(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2014/0277219 A1
`(43) Pub. Date:
`Sep. 18, 2014
`Nanda
`
`US 20140277219A1
`
`(54) MULTI-MODALITY TREATMENT SYSTEMS,
`METHODS AND APPARATUS FOR
`ALTERING SUBCUTANEOUSLPD-RICH
`TSSUE
`
`(71) Applicant: ZELTIQ AESTHETICS, INC.,
`Pleasanton, CA (US)
`(72) Inventor: Gurvinder Singh Nanda, Fremont, CA
`(US)
`
`(21) Appl. No.: 13/830,413
`
`(22) Filed:
`
`Mar 14, 2013
`
`Publication Classification
`
`(51) Int. Cl.
`A6 IN L/32
`A6 IN L/40
`A6DF 7700
`
`
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl.
`CPC. A61N I/327 (2013.01); A61F 7700 (2013.01);
`A61N I/403 (2013.01)
`USPC .............................................................. 607/3
`ABSTRACT
`(57)
`Systems and methods that enable tissue cooling applications
`and delivery of electrical energy to adipose tissue for alter
`ation and reduction of body fat are described herein. Aspects
`of the disclosure are directed to, for example, temperature
`controlled electroporation of subcutaneous lipid-rich cells.
`Additional aspects of the disclosure are directed to treatment
`methods for treating a target region of a human Subject’s body
`to achieve an alteration of Subcutaneous adipose tissue. The
`method can include, for example, removing heat from the
`target region of the human Subject during a treatment process
`to cool Subcutaneous lipid-rich cells in the target region to a
`temperature below normal body temperature. Furthermore,
`the method can include delivering energy to the target region
`to produce an electric field in an amount Sufficient to create
`pores in membranes of the Subcutaneous lipid-rich cells that
`have been cooled to the temperature below normal body
`temperature.
`
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`700
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`
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`POSITION APPLICATOR ON SUBJECT
`
`REMOVE HEAT FROM THE TARGET REGION OF THE
`SUBJECT TO COOL SUBCUTANEOUSLIPID-RICH CELLS
`IN THE TARGET REGION TOATEMPERATURE BELOW
`NORMAL BODY TEMPERATURE
`
`DELIVER ENERGY TO THE TARGET REGION TO
`OPEN PORES IN MEMBRANES OF THE SUBCUTANEOUS
`LPD-RICH CELLS THAT HAVE BEEN COOLED
`TO THE TEMPERATURE BELOW NORMAL
`BODY TEMPERATURE
`
`FIG. 7
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`MULTI-MODALITY TREATMENT SYSTEMS,
`METHODS AND APPARATUS FOR
`ALTERING SUBCUTANEOUSLPD-RICH
`TSSUE
`
`INCORPORATION BY REFERENCE OF
`COMMONLYOWNED APPLICATIONS AND
`PATENTS
`0001. The following commonly assigned U.S. patent
`applications and U.S. patents are incorporated herein by ref
`erence in their entirety:
`0002 U.S. Patent Publication No. 2008/0287839 entitled
`METHOD OF ENHANCED REMOVAL OF HEAT FROM
`SUBCUTANEOUS LIPID-RICH CELLS AND TREAT
`MENT APPARATUS HAVING AN ACTUATOR:
`0003 U.S. Pat. No. 6,032,675 entitled “FREEZING
`METHOD FOR CONTROLLED REMOVAL OF FATTY
`TISSUE BY LIPOSUCTION:
`0004 U.S. Patent Publication No. 2007/0255362 entitled
`“CRYOPROTECTANT FOR USE WITH A TREATMENT
`DEVICE FOR IMPROVED COOLING OF SUBCUTANE
`OUS LIPID-RICH CELLS:
`0005 U.S. Pat. No. 7,854,754 entitled “COOLING
`DEVICE FOR REMOVING HEAT FROMSUBCUTANE
`OUS LIPID-RICH CELLS:
`0006 U.S. Patent Publication No. 2011/0066216 entitled
`“COOLING DEVICE FOR REMOVING HEAT FROM
`SUBCUTANEOUS LIPID-RICH CELLS:
`0007 U.S. Patent Publication No. 2008/00772.01 entitled
`“COOLING DEVICES WITH FLEXIBLE SENSORS:
`0008 U.S. Patent Publication No. 2008/0077211 entitled
`“COOLING DEVICE HAVING A PLURALITY OF CON
`TROLLABLE COOLING ELEMENTS TO PROVIDE A
`PREDETERMINED COOLING PROFILE:
`0009 U.S. Patent Publication No. 2009/01 18722, filed
`Oct. 31, 2007, entitled “METHOD AND APPARATUS FOR
`COOLING SUBCUTANEOUS LIPID-RICH CELLS OR
`TISSUE;
`0010 U.S. Patent Publication No. 2009/0018624 entitled
`LIMITING USE OF DISPOSABLE SUBJECT 11 PRO
`TECTION DEVICES;
`0011 U.S. Patent Publication No. 2009/0018623 entitled
`“SYSTEM FOR TREATING LIPID-RICH REGIONS:
`0012 U.S. Patent Publication No. 2009/0018625 entitled
`MANAGING SYSTEM TEMPERATURE TO REMOVE
`HEAT FROM LIPID-RICH REGIONS:
`0013 U.S. Patent Publication No. 2009/0018627 entitled
`“SECURE SYSTEM FOR REMOVING HEAT FROM
`LIPID-RICH REGIONS:
`0014 U.S. Patent Publication No. 2009/0018626 entitled
`USER INTERFACES FORASYSTEM THAT REMOVES
`HEAT FROM LIPID-RICH REGIONS:
`0.015
`U.S. Pat. No. 6,041,787 entitled “USE OF CRYO
`PROTECTIVE AGENT COMPOUNDS DURING CRYO
`SURGERY:
`0016 U.S. Pat. No. 8,285,390 entitled “MONITORING
`THE COOLING OF SUBCUTANEOUS LIPID-RICH
`CELLS, SUCH AS THE COOLING OF ADIPOSE TIS
`SUE:
`0017 U.S. Provisional Patent Application Ser. No.
`60/941,567 entitled “METHODS, APPARATUSES AND
`SYSTEMS FOR COOLING THE SKIN AND SUBCUTA
`NEOUSTISSUE;
`
`0018 U.S. Pat. No. 8,275,442 entitled “TREATMENT
`PLANNING SYSTEMS AND METHODS FOR BODY
`CONTOURING APPLICATIONS:
`(0019 U.S. patent application Ser. No. 12/275,002 entitled
`APPARATUS WITH HYDROPHILIC RESERVOIRS FOR
`COOLING SUBCUTANEOUS LIPID-RICH CELLS:
`(0020 U.S. patent application Ser. No. 12/275,014 entitled
`APPARATUS WITH HYDROPHOBIC FILTERS FOR
`REMOVING HEAT FROM SUBCUTANEOUS LIPID
`RICH CELLS:
`0021 U.S. Patent Publication No. 2010/0152824 entitled
`SYSTEMS AND METHODS WITH INTERRUPTRE
`SUME CAPABILITIES FOR COOLING SUBCUTANE
`OUS LIPID-RICH CELLS:
`0022 U.S. Pat. No. 8,192.474 entitled “TISSUE TREAT
`MENT METHODS”;
`0023 U.S. Patent Publication No. 2010/0280582 entitled
`“DEVICE, SYSTEM AND METHOD FOR REMOVING
`HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS:
`0024 U.S. Patent Publication No. 2012/0022518 entitled
`“COMBINED MODALITY TREATMENT SYSTEMS,
`METHODS AND APPARATUS FOR BODY CONTOUR
`ING APPLICATIONS:
`0025 U.S. Publication No. 2011/0238050 entitled
`HOME-USE APPLICATORS FOR NON-INVASIVELY
`REMOVING HEAT FROM SUBCUTANEOUS LIPID
`RICH CELLSVIA PHASE CHANGE COOLANTS, AND
`ASSOCIATED DEVICES, SYSTEMS AND METHODS”;
`0026 U.S. Publication No. 2011/0238051 entitled
`HOME-USE APPLICATORS FOR NON-INVASIVELY
`REMOVING HEAT FROM SUBCUTANEOUS LIPID
`RICH CELLSVIA PHASE CHANGE COOLANTS, AND
`ASSOCIATED DEVICES, SYSTEMS AND METHODS”;
`and
`0027 U.S. Publication No. 2012/0239123 entitled
`“DEVICES, APPLICATION SYSTEMS AND METHODS
`WITH LOCALIZED HEAT FLUX ZONES FOR REMOV
`ING HEAT FROM SUBCUTANEOUS LIPID-RICH
`CELLS.
`
`TECHNICAL FIELD
`0028. The present application relates generally to multi
`modality treatment systems, methods and apparatus for alter
`ing tissue (e.g., Subcutaneous lipid-rich tissue) including sys
`tems and methods for generating electrical fields and
`removing heat to affect targeted tissue. The present applica
`tion also relates to temperature-controlled electroporation
`treatment systems and methods for altering targeted tissue.
`
`BACKGROUND
`0029. Excess body fat, or adipose tissue, may be present in
`various locations of the body, including, for example, the
`thigh, buttocks, abdomen, knees, back, face, arms, and other
`areas. Excess adipose tissue can detract from personal
`appearance and athletic performance. Moreover, excess adi
`pose tissue is thought to magnify the unattractive appearance
`of cellulite, which forms when subcutaneous fat lobules pro
`trude or penetrate into the dermis and create dimples where
`the skin is attached to underlying structural fibrous strands.
`Cellulite and excessive amounts of adipose tissue are often
`considered to be cosmetically unappealing. Moreover, sig
`nificant health risks may be associated with higher amounts
`of excess body fat.
`
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`0030 A variety of methods have been used to treat indi
`viduals having excess body fat and, in many instances, non
`invasive removal of excess Subcutaneous adipose tissue can
`eliminate unnecessary recovery time and discomfort associ
`ated with invasive procedures Such as liposuction. Conven
`tional non-invasive treatments for removing excess body fat
`typically include topical agents, weight-loss drugs, regular
`exercise, dieting, or a combination of these treatments. One
`drawback of these treatments is that they may not be effective
`or even possible under certain circumstances. For example,
`when a person is physically injured or ill, regular exercise
`may not be an option. Similarly, weight-loss drugs or topical
`agents are not an option when they cause an allergic or nega
`tive reaction. Furthermore, fat loss in selective areas of a
`person’s body often cannot be achieved using general or
`systemic weight-loss methods.
`0031. Other methods designed to reduce subcutaneous
`adipose tissue include laser-assisted liposuction and meso
`therapy. Newer non-invasive methods include applying radi
`ant energy to Subcutaneous lipid-rich cells via, e.g., radio
`frequency and/or light energy, such as described in U.S.
`Patent Publication No. 2006/0036300 and U.S. Pat. No.
`5,143,063, or via, e.g., high intensity focused ultrasound
`(HIFU) radiation such as described in U.S. Pat. Nos. 7,258,
`674 and 7.347,855. Additional methods and devices for non
`invasively reducing Subcutaneous adipose tissue by cooling
`are disclosed in U.S. Pat. No. 7,367,341 entitled “METHODS
`AND DEVICES FOR SELECTIVE DISRUPTION OF
`FATTYTISSUEBY CONTROLLED COOLING' to Ander
`son et al. and U.S. Patent Publication No. 2005/0251 120
`entitled METHODS AND DEVICES FOR DETECTION
`AND CONTROL OF SELECTIVE DISRUPTION OF
`FATTY TISSUEBY CONTROLLED COOLING to Ander
`son et al., the entire disclosures of which are incorporated
`herein by reference.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`0032. In the drawings, identical reference numbers iden
`tify similar elements or acts. The sizes and relative positions
`of elements in the drawings are not necessarily drawn to scale.
`For example, the shapes of various elements and angles may
`not be drawn to scale, and some of these elements are arbi
`trarily enlarged and positioned to improve drawing legibility.
`Further, the particular shapes of the elements as drawn are not
`intended to convey any information regarding the actual
`shape of the particular elements, and have been solely
`selected for ease of recognition in the drawings.
`0033 FIG. 1 is an isometric view schematically illustrat
`ing a treatment system for treating Subcutaneous lipid-rich
`regions of a patient in accordance with an embodiment of the
`disclosure.
`0034 FIGS. 2A and 2B are schematic cross-sectional
`views of the lipid bilayer of a cell membrane shown (A)
`before and (B) after applying energy Sufficient to create pores
`in the lipid bilayer.
`0035 FIGS. 3A and 3B are schematic cross-sectional
`views of the skin and Subcutaneous tissue of a subject illus
`trating the application of (A) bipolar and (B) monopolar
`electrical pulses thereto.
`0036 FIG. 4 is a partial cross-sectional view illustrating a
`multi-modality applicator suitable to be used in the system of
`FIG. 1 in accordance with embodiments of the technology.
`
`0037 FIG. 5 is a partial cross-sectional view illustrating a
`multi-modality applicator suitable to be used in the system of
`FIG. 1 in accordance with another embodiment of the tech
`nology.
`0038 FIG. 6 is a partial cross-sectional view illustrating a
`multi-modality applicator suitable to be used in the system of
`FIG. 1 in accordance with a further embodiment of the tech
`nology.
`0039 FIG. 7 is a flow diagram illustrating a method for
`non-invasively removing heat from a target region and apply
`ing energy to generate an electric field for selectively elec
`troporating Subcutaneous lipid-rich cells in the target region
`in accordance with a further embodiment of the technology.
`0040 FIG. 8 is a schematic block diagram illustrating
`computing system Software modules and Subcomponents of a
`computing device suitable to be used in the system of FIG. 1
`in accordance with an embodiment of the technology.
`
`DETAILED DESCRIPTION
`
`A. Overview
`0041) Systems, devices and methods are provided herein
`that enable simultaneous or sequential cooling and delivery of
`energy to a target region selectively to affect targeted cells.
`Several of the details set forth below are provided to describe
`the following examples and methods in a manner Sufficient to
`enable a person skilled in the relevant art to practice, make
`and use them. Several of the details and advantages described
`below, however, may not be necessary to practice certain
`examples and methods of the technology. Additionally, the
`technology may include other examples and methods that are
`within the scope of the claims but are not described in detail.
`0042. Reference throughout this specification to “one
`example.” “an example.” “one embodiment,” or “an embodi
`ment’ means that a particular feature, structure, or character
`istic described in connection with the example is included in
`at least one example of the present technology. Thus, the
`occurrences of the phrases "in one example.” “in an example.”
`“one embodiment, or “an embodiment” in various places
`throughout this specification are not necessarily all referring
`to the same example. Furthermore, the particular features,
`structures, routines, stages, or characteristics may be com
`bined in any Suitable manner in one or more examples of the
`technology. The headings provided herein are for conve
`nience only and are not intended to limit or interpret the scope
`or meaning of the claimed technology.
`0043. As used herein, the terms “bipolar' and “monopo
`lar can refer to an electrode configuration or in other embodi
`ments to an electrical pulse, or pulse waveform. For example,
`a “bipolar electrode configuration” or “bipolar configuration'
`can refer to having two or more electrodes between which an
`electric field can be generated. In other embodiments, “bipo
`lar can refer to the waveform of an electrical signal generated
`and/or delivered to two or more electrodes, and such as
`described in U.S. Pat. No. 7,054,685, which is incorporated
`herein by reference in its entirety. Likewise, “monopolar elec
`trode configuration' or monopolar configuration' can refer to
`having one or more electrodes that generate an electric field
`that can dissipate at a particular depth or distance away from
`the electrode(s). “Monopolar can also refer to the electrical
`pulse or waveform generated and delivered to the electrode
`(s), such as described further in U.S. Pat. No. 7,054,685.
`0044 Some embodiments of the disclosure are directed to
`a system for affecting lipid-rich cells in a region of a human
`
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`Subject’s body. The system can include a treatment unit con
`figured to house a coolant. In one embodiment, the treatment
`unit can be in thermal communication with a fluid chamber
`for holding the coolant. The system can also include an
`energy generating unit, for example for generating electrical
`pulses, and an applicator in fluid communication with the
`treatment unit and in electrical communication with the
`energy generating unit. The system can further include a
`controller in communication with the treatment unit and the
`energy generating unit. In one embodiment, the controller has
`instructions for causing the applicator to reduce a temperature
`of (e.g., extract heat from) a target region beneath the epider
`mis of the Subject to reduce a temperature of Subcutaneous
`lipid-rich cells in the target region to a second temperature
`less than 37°C. After reducing the temperature of the target
`region, the instructions can cause the applicator to apply
`energy across the target region to form pores in membranes of
`the subcutaneous lipid-rich cells. In one embodiment, the
`instructions can cause the applicator to apply Voltage across
`the target region to produce a pulsed electric field in an
`amount Sufficient to form the pores.
`0045. Other aspects of the disclosure are directed toward a
`temperature-controlled electroporation treatment system for
`cosmetically altering a target region of a human Subjects
`body to achieve a cosmetically beneficial alteration of tissue,
`Such as Subcutaneous adipose tissue. The temperature-con
`trolled electroporation treatment system can include a treat
`ment unit in thermal communication with a fluid chamber.
`The temperature-controlled electroporation treatment system
`can also include an electroporation energy source, a control
`ler and an applicator. The applicator can include a first elec
`trode and a second electrode in electrical communication
`with the electroporation energy source and a cooling element
`in communication with the treatment unit. In one embodi
`ment, the controller includes instructions that cause the appli
`cator to remove heat from the target region of the Subject to
`reduce a natural body temperature to a lower temperature.
`The controller can also include instructions that cause the
`applicator to deliver an electric field through the target region
`Such that Subcutaneous lipid-rich cells at the target region are
`substantially affected while non-lipid-rich cells at the target
`region are not substantially affected. The controller can fur
`ther include instructions that cause the applicator to maintain
`the lower temperature for a period after the electric field is
`removed.
`0046 Additional embodiments of the disclosure are
`directed to cosmetic methods for affecting a target region of a
`human body to achieve a cosmetically beneficial alteration.
`For example, the method can include removing heat from the
`target region of the human Subject to cool Subcutaneous lipid
`rich cells in the target region to a temperature below normal
`body temperature. The method can also include delivering
`energy to the target region to produce an electric field in an
`amount Sufficient to create pores in membranes of the Subcu
`taneous lipid-rich cells that have been cooled to the tempera
`ture below normal body temperature. The pores can compro
`mise cell volume and/or cell viability, and the method can
`thereby achieve a cosmetically beneficial alteration of subcu
`taneous adipose tissue.
`0047. Some of the embodiments disclosed herein can be
`for cosmetically beneficial alterations of a variety of body
`regions. As such, Some treatment procedures may be for the
`sole purpose of altering the body region to conform to a
`cosmetically desirable look, feel, size, shape or other desir
`
`able cosmetic characteristic or feature. Accordingly, at least
`Some embodiments of the cosmetic procedures can be per
`formed without providing any, or in another embodiment,
`providing minimal therapeutic effect. For example, some
`treatment procedures may be directed to treatment goals that
`do not include restoration of health, physical integrity, or the
`physical well being of a subject. In other embodiments, how
`ever, the cosmetically desirable treatments may have thera
`peutic outcomes (whether intended or not). Such as, psycho
`logical benefits, alteration of body hormones levels (by the
`reduction of adipose tissue), etc. The cosmetic methods can
`target Subcutaneous regions to change a Subject's appearance
`Such as, for example, procedures performed on a subjects
`“love-handles” (i.e., excess adipose tissue at the side of a
`subjects waistline).
`B. Multi-Modality Treatment System
`0048 FIG. 1 and the following discussion provide a brief,
`general description of an example of a Suitable multi-modal
`ity treatment system 100 in which aspects of the disclosure
`can be implemented. In some embodiments, the multi-mo
`dality treatment system 100 can be a temperature-controlled
`electroporation treatment system. Those skilled in the rel
`evantart will appreciate that other examples of the disclosure
`can be practiced with other treatment systems and treatment
`protocols, including invasive, minimally invasive, other non
`invasive medical treatment systems, and/or combinations of
`one or more of the above for treating a subject 101. In general,
`the term “treatment system’, as used generally herein, refers
`to any of the above-referenced categories of medical treat
`ment systems as well as any treatment regimes or medical
`device usage.
`0049. In one embodiment, the multi-modality treatment
`system 100 is suitable for altering a human subject's subcu
`taneous adipose tissue, including Such as by cooling and/or by
`delivering energy. The term "subcutaneous tissue' means
`tissue lying beneath the dermis and includes Subcutaneous
`fat, or adipose tissue, which primarily is composed of lipid
`rich cells, or adipocytes. Such alteration (e.g., by cooling,
`energy delivery and/or combination of cooling and energy
`delivery) is believed to be an intermediate and/or final result
`of one or more mechanisms acting alone or in combination. It
`is thought that Such mechanism or mechanisms can triggeran
`apoptotic cascade, which is believed to be the dominant form
`of lipid-rich cell death by non-invasive cooling alone or in
`combination with other forms of cell interrogation.
`0050. In several embodiments, apoptosis of the subcuta
`neous lipid-rich cells in the region of the subject 101 being
`treated is a desirable outcome for beneficially altering (e.g.,
`sculpting and/or reducing) adipose tissue. Apoptosis, also
`referred to as “programmed cell death', is a genetically
`induced death mechanism by which cells self-destruct with
`out incurring damage to Surrounding tissues. An ordered
`series of biochemical events induce cells to morphologically
`change. These changes include cellular blebbing, loss of cell
`membrane asymmetry and attachment, cell shrinkage, chro
`matin condensation, and chromosomal DNA fragmentation.
`Injury via an external stimulus, Such as cold exposure, is one
`mechanism that can induce apoptosis in cells. Nagle, W. A.,
`Soloff, B. L., Moss, A. J. Jr., Henle, K. J. "Cultured Chinese
`Hamster Cells Undergo Apoptosis After Exposure to Cold but
`Nonfreezing Temperatures' Cryobiology 27, 439-451
`(1990). One aspect of apoptosis, in contrast to cellular necro
`sis (a traumatic form of cell death causing local inflamma
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`tion), is that apoptotic cells express and display phagocytic
`markers on the Surface of the cell membrane, thus marking the
`cells for phagocytosis by, for example, macrophages. As a
`result, phagocytes can engulf and remove the dying cells
`(e.g., the lipid-rich cells) without eliciting an immune
`response.
`0051. Without being bound by theory, one mechanism of
`apoptotic lipid-rich cell death by cooling is believed to
`involve localized crystallization of lipids within the adipo
`cytes at temperatures that do not induce crystallization in
`non-lipid-rich cells. The crystallized lipids may selectively
`injure these cells, inducing apoptosis (and may also induce
`necrotic death if the crystallized lipids damage or rupture the
`bilayer lipid membrane of the adipocyte). Another mecha
`nism of injury involves the lipid phase transition of those
`lipids within the cell's bilayer lipid membrane, which results
`in membrane disruption, thereby inducing apoptosis. This
`mechanism is well documented for many cell types and may
`be active when adipocytes, or lipid-rich cells, are cooled.
`Mazur, P., “Cryobiology: the Freezing of Biological Sys
`tems' Science, 68: 939-949 (1970); Quinn, P. J., “A Lipid
`Phase Separation Model of Low Temperature Damage to
`Biological Membranes' Cryobiology, 22: 128-147 (1985);
`Rubinsky, B., “Principles of Low Temperature Preservation'
`Heart Failure Reviews, 8, 277-284 (2003). Other possible
`mechanisms of adipocyte damage, described in U.S. Pat. No.
`8,192.474, relates to ischemia/reperfusion injury that may
`occur under certain conditions when such cells are cooled as
`described herein. For instance, during treatment by cooling as
`described herein, the targeted adipose tissue may experience
`a restriction in blood Supply and thus be starved of oxygen
`due to isolation while pulled into, e.g., a vacuum cup, or
`simply as a result of the cooling which may affect vasocon
`striction in the cooled tissue. In addition to the ischemic
`damage caused by oxygen starvation and the build up of
`metabolic waste products in the tissue during the period of
`restricted blood flow, restoration of blood flow after cooling
`treatment may additionally produce reperfusion injury to the
`adipocytes due to inflammation and oxidative damage that is
`known to occur when oxygenated blood is restored to tissue
`that has undergone a period of ischemia. This type of injury
`may be accelerated by exposing the adipocytes to an energy
`Source (via, e.g., thermal, electrical, chemical, mechanical,
`acoustic or other means) or otherwise increasing the blood
`flow rate in connection with or after cooling treatment as
`described herein. Increasing vasoconstriction in Such adipose
`tissue by, e.g., various mechanical means (e.g., application of
`pressure or massage), chemical means or certain cooling con
`ditions, as well as the local introduction of oxygen radical
`forming compounds to stimulate inflammation and/or leuko
`cyte activity in adipose tissue may also contribute to
`accelerating injury to Such cells. Other yet-to-be understood
`mechanisms of injury may exist.
`0052. In addition to the apoptotic mechanisms involved in
`lipid-rich cell death, local cold exposure may induce lipolysis
`(i.e., fat metabolism) of lipid-rich cells. For example, cold
`stress has been shown to enhance rates of lipolysis from that
`observed under normal conditions which serves to further
`increase the volumetric reduction of subcutaneous lipid-rich
`cells. Vallerand, A. L., Zamecnik. J., Jones, P. J. H., Jacobs, I.
`“Cold Stress Increases Lipolysis, FFA Ra and TG/FFA
`Cycling in Humans' Aviation, Space and Environmental
`Medicine 70, 42-50 (1999).
`
`0053 When cooling the subcutaneous tissues to a tem
`perature lower than 37°C., subcutaneous lipid-rich cells can
`selectively be affected. In general, the epidermis and dermis
`of the subject 101 have lower amounts of lipids compared to
`the underlying lipid-rich cells forming the Subcutaneous tis
`Sues. Because non-lipid-rich cells usually can withstand
`colder temperatures better than lipid-rich cells, the subcuta
`neous lipid-rich cells selectively can be affected while main
`taining the integrity of the non-lipid-rich cells in the dermis
`and/or epidermis. In some embodiments, the multi-modality
`treatment system 100 can cool the skin of the patient to a
`temperature in a range of from about -20°C. to about 20°C.
`In other embodiments, the cooling temperatures can be from
`about -20°C. to about 10°C., from about -15°C. to about 5°
`C., or from about -10°C. to about 0°C.
`0054 Without being bound by theory, the selective effect
`of cooling on lipid-rich cells is believed to result in, for
`example, membrane disruption, shrinkage, disabling,
`destroying, removing, killing, or another method of lipid-rich
`cell alteration. Depending on the duration and final cooling
`temperature, Subcutaneous lipid-rich cells can selectively
`become altered in a manner that makes the cells more Sus
`ceptible to further interrogation and/or cell injury than non
`lipid-rich cells in the same region. Such alteration (e.g., by
`cooling, energy delivery and/or combination of cooling and
`energy delivery) is believed to be an intermediate and/or final
`result of one or more mechanisms acting alone or in combi
`nation. It is thought that such mechanism or mechanisms can
`trigger an apoptotic cascade, which is believed to be the
`dominant form of lipid-rich cell death by non-invasive cool
`ing alone or in combination with other forms of cell interro
`gation. Temperature exposures and/or other energy delivery
`modalities that elicit these apoptotic events in lipid-rich cells
`may contribute to long-lasting and/or permanent reduction
`and reshaping of Subcutaneous adipose tissue.
`0055 One form of cell interrogation is electroporation, or
`electropermeabilization, which refers to the permeabilization
`of a cell membrane as a consequence of the application of
`electric fields. The electric fields can be pulsed or continuous.
`Short and intense electric fields across the cell membrane, the
`cells or the tissues can cause permeabilization. The perme
`abilization can be temporary (e.g., reversible permeabiliza
`tion) or permanent (e.g., irreversible permeabilization) based
`on the electric field magnitude, electric field duration, number
`of pulses, frequency of pulse, duration of pulses, or the like.
`0056 FIGS. 2A and 2B are schematic cross-sectional
`views of a lipid bilayer 202 of a cell membrane 200 shown
`before (FIG. 2A) and after (FIG. 2B) applying an external
`energy Sufficient to create (e.g., open) pores 204 in the lipid
`bilayer 202, a basic component of plasma membranes of
`almost all living organisms, including humans. Referring to
`FIGS. 2A and 2B together, the cell membrane 200 can include
`the lipid molecules 203 of the cell's lipid bilayer 202, proteins
`205 and cell surface carbohydrates 206. During electropora
`tion, the lipid molecules 203 of the lipid bilayer 202 shift
`positions. This shift creates pores 204 which act as conductive
`pathways 208 through the bilayer 202 as it is filled with water
`and/or interstitial fluid. A lipid bilayer 202 has a strongly
`polar and hydrophilic (polar) head region 210 represented by
`phosphate groups and a strongly nonpolar and hydrophobic
`(nonpolar) tail region 212 represented by fatty acid chains.
`The lipid bilayer 202 is configured so that the tail regions 212
`are isolated from the surrounding polar fluid while the more
`hydrophilic head regions 210 are associated with the intrac
`
`LUMENIS EX1010
`Page 12
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`US 2014/0277219 A1
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`Sep. 18, 2014
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`ellular and extracellular faces of the bilayer. This alignment of
`head 210-to-tail 212 regions result in, among other things, an
`electric potential (the “trans-membrane potential) at the
`point where the regions 210, 212 meet. When an electric field
`is applied at a Voltage higher than that potential, a focused
`pulse (FP) of current disturbs it. As shown in FIG. 2B, some
`head regions 210 and tail regions 212 will then separate; some
`will “flip' end-for-end. As the bonds between head and tail
`regions fail, the pores 204 can form in the cell membrane 200.
`Without being bound by theory, it is believed that the pores
`204 formed in the lipid bilayer 202 allow for cell lysis, intra
`cellular content outflow from the cells, and/or fluid exchange
`with interstitial fluid that can trigger an apoptotic cascade or
`other form of cell death (e.g., necrosis).
`0057 Delivery of energy, such as high voltage or low
`Voltage energy, to Subcutaneous tissue to generate an electric
`field across the tissue selectively can increase the electrical
`conductivity and permeability of the cell plasma membranes
`of the lipid-rich cells. For a given pulse duration and shape, a
`specific transmembrane Voltage or energy threshold exists for
`the manifestation of the electroporation phenomenon (e.g.,
`from about 0.5V to about 1 V, from about 1 V to about 2V, or
`from about 2V to about 5V per cell). Accordingly, there is an
`electric field magnitude threshold for electroporation wherein
`only the cells exposed to an electric field equal to or greater
`than a first, lower electroporation threshold of the specific
`cell, can be electroporated (e.g., pores form and/or openin the
`cell membrane). Above the first, lower electroporation thresh
`old, the number of pores and/or the pore diameter increases
`with both the amplitude and duration of the electric field
`pulses. Removing the electric field pulses enables the induced
`pores to reseal. Depending on the number, diameter and life
`time of pores in the membrane, electroporation of the cell
`may result in significant injury to t