Liquid cooling agents can comprise, for example, saline, glycerol, alcohol, or water/alcohol mixtures. Where the cooling
`element includes a circulating cooling agent, preferably the temperature of the cooling agent is constant. Salts can be
`combined with liquid mixtures to obtain desired temperatures. Gasses can include, for example, cold airor liquid nitrogen.
`[0018]
`In one embodiment, cooling elements can be applied such that direct contact is made with a subject, via either
`the agent orthe element. In another embodiment, direct contact is made viathe agent alone. In yet another embodiment,
`no direct contact is made via either the agent or the element; cooling is a carried out by proximal positioning of the
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`EP1917 935 B1
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`cooling element and/or agent.
`[0019]
`Preferably, the temperature of the cooling agent is less than about 37°C, but not less than -196°C (i.e, the
`temperature of liquid nitrogen).
`[0020]
`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.
`[0021] The cooling element and/or agent can be applied for up to two hours. Preferably, the cooling element is applied
`for between 1
`to 30 minutes. The cooling element can be applied for at least one hundred milliseconds (e.g., shorter
`durations are envisioned, for instance, with sprays). For example, liquid nitrogen can be applied in very short intervals
`(e.g., about 1 second), repeatedly (e.g., about 10—100 times) and between applications, a temperature that does not
`cause epidermal damage is maintained (e.g., about 0°C to -10°C, depending on the length of exposure). In a gentle
`cooling regime, for example, the liquid nitrogen can be sprayed from a distance (e.g., from about 1 O to 30 cm) wherein
`some portion of the liquid nitrogen droplets evaporate during the spraying and/or mix with ambient air.
`[0022] Cooling elements and/or agents are applied, for example, to the skin surface through either direct or indirect
`contact. A subject’s skin 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 skin surface.
`[0023] The cooling element and/or agent can be applied more than once, for example, in repetitious cycles. The cooling
`agent can be applied in a pulsed or continuous manner. The cooling element and/or agent can be applied by all con-
`ventional methods known in the art, including topical application by spray if in liquid form, gas or particulate solid material.
`Application is by external means.
`[0024] Methods of the present invention are non—invasive (e.g., superficial, laparoscopic or topical procedures not
`requiring invasive surgical techniques).
`[0025] The cooling element and/or agent can be applied to one defined area or multiple areas. Spatial distribution of
`the cooling element and/or agent can be controlled as needed. Generally, the dimension of the surface area (e.g., where
`the cooling agent is in contact with the skin) should be at least three times the depth of subcutaneous fatty tissue that
`is targeted for cooling. Preferably, the minimum diameter of the surface area is at least 1 cm2. Even more preferably,
`the diameter of the surface area is between 3 to 20 cm2. Determination of the optimal surface area will require routine
`variation of several parameters. Forexample, larger surface areas, such as those over3500 cm2, can be cooled according
`to the methods ofthe present invention if hypothermia is prevented by additional means. Hypothermia can be prevented
`by compensating for the heat transfer away from the body at other sites (e.g., applying warm water at one or more
`additional sites). Multiple cooling elements and/or agents can be employed, for example, in contacting larger surface
`areas (e.g., greater than 3500 cm2).
`[0026] The cooling element and/or agent can follow the contour of the area to which it is applied. For example, a
`flexible apparatus can be used to follow the contour of the surface area where cooling is applied. The apparatus can
`also modify the shape of the contacted surface such that the surface is contoured around or within the cooling agent or
`the apparatus containing the cooling agent upon contact. The cooling element and/or agent can contact more than one
`surface at once, for example, when the surface is folded and contacted on either side by the cooling element and/or
`agent. Preferably, a skin fold is contacted on both sides by the cooling element and/or agent to increase the efficiency
`of cooling.
`[0027]
`Preferably, the solid cooling element and/or agent is shaped to enhance thermodynamic heat exchange ("ther-
`mal exchange") at the contacted surface (e.g., skin surface). In order to enhance conduction, a liquid can be used at
`the interface between the solid cooling agent and the contacted surface.
`[0028] Where necessary, application ofthe cooling elementand/oragent can be coupled with use ofa pain management
`agent, such as an anesthetic oranalgesic (cooling alone has analgesic properties, thus use ofadditional pain management
`agents is optional). Local anesthetics, for example, can be topically applied at the point of contact either before, after or
`during application of the cooling agent. Where necessary, systemic administration of the anesthetic can be provided
`through conventional methods, such as injection or oral administration. The temperature of the cooling agent can be
`changed during the treatment, for example, so that the cooling rate is decreased in order to provide a treatment causing
`less discomfort. In addition, methods of the present invention can be performed in combination with otherfat reduction
`procedures known in the art, such as liposuction.
`lipid-rich cells
`[0029]
`Preferably,
`lipid-rich cells are adipocytes within subcutaneous fatty tissue or cellulite. Thus,
`comprising the subcutaneous adipose tissue are targeted for disruption by methods of the present invention. In addition,
`it is within the ambit of the invention to target disruption of lipid-rich cells comprising adventicia surrounding organs or
`other internal anatomical structures.
`
`[0030] The intracellular lipids of adipocytes are confined within the paraplasmatic vacuole. There are univacular and
`plurivacular adipocytes within the Subcutaneous fatty tissue. Most are univacular, and greater than about 100um in
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`EP1917 935 B1
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`diameter. This size can increase dramatically in obese subjects clue to an increase in intracellular lipid content.
`[0031]
`Preferably, lipid-rich cells in the present invention have a total intracellular lipid content of between 20-99 %.
`Preferably, lipid-rich cells ofthe present invention have an intracellular lipid content comprised of about 20- 50% saturated
`triglycerides, and even more preferably about 30-40% saturated triglycerides. Intracellular triglycerides include, but are
`not limited to, saturated fatty acids e.g., myristic, palmitic and stearic acid; monounsaturated fatty acids, e.g., palmitoleic
`and oleic acid; and polyunsaturated fatty acids e.g., linoleic and linolenic acid.
`[0032]
`Preferably, lipid-rich cells in the present invention are located within subcutaneous adiposetissue. The saturated
`fatty acid composition of subcutaneous adipose tissue varies at different anatomical positions in the human body. For
`example, human subcutaneous adipose tissue in the abdomen can have the following composition of saturated fatty
`acids: myristic (2.6 %), palmitic (23.8 %), palmitoleic (4.9%), stearic (6.5%), oleic (45.6%), linoleic (15.4 %) and linolenic
`acid (0.6%). The subcutaneous adipose tissue of the abdominal area can comprise about 35% saturated fatty acids.
`This is comparatively higher than the buttock area, which can comprise about 32% saturated fatty acids. At room
`temperature, saturated fatty acids of the abdominal area are in a semisolid 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 the
`response to cooling methods of the present invention.
`[0033]
`Preferably, non lipid-rich cells in the present invention have a total intracellular lipid content of less than 20%,
`and/or are not disrupted by cooling methods of the present invention. Preferably, non lipid-rich cells in the present
`invention include cells having an intracellular lipid content comprising less than about 20% highly saturated triglycerides,
`even more preferably less than about 7-1 0% highly saturated triglycerides. Non lipid-rich cells include, but are not limited
`to, those surrounding the subcutaneous fattytissue, such as cells ofthevasculature, peripheral nervous system, epidermis
`(e.g., melanocytes) and dermis (e.g., fibrocytes).
`[0034] Damage to the dermis and/or epidermis that is avoided by the methods of the present invention can involve,
`for example, inflammation, irritation, swelling, formation of lesions and hyper or hypopigmentation of melanocytes.
`[0035] Without being bound by theory, it is believed that selective disruption of lipid—rich cells results from localized
`crystalization of highly saturated fatty acids upon cooling at temperatures that do not induce crystalization of highly
`saturated fatty acids in non lipid-rich cells. The crystals rupture the bilayer membrane of lipid-rich cells, causing necrosis.
`Thus, damage of non lipid-rich cells, such as dermal cells, is avoided at temperatures that induce crystal formation in
`lipid-rich cells. It is also believed that cooling induces lipolysis (e.g., metabolism) of lipid-rich cells, further enhancing the
`reduction in subcutaneous adipose tissue. Lipolysis may be enhanced by local cold exposure inducing stimulation of
`the symapthetic nervous system.
`[0036]
`In one embodiment, the temperature of the lipid-rich cells is not less than about - 10°C. Preferably, the tem-
`perature 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, thetemperature ofthe 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, the lipid—rich cells are preferably maintained
`at an average temperature of between about —10°C and about 37°C, 35, 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; about —2°C and about 35, 30°C, 25°C, 20°C, 15°C, 10°C,
`or 5°C.
`
`In yet another embodiment, the temperature range of the lipid-rich cells oscillates between 37°C and -10°C.
`[0037]
`Methods of pulse cooling followed by brief periods of wanning can be used to minimize collateral damage to non lipid-
`rich cells. More preferably, the temperature range of the lipid-rich cells oscillates between -8°C and 33°C. Even more
`preferably, the temperature range of the lipid-rich cells oscillates between -2°C and 15°C. The temporal profile of the
`cooling of the skin can be performed in one continuous cooling act or in multiple cooling cycles or actually a combination
`of cooling with active heating cycles.
`[0038] Cooling methods of the present invention advantageously eliminate unwanted effects in the epidermis. In one
`embodiment, the temperature of the epidermis is not 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.
`In one
`[0039] Cooling methods of the present invention advantageously eliminate unwanted effects in the dermis.
`embodiment, the temperature of the dermis is not less than about -15°C. Preferably, the temperature of the dermis is
`between about -10°C and 20°C. More preferably, the temperature of the dermis is between about -8°C and 15°C. Even
`more preferably, the temperature of the dermis 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°C. In a most preferred embodiment, the lipid-rich cells are cooled to about -5 to 15°C for times
`ranging from about a minute, up to about two hours.
`1 minute, 5 minute, 15 minute, 30
`[0040] Methods of the present invention can be applied in short intervals (e.g.,
`minute and 60 minute time intervals) or long intervals (e.g., 12 hour and 24 hourtime intervals). Preferably intervals are
`between 5 and 20 minutes. Heat can optionally be applied between intervals of cooling.
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`EP1917 935 B1
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`Feedback mechanisms are employed to monitor and control temperatures in the skin (i.e., dermis, epidermis
`[0041]
`or a combination thereof) subcutaneous adipose tissue. A feedback mechanism can monitor the temperature of a
`subject’s skin to ensure that the temperature therein in does not fall below a predetermined minimum temperature, for
`example, about -10°C to about 30°C. A non-invasive device can be externally applied to measure surface temperature
`at the point of contact and/or the surrounding region.
`[0042]
`Feedback mechanisms can include all known in the artto monitortemperature and/or crystal formation. Crystal
`formation can be measured, for example by ultrasound imaging and acoustical, optical, and mechanical measurements.
`Mechanical measurements can include, for example, measurements of tensile strength.
`[0043]
`In one embodiment, a multilayer model can be employed to estimate temperature profiles over time and within
`different depths. Temperature profiles are designed to produce a temperature gradient within the tissue, having a lower
`temperature at the surface. In a preferred embodiment, temperature profiles are designed to minimize blood flow during
`cooling. Feedback mechanisms comprising, for example, thermocouples, ultrasound (e.g., to detect phase changes of
`the subcutaneous adipose tissue) or shock wave propagation (e.g., propagation of a shock wave is altered if a phase
`transition occurs) can be employed to achieve optimal temperature gradients.
`[0044]
`Substantial cooling of the subcutaneous adipose layer, for example to a target temperature between about-
`5°C and 15°C, by cooling at the skin surface has several requirements. Heat extracted from the skin surface establishes
`a temperature gradient within the skin, which in turn cools first the epidermis, dermis, and finally subcutaneous adipose
`layers. Dermal blood flow brings heat from the body core to the dermis. Dermal blood flow can therefore severely limit
`cooling of the deep dermis and subcutaneous adipose. Therefore, it is strongly preferred to temporarily limit or eliminate
`cutaneous blood flow, for example by locally applying a pressure to the skin greater than the systolic blood pressure,
`while cooling as a treatment to achieve reduction in subcutaneous adipose. A general requirement is that the time of
`cooling at the skin surface must be long enough to allow heat to flow from the dermis and subcutaneous adipose layers
`in orderto achieve the desired temperature for treatment of the same. When the subcutaneous adipose is cooled to a
`temperature below that for crystallization of its lipids, the latent heat of freezing for these lipids must also be removed,
`by diffusion. The skin surface cooling temperature and cooling time can be adjusted to control depth of treatment, for
`example the anatomical depth to which subcutaneous adipose is affected. Heat diffusion is a passive process, and the
`body core temperature is nearly always close to 37°C. Therefore, another general requirement is that the skin surface
`temperature during cooling, must be lower than the desired target (e.g., adipocytes) temperature for treatment of the
`region, for at least part of the time during which cooling is performed.
`[0045] When cooling a diameter of skin greaterthan about2 cm, and with no blood flow, one-dimensional heat diffusion
`offers a good approximation forestimatingtemperatu re profiles in skin overtime during cooling. Heat diffusion is governed
`by the general diffusion equation, 6T/8t = KSZT/BZ2, where T (z,t) is the temperature in skin as a function of depth 2 and
`time t, and K is the thermal diffusivity, which is approximately 1 .3 x10'3 cm25'1 for skin tissue. Solutions and approximate
`solutions to the heat diffusion equation have been made for planar geometry of a semi-infinite slab, approximating the
`situation for skin. When the surface of the skin (2 = O) is held at a given lower temperature, a useful approximation is
`that heat flow from a depth 2 requires a time of approximately t E z2 to achieve a temperature difference 1/2 of the initial
`difference, where t is in seconds and z is in millimeters. Thus, 22 can be considered an approximate value for a thermal
`time constant. For example, if the initial skin temperature is 30 C, and ice at 0 C is placed firmly against the skin surface,
`it requires about 1 second for the temperature at a depth of 1 millimeter, to reach about 15 C. The subcutaneous fat
`layer typically begins at about 2 2 3 mm, and extends for millimeters up to many centimeters thick. The thermal time
`constant for heat transfer from the top of the subcutaneous adipose layer, is therefore about 10 seconds. To achieve
`substantial cooling of subcutaneous adipose, at least several and preferably greaterthan 1O thermal time constants of
`cooling time are required. Therefore, cooling must be maintained for about 30-100 seconds at the skin surface, and in
`the absence of Dermal blood flow, forthe temperature of the topmost portion of subcutaneous adipose to approach that
`of the cooled skin surface. The latent heat of crystallization for lipids, mentioned above, must also be removed when
`the fat temperature drops below that for crystallization. Therefore in general, cooling times over 1 minute are desired,
`and cooling times greater than about 1 minute can be used to adjust the depth of adipocytes affected, for times up to
`more than an hour.
`
`[0046] Accordingly, in yet another embodiment, the dermis is cooled at a rate sufficient to induce vasoconstriction.
`Blood circulation within the dermis stabilizes the temperature of the dermis close to body temperature. In orderto cool
`subcutaneous adipose tissue to temperatures below body temperature, blood flow can be minimized. Fast cooling of
`the epidermal surface can achieve reflectory vasoconstriction that limits blood circulation in an appropriate way.
`[0047]
`In yet another embodiment, a vasoconstrictive drug is administered to induce vasoconstriction. Vasoconstrictive
`drugs, for example, can be topically applied at the point of contact either before, after or during application of the cooling
`agent. Where necessary, systemic administration of the vasoconstrictive drug can be provided through conventional
`methods, such as injection or oral administration. The vasoconstrictive drug can be any known in the art. Preferably,
`the vasoconstrictive drug is EMLA cream or epinephrine.
`[0048]
`In yet another embodiment, pressure is applied to a surface, either at the point of contact with the cooling agent
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`10
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`EP1917 935 B1
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`or in proximity thereto, such that lateral blood flow is limited. Pressure can be applied, for example, to a skin surface by
`compressing the skin surface into a skin fold comprising single or multiple folds. Pressure can also be by applying a
`vaccum either at the point of contact with the cooling agent or in proximity thereto.
`[0049] Without being bound bytheory, it is believed that the rate of formation of crystals in lipid-rich cells can be altered
`by the application of pressure during the cooling process. Sudden crystalization, rather than a slow accumulation of
`crystals, would cause greater damage to the lipid-rich cells. It is also believed that the application of pressure can force
`the movement of the crystals within the lipid-rich cells, enhancing the damage to the bilayer membrane. Furthermore,
`different compartments of the subcutaneous adipose tissue have different viscosities.
`In general, the viscositiy is en-
`hanced at colder tempertures (e.g., those particulary close to the point of phase change). Because the phase change
`for lipid-rich cells occurs at higher temperatures than non lipid-rich cells, non-uniform tension lines form within the
`subcutaneous adipose tissue upon the application of pressure. It is believed that pronounced damage occurs within
`these tension lines.
`
`In yet another aspect, the temperature of the dermis and/or epidermis oscillates between 35°C and -15°C