WO2021247843A1 - Systèmes de réduction de graisse et d'amélioration de l'aspect de la peau à l'aide de modalités multiples - Google Patents

Systèmes de réduction de graisse et d'amélioration de l'aspect de la peau à l'aide de modalités multiples Download PDF

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WO2021247843A1
WO2021247843A1 PCT/US2021/035675 US2021035675W WO2021247843A1 WO 2021247843 A1 WO2021247843 A1 WO 2021247843A1 US 2021035675 W US2021035675 W US 2021035675W WO 2021247843 A1 WO2021247843 A1 WO 2021247843A1
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treatment
cold solution
energy
treatment according
treatment site
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PCT/US2021/035675
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English (en)
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Rainuka Gupta
Emilia JAVORSKY
Karen E. MILLER
Christopher VELIS
Tarik CHAUDHRY
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Miraki Innovation Think Tank Llc
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    • A61B18/0218—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques with open-end cryogenic probe, e.g. for spraying fluid directly on tissue or via a tissue-contacting porous tip
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Definitions

  • This disclosure is directed to systems and methods for reducing fat and improving the appearance of skin using multiple modalities, by administering a cold solution in combination with one or more additional modalities, to a subject.
  • Subcutaneous adipose tissue is fat stored just beneath the skin, and is present in varying amounts that generally correlate with genetic and lifestyle factors.
  • Subcutaneous fat helps store energy for the body, provides minor thermoregulation through insulation, and provides a layer of protection for muscles and bones against potential injury through impact.
  • subcutaneous fat may impact health, fitness, and appearance, and has been shown to play a role in metabolic dysfunction and systemic inflammation in human subjects. Excess subcutaneous fat leads to serious health issues which are associated with decreased life expectancy, such as type II diabetes and cardiovascular disease. In many cases, individuals desire to reduce subcutaneous fat and have difficultly doing so through diet and exercise alone.
  • Subcutaneous adipose tissue is composed of adipocytes (fat cells) grouped together in lobules separated by connective tissues and is not homogenous across all body areas.
  • the size of adipocytes varies according to the nutritional state of the body, and the biology of adipocytes varies among different areas of the body.
  • the subcutaneous adipose tissue is divided into two layers separated by a fascial plane. The upper layer is called the “superficial subcutaneous adipose tissue” (sSAT).
  • the sSAT is characterized by a lamellar pattern having regular, defined cuboid fat lobules tightly organized within vertically oriented fibrous septae.
  • the lower layer is called the “deep subcutaneous adipose tissue” (dSAT).
  • dSAT deep subcutaneous adipose tissue
  • the dSAT is characterized by a loose areolar pattern and has fat lobules are flat shaped, irregular in size, and are surrounded by high amounts of loose connective tissue. Both sSAT and dSAT layers also comprise sublayers.
  • Invasive fat reduction procedures include liposuction, abdominoplasty ("tummy tuck"), gluteoplasty (buttock lifts), brachioplasty (arm lift), thighplasty (thigh lift), lower rhytidectomy (neck lift), and mentoplasty (chin tightening).
  • Invasive therapies carry risks associated with surgical procedures, some of which can be life threatening. These include infection, scarring, perforation of organs and vessels, and hemorrhage. Additionally, invasive therapies are often painful and typically require a lengthy recovery period.
  • dSAT is the main target of liposuction. Because dSAT has a loose density compared to the lamellar density of sSAT, dSAT is easier to remove using suction through a cannula. Removal of dSAT can allow for a more dramatic cosmetic and aesthetic improvement. Further, dSAT has an overlying layer of sSAT to mask the appearance of any irregularities and is more forgiving cosmetically than sSAT. Removal of fat has very little margin for error in areas of the body that have an sSAT layer but not a dSAT layer. Any minor irregularities in fat removal in the sSAT layer result in contour deformities in overlying skin, thereby contributing to a poor aesthetic result.
  • Minimally-invasive fat reduction procedures include laser-assisted liposuction, laser lipolysis (e.g., the breakdown of lipids), radiofrequency lipolysis, ultrasound lipolysis, and injection lipolysis (e.g. injection of deoxy cholic acid; KYBELLA). These procedures may require a surgical incision and/or the delivery of chemicals into the body, which can carry risks to the subject, and are often painful and produce non-uniform results.
  • Noninvasive procedures to reduce undesirable subcutaneous fat include the use of cryolipolysis.
  • Cryolipolysis or fat freezing, refers to cold-induced reduction of adipocytes.
  • lipid rich cells such as subcutaneous fat and visceral fat
  • water-rich cells such as skin and muscle
  • topical cryolipolysis Treatments are longer and colder than needed to selectively target fat, as the cold temperature needs to diffuse through the skin to the underlying subcutaneous fat. Further, topical cryolipolysis relies on an applicator which greatly limits the anatomic areas that can be treated (i.e., an area can only be treated if it can be accommodated by a standard applicator). Topical cryolipolysis also lacks precision, as the cold diffuses in an uncontrolled manner over a broad area during lengthy treatment times that are necessary for topical application. Because cooling of the fat can only be achieved by diffusion of cold through the skin to the subcutaneous fat, this greatly limits the depth and amount of fat that can be removed.
  • minimally-invasive fat reduction modalities have been combined with topical cryolipolysis.
  • some methods include heating fibrous tissue to thin and reduce cellulite, and/or break up fibrous tissue, while topically cooling the skin.
  • Other methods include use of topically applied laser, radiofrequency, ultrasound, optical agents, acoustics, infrared or microwaves together with topical cooling of the skin.
  • Other methods include use of electromagnetic radiation to inhibit freezing of the epidermis during topical cooling of the skin, or use of magnetic muscle stimulation.
  • Other methods include the use of mechanical energy, such as vibration, massage, or pulsation, in combination with topical cooling of the skin.
  • the presence of excess fat causes a variety of health and cosmetic related concerns. Accordingly, there is a desire to provide methods for fat removal which are not limited by depth, and which improve the appearance of skin.
  • the present invention provides systems and methods for reducing fat and improving the appearance of skin using multiple modalities, by administering to a subject a cold solution, in combination with one or more additional modalities.
  • the cold solution can be substantially liquid, substantially solid, or a slurry comprising both liquid and solid ice particles.
  • the present invention provides:
  • a method for treatment of subcutaneous adipose tissue comprising: administering a cold solution and one or more additional modalities to a treatment site of a subject, wherein the treatment site is superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue or superficial subcutaneous adipose tissue and deep subcutaneous tissue, wherein the cold solution comprises liquid water and/or solid ice particles.
  • thermo energy is administered through application of a warm cloth, warm water bottle, ultrasound, heating pad, heat therapy wrap, hydrocollator heat pack and/or injection of a warm solution.
  • radiant energy is administered through a laser, solar energy, visible light, infrared waves, radio waves, ultraviolet waves, microwaves and/or radium.
  • a method for treatment of subcutaneous adipose tissue comprising inserting a sheath comprising a lumen into a treatment site of a subject, inserting a device through the lumen into the treatment site, and administering a cold solution to the treatment site, wherein the treatment site is superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue or superficial subcutaneous adipose tissue and deep subcutaneous tissue, and wherein the cold solution comprises liquid water and/or solid ice particles.
  • a method for treatment of subcutaneous adipose tissue comprising: inserting a sheath comprising a first lumen and a second lumen into a treatment site of a subject, inserting a device through the first lumen into the treatment site, and administering a cold solution through the second lumen into the treatment site, wherein the treatment site is superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue or superficial subcutaneous adipose tissue and deep subcutaneous tissue, and wherein the cold solution comprises liquid water and/or solid ice particles.
  • the device is an energy device selected from the group consisting of an ultrasonic device, a resistive heater, an ultrasonically actuated cutting tip, a light guide and an optical fiber.
  • a system for treatment of subcutaneous adipose tissue comprising: a sheath comprising a lumen, an energy device configured to administer energy to a subject via the lumen, and a cold solution supply source configured to supply a cold solution comprising liquid water and/or solid ice particles, the cold solution to be administered to a treatment site of the subject via the lumen.
  • the energy device is selected from the group consisting of an ultrasonic device, a resistive heater, an ultrasonically actuated cutting tip, a light guide and an optical fiber.
  • a method for treatment of subcutaneous adipose tissue comprising: administering a cold solution to a treatment site of a subject, simultaneously administering a secondary solution comprising a second agent together with the administration of the cold solution, and activating the second agent secondarily, wherein the treatment site is superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue or superficial subcutaneous adipose tissue and deep subcutaneous tissue, and the cold solution comprises liquid water and/or solid ice particles.
  • a system for treatment of subcutaneous adipose tissue comprising: a sheath comprising a first lumen and a second lumen, a cold solution supply source configured to supply a cold solution comprising liquid water and/or solid ice particles, the cold solution to be administered to a treatment site of a subject via the first lumen, and a secondary solution supply source configured to supply a secondary solution comprising a second agent, the secondary solution to be administered to a treatment site of a subject via the second lumen.
  • a method for treatment of subcutaneous adipose tissue comprising: inserting a fenestrated needle into a treatment site of a subject, and administering a cold solution to the treatment site, wherein the treatment site is superficial subcutaneous adipose tissue, deep subcutaneous adipose tissue or superficial subcutaneous adipose tissue and deep subcutaneous tissue, wherein the cold solution comprises liquid water and/or solid ice particles, and wherein the fenestrated needle is inserted into the treatment site prior to administration of the cold solution to the treatment site.
  • a system for treatment of subcutaneous adipose tissue comprising: a fenestrated needle, a sheath comprising a lumen, a cold solution supply source configured to supply a cold solution comprising liquid water and/or solid ice particles, the cold solution to be administered to a treatment site of a subject via the lumen, a target molecule solution source configured to supply the target molecule solution into the treatment site of the subject via the fenestrated needle, and optionally an energy source configured to be administered to the treatment site of the subject via the fenestrated needle.
  • a system for treatment of subcutaneous adipose tissue comprising: a delivery device for delivering a cold solution comprising liquid water and/or solid particles to a treatment site of a subject, a cold solution supply source configured to supply the cold solution, one or more additional modalities configured for administration to the treatment site.
  • thermo energy device selected from the group consisting of a warm cloth, warm water bottle, ultrasound machine, heating pad, heat therapy wrap, hydrocollator heat pack and injectable warm solution.
  • a radiant energy device selected from the group consisting of a laser, and a device which may provide solar energy, visible light, infrared waves, radio waves, ultraviolet waves, microwaves and/or radium.
  • FIG. 1 provides lateral, anterior, and posterior views the body, and indicates treatment sites which are suitable for the methods of fat reduction described herein.
  • FIG. 2 is a view of an example device for delivering a cold solution.
  • FIG. 3 is a diagram of a cold solution being delivered.
  • FIG. 4 is a view of an example device for delivering a cold solution.
  • FIG. 5 is a diagram of an approach to generating a cold solution inside a subject’s body.
  • FIG. 6 is a view of a generating end of a point of delivery generation device for forming a cold solution from liquid water and solid water.
  • FIG. 7A is a view of a generating end of another point of delivery generation device for forming a cold solution from liquid water and solid water.
  • FIG. 7B is a sectional view of the generating end of FIG. 7A.
  • FIG. 8 is a view of a generating end of a point of delivery generation device for forming solid water from a first supply of liquid water and then forming a cold solution from the solid water and a second supply of liquid water.
  • FIG. 9 is a view of a generating end of a point of delivery generation device for forming a cold solution from supercooled water and ice pellets.
  • FIGS. 10A and 10B are views of a generating end of a point of delivery generation device for forming a cold solution inside a balloon.
  • FIG. 11 is a view of a point of delivery generation device for generating and replenishing cold solution.
  • FIG. 12 is a view of a point of delivery generation device having multiple working channels.
  • FIG. 13 shows a cooling treatment system
  • FIG. 14 is a schematic illustration of the cooling treatment system of FIG. 13.
  • FIG. 15 shows the cooling treatment system of FIG. 13 including a warming unit, thermal imaging, and depth imaging.
  • FIG. 16 is a schematic illustration of the cooling treatment system of FIG. 15.
  • FIG. 17 shows an interface and a delivery device of the cooling treatment system of FIG. 13 where the delivery device includes shorter protrusions.
  • FIG. 18 shows an interface and a delivery device of the cooling treatment system of FIG. 13 where the delivery device includes longer protrusions.
  • FIG. 19 shows an interface and a delivery device of the cooling treatment system of FIG. 13 where the delivery device defines a larger area and includes shorter protrusions.
  • FIG. 20 shows an interface and a delivery device of the cooling treatment system of FIG. 13 where the delivery device defines a larger area and includes longer protrusions.
  • FIG. 21 shows an interface and a delivery device of the cooling treatment system of FIG. 13 where the delivery device defines an arcuate shape.
  • FIG. 22 A shows a delivery device of the cooling treatment system of FIG. 13 where the delivery device defines a rod shape with protrusions extending from substantially half of a circumference of the rod.
  • FIG. 22B is a top view of the delivery device of FIG. 22A.
  • FIG. 23 A shows a delivery device of the cooling treatment system of FIG. 13 where the delivery device defines a rod shape with protrusions extending circumferentially around the rod.
  • FIG. 23B is a top view of the delivery device of FIG. 23 A.
  • FIG. 24 shows a protrusion of the cooling treatment system of FIG. 13 configured to be cooled by conduction.
  • FIG. 25 shows a protrusion of the cooling treatment system of FIG. 13 having an insulating jacket.
  • FIG. 26 shows a protrusion of the cooling treatment system of FIG. 13 configured to be actively cooling via a circulating cryogen.
  • FIG. 27 shows a protrusion of the cooling treatment system of FIG. 13 where a proximal end of the protrusion is actively insulated/warmed.
  • FIG. 28A shows a plurality of protrusions of the cooling treatment system of FIG. 13 in the form of a plurality of needles configured to inject a cold solution according to one aspect of the present disclosure.
  • FIG. 28B shows a plurality of protrusions of the cooling treatment system of FIG. 13 in the form of a plurality of needles coupled to a manifold and configured to inject a cold solution.
  • FIG. 29 shows a protrusion of the cooling treatment system of FIG. 13 in the form of a needle configured to inject a cold solution in a bulk cooling pattern.
  • FIG. 30 shows a protrusion of the cooling treatment system of FIG. 13 in the form of a needle having a cooling apparatus in a contracted state.
  • FIG. 31 shows the protrusion of FIG. 30 with the cooling apparatus in an expanded state.
  • FIG. 32 shows a protrusion of the cooling treatment system of FIG. 13 in the form of a needle having a plurality of tips configured to impart a fractional cooling pattern.
  • FIG. 33 shows a protrusion of the cooling treatment system of FIG. 13 in the form of a needle having a plurality radially extending of tips configured to impart a fractional cooling pattern.
  • FIG. 34 illustrates one non-limiting fractional cooling pattern achievable by the cooling treatment system of FIG. 13.
  • FIG. 35 illustrates one non-limiting example of an array bulk cooling pattern achievable by the cooling treatment system of FIG. 13.
  • FIG. 36 illustrates one non-limiting example of a bulk cooling pattern achievable by the cooling treatment system of FIG. 13 using a protrusion.
  • FIG. 37 illustrates one non-limiting example of a bulk cooling pattern achievable by the cooling treatment system of FIG. 13 following a fanning injection through a needle.
  • FIG. 38A illustrates a non-limiting example of a delivery device having a sheath/cannula, wherein a device, such as an energy device, may be inserted into the treatment site via the sheath/cannula.
  • a device such as an energy device
  • FIG. 38B illustrates the cold solution may be administered into the treatment site via the sheath/cannula shown in FIG. 38 A, according to one aspect of the present invention.
  • FIG. 38C illustrates a non-limiting example of a multi-lumen delivery device, which includes a first lumen and a second lumen within a sheath/cannula, wherein an energy device may be inserted into the treatment site via the first lumen, and the cold solution may be administered into the treatment site via the second lumen.
  • FIG. 39 illustrates a non-limiting example of a multi -lumen delivery device, which includes a first lumen (Lumen 1) and a second lumen (Lumen 2), wherein the cold solution may be administered to the treatment site via the first lumen, and a secondary solution with target molecules may be administered to the treatment site via the second lumen.
  • FIG. 40A illustrates a non-limiting example of a fenestrated needle, which may be inserted into the treatment site, through which a target molecule solution is administered to the treatment site.
  • FIG. 40B illustrates a non-limiting example of a treatment site, wherein a target molecule solution has been administered to the treatment site through a fenestrated needle as shown in FIG. 40A, wherein the target molecule solution is light activated through the fenestrations.
  • the invention provides systems and methods for reducing fat and/or activating fat, and improving the appearance of skin using multiple modalities, wherein a cold solution is administered to a subject, in combination with one or more additional modalities.
  • the cold solution may comprise liquid water and/or solid ice particles.
  • the cold solution can be substantially liquid, substantially solid, or a slurry comprising both liquid and solid ice particles.
  • a cold solution In addition to fat reduction and/or activation and improving the appearance of skin, the administration of a cold solution has additional benefits, including but not limited to, angiogenesis promotion, improved blood flow, improved skin pigmentation, and reduced appearance of stretch marks.
  • Types of fat can include but are not limited to subcutaneous fat, white fat, brown fat, beige fat, visceral fat, airway fat, epicardial fat, ectopic fat, and other fatty tissues such as lipomas and lipedema.
  • the cold solution may include water.
  • the cold solution may include water and one or more additives.
  • the one or more additives are inactive, biocompatible ingredients, including any substance (at or below their respective concentrations) in the FDA GRAS list, which is incorporated by reference in its entirety herein.
  • the additives comprise one or more of a salt, a sugar, and a thickener.
  • the cold solution comprises potassium chloride at about 0.02% by mass or lower, for example, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0% by mass.
  • the cold solution comprises calcium chloride at about 0.02% by mass or lower, for example, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0% by mass.
  • the cold solution comprises sodium chloride at about 2.25% by mass or lower, for example at about 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,
  • the cold solution comprises magnesium chloride at about 0.02% by mass or lower, for example, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0% by mass.
  • the cold solution comprises sucrose at about 5% by mass or lower, for example at about 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises dextrose at about 5.6% by mass or lower, for example at about 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises mannitol at about 4.95% by mass or lower, for example at about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises lactose at about 0.45% by mass or lower, for example at about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, or 0% by mass. In some aspects, the cold solution comprises sorbitol at about 4.7% by mass or lower, for example at about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises glycerol at about 2% by mass or lower, for example at about 1.9, 1.8, 1,7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • the cold solution comprises hetastarch at about 6% by mass or lower, for example at about 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises pectin at about 16.7% by mass or lower, for example at about 16, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0% by mass.
  • the cold solution comprises polyethylene glycol at about 20% by mass or lower, for example at about 20, 15, 10,
  • the cold solution comprises gelatin at about 16% by mass or lower, for example at about 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0% by mass.
  • the cold solution comprises sodium methylcellulose at about 5% by mass or lower, for example at about 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises a sodium alginate at about 5% by mass or lower, for example at about 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0% by mass.
  • the cold solution comprises polyvinyl alcohol at about 5% by mass or lower, for example at about 5, 4.5, 4, 3.5, 3,
  • the cold solution comprises polyvinyl pyrrolidone (PVP) at about 5% by mass or lower, for example at about 5, 4.5, 4, 3.5, 3, 2.5, 2,
  • PVP polyvinyl pyrrolidone
  • the cold solution comprises Xanthan Gum at about 0.75% by mass or lower, for example at about 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • the cold solution comprises CMC at about 0.75% by mass or lower, for example at about 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • the cold solution comprises guar gum at about 1% by mass or lower, for example at about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • the cold solution comprises locust bean gum at about 1% by mass or lower, for example at about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • the cold solution comprises gum tragacanth at about 1% by mass or lower, for example at about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • the cold solution comprises carbomer at about 1% by mass or lower, for example at about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0% by mass.
  • Additional exemplary additives include bulking agents, such as sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffmose, glycine, histidine, PVP (K40); salts such as potassium, calcium, magnesium, hydrogen phosphate, hydrogen carbonate; buffering agents, such as sodium citrate, sodium phosphate, sodium hydroxide, tris base-65, tris acetate, tris HC1- 65; tonicity modifiers, such as dextrose; collapse temperature modifiers such as dextran, ficoll, gelatin, and hydroxyethyl starch; antimicrobial preservatives such as benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, myristyl gamma-picolinium chloride, paraben methyl, paraben propyl, phenol, 2-phenoxyethanol, phenyl mercuric n
  • the cold solution can include one or more therapeutic agents, for example, an antioxidant, an anesthetic, a vasoconstrictor, an antibacterial, and a neuroprotectant.
  • the cold solution can include a pharmacological agent to stimulate browning of fat, such as an agent to stimulate uncoupling protein 1 (UCP1) expression in adipocytes.
  • UCP1 uncoupling protein 1
  • the cold solution can be delivered to a subject such as a human or an animal, therefore the solution can be sterile and have an osmolality and pH such that it does not harm target or non-target tissue.
  • the cold solution may have an osmolality of less than about 2,200 milli-Osmoles/kilogram.
  • the cold solution may have an osmolality of less than about 1,000 milli-Osmoles/kilogram.
  • the osmolality may be less than about 600 milli-Osmoles/kilogram.
  • the pH is between about 4.5 and about 9.
  • the cold solution is substantially liquid such as the cold solution described in PCT/US2019/55605 filed on October 10, 2019, which is incorporated by reference in its entirety herein.
  • the cold solution can be cooled or supercooled to a temperature just before spontaneous nucleation occurs.
  • the cold solution can be cooled or supercooled to a temperature approximate to or lower than where spontaneous nucleation occurs, then warmed such that all ice particles melt prior to delivery to a subject.
  • a cold solution is water that is supercooled. Water normally freezes at 273.15 K (0 °C or 32 °F), but it can be supercooled at standard pressure down to its crystal homogeneous nucleation at almost 224.8 K (-48.3 °C/-55 °F).
  • the supercooling process requires that water be pure and free of nucleation sites. This can be done by processes like reverse osmosis or chemical demineralization. Rapidly cooling of water at a rate on the order of 10 L 6 K/s avoids crystal nucleation and water becomes a glass, i.e., an amorphous (non-crystalline) solid.
  • the temperature of the cold solution can be cooled to a temperature ranging from at about 10° C to at about -50° C.
  • One or more additives can be selected and included in the cold solution to change the freezing point of the cold solution.
  • the cold solution is substantially solid, i.e., substantially ice, such as the substantially solid solution.
  • substantially solid solutions, systems and methods for generating substantially solid solutions, and methods for administering substantially solid solutions are described in U.S. Provisional Patent Application Ser. No. 62/953,272 filed on December 24, 2019, which is incorporated by reference in its entirety herein.
  • the cold solution can comprise ice at a concentration of about 71% to about 100%, including 71, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 and 100%.
  • the cold solution may comprise 95 to 100% of ice in a solid state, e.g., an ice composition.
  • the cold solution comprising 95% to 100% ice in a solid state is an ice needle composition, which may be generated and/or delivered via a cannula such as a needle.
  • the cold solution is a slurry, including a liquid and solid ice particles, such as the slurry described in International Patent Applications PCT/US2019/54828 filed on October 4, 2019 and PCT/US2015/047301 filed on August 27, 2015, both of which are incorporated by reference in their entirety herein.
  • Systems and methods for making a slurry are described in International Patent Application PCT/US2019/55634 filed on October 10, 2019, which is incorporated by reference in its entirety herein.
  • One or more additives can be selected to optimize flowability which is the ability of the slurry to flow through a device or within a subject.
  • flowability describes how easy it is for the slurry to move, either within the system for making the slurry, a delivery device for delivering the slurry such as a cannula, or within the body of a human subject.
  • Flowability is dependent on several factors, including ice particle size, ice particle shape (as they relate to the configuration of the delivery device, for example, needle gauge) and viscosity.
  • the slurry includes ice particles, for example at a concentration of about 2% to about 70%.
  • the ice concentration is about 20% to about 50%, for example, at about 30% to about 40%, for example, about 31, 32, 33, 34, 35, 36, 37, 38, or 39%.
  • the ice particles can be substantially rounded and uniform in shape and size. Ice crystal size can be based upon the size of the delivery device, for example, an ice particle size of about 100 pm may allow injection through a needle having an inside diameter of about 1.0 mm or smaller. In some aspects, the ice particle size may be less than about 1mm, or less than about 0.25mm.
  • the temperature of the slurry can range from about -25°C to about 10°C, for example, from about -6°C to about 0°C, for example, about -5°C, -4°C, -3°C, -2°C, -1°C.
  • the type of cold solution(s) i.e., substantially liquid, substantially solid, or slurry
  • characteristics thereof e.g., osmolality, volume, temperature, ice content, ice shape/size
  • a single treatment can include the delivery of one or more types of cold solution to one or more treatment sites via any suitable delivery method and any combination thereof.
  • Methods for reducing fat and improving the appearance of skin using multiple modalities comprise administering a cold solution to a subject, in combination with one or additional modalities.
  • the cold solution may be administered in a single treatment, or may be administered as a series of treatments, for example a pre-treatment, followed by a treatment, followed by a post-treatment.
  • the pre-treatment, treatment and post-treatment may occur in the same session.
  • the pre-treatment and post-treatment may occur in sessions before and after the treatment session, respectively.
  • the pre treatment may occur 24 hours prior to the treatment. In another aspects, the pre-treatment may occur 24 hours after the treatment.
  • the one or more additional modalities may be administered in one or more of the pre-treatment, treatment or post-treatment sessions, or may occur before, between, or after one or more of the sessions.
  • the cold solution may be administered by injection into sSAT only, injection into dSAT only, injection into dSAT followed by injection into sSAT, injection into sSAT followed by injection into dSAT, and injection into dSAT and sSAT simultaneously, thus allowing for selective targeting of sSAT and dSAT.
  • injection into the dSAT followed by injection into the sSAT is utilized to allow for visualization of each layer during the injection.
  • multiple treatments may be performed, for example with a first session targeting the sSAT and a second session targeting the dSAT. Any layer(s) can be treated in any order in any number of treatments.
  • a force e.g., a vacuum, may be applied to the skin prior to injection to enable injection at varying angles and/or to reach a deeper layer of fat.
  • methods of the invention may further comprise administering an anesthetic to an area for treatment of the subject prior to injecting the cold solution, topically and/or via injection.
  • the anesthetic may be a local anesthetic, such as lidocaine.
  • the anesthetic may be administered to a subject a suitable amount of time in advance of the treatment in order to numb the injection area before treatment of the cold solution.
  • the cold solution is administered to a human subject by any suitable method.
  • the cold solution is injected by any suitable means, such as injection by a cannula such as a needle.
  • the needle may be any suitable type of surgical needle.
  • the needle is a fenestrated needle.
  • the needle may be a surgical needle of any suitable size.
  • the needle comprises a gauge size of about 8G to about 25G.
  • the cold solution may also be administered with internal or external pressure on or near the treatment site to modify administration and/or effect of the cold solution.
  • a balloon structure may be deployed at or near a point of delivery to act as an internal pressure device obstructing the flow of blood into a treatment area thus achieving extended cooling after injection.
  • Approaches to delivery of a cold solution utilizing balloon structures are disclosed, for example, in International Application Publication No. PCT/US2018/026273, filed April 5, 2018; U.S. Patent Application Publication No. 2018-0289538, filed October 11, 2018; and U.S. Provisional Application No. 62/482,008, filed April 5, 2017, the contents of which are incorporated herein by reference in their entirety.
  • a vasoconstrictor is administered to the subject to reduce blood flow to achieve extended cooling. Pressure may also be applied externally using hand pressure and/or an applicator on the surface of the dermis.
  • a treatment may include delivering a volume of cold solution to one or more treatment sites.
  • the site may be treated via one or more injection sites, i.e., puncture site, and one or more deposition sites.
  • the deposition site is where the cold solution is deposited, regardless of the injection site, and may be a different site than the injection site or the same site.
  • One or more treatments can be required to achieve a desired effect.
  • the amount of cold solution injected may be about 2L or less per injection site. In some examples, the amount of cold solution injected is about 1 mL to about 2L per injection site.
  • different subjects have different amounts of subcutaneous fat, and therefore, some subjects may require injection of greater amounts of cold solution in order to produce visible effects of reduction and removal of subcutaneous fat. Other subjects may require multiple treatments to produce effects of removal or reduction of subcutaneous fat or tightening of the skin as a result of a collagen response.
  • the amount of cold solution injected may be about 1 mL to about 1L per injection site.
  • a cold solution can be delivered to the entire outer circumference of the neck or any portion or portions thereof.
  • a cold solution for use in the invention may be injected at multiple treatment sites.
  • the selected treatment sites may be the superficial subcutaneous fat layer, the deep subcutaneous fat layer, or both.
  • the cold solution may be injected into the superficial subcutaneous fat layer or deep subcutaneous fat layer at a plurality of injection sites.
  • the cold solution is injected at a plurality of injection sites into both subcutaneous fat layers.
  • the superficial subcutaneous fat layer is treated at the same time as the deep subcutaneous fat layer.
  • the cold solution is injected into superficial subcutaneous fat, and then the needle is moved deeper in the deep subcutaneous fat regions.
  • a fenestrated needle having a suitable length with fenestrations in both the first subcutaneous fat layer and the second subcutaneous fat layer is used to treat the first and second subcutaneous fat layers at the same time.
  • the superficial subcutaneous fat layer and the deep subcutaneous fat layer are treated at the same time by injecting a needle and slowly withdrawing the needle, releasing cold solution in both subcutaneous fat layers.
  • the injection sites may form a pattern, such as a plow, fan, or grid-like pattern, or in a single bolus or multiple bolus injections.
  • one injection site is used repeatedly, thereby reducing the number of injection sites and concomitant scarring potential.
  • a plow injection pattern a single initial target injection site is used followed by a moving needle for additional deposition sites, for example in a linear pattern.
  • deposition sites form an arc from 1 to 360 degrees.
  • the cold solution is deposited in a single injection site.
  • the injection pattern and/or cold solution can be determined based on the subject's profile, treatment plan (as described below), or based on the target site to be treated, i.e., treatment site.
  • an injection pattern and/or volume may be selected to optimize consistency of temperature at the treatment site.
  • the injection pattern and/or volume is selected in order to achieve gradient cooling of the tissue proximate to or at a treatment site or injection site.
  • Injection techniques including the patterns described herein, are known to those of skill in the art.
  • Treatment with the cold solution comprises reduction or removal of fat cells in the human subject by freezing, or cryolipolysis.
  • Treatment may also comprise tightening of skin of the human subject. The tightening of the skin results from a collagen response upon removal and reduction of the fat cells in the subcutaneous fat layer.
  • Reduction of subcutaneous fat may also reduce adipose tissue hypoxia or inflammatory signaling in overweight and obese individuals.
  • the cold solution may be utilized to mechanically disrupt fibrous tissue to break up compartments found within the subcutaneous fat, allowing the subcutaneous fat to spread and create a visually smoother appearance, for example in the treatment of cellulite.
  • Treatment with the cold solution may be optimized for cosmetic or aesthetic results, for example to achieve smoothing and to avoid the appearance of sharp edges in the subcutaneous layer or layers.
  • a profile can be created that correlates to the ice coefficient in the cold solution.
  • the ice coefficient is defined as the percentage of ice, i.e., the percent by volume of water in a solid state in the cold solution, or the amount of ice by weight.
  • a cold solution with a higher ice coefficient can be used to treat the center of a treatment site, while a cold solution with a lower ice coefficient can be used to treat to the outer perimeter of the treatment site.
  • Any of the cold solution properties such as ice coefficient, ice size and ice shape, can be varied to achieve a desired result.
  • a treatment plan may be created for a subject, for example to determine one or more of type of cold solution, the cold solution properties (for example, ingredients, tonicity and/or ice content, amount of cold solution to be delivered, delivery method(s) (e.g., ingestion, inhalation, injection, topical/contact, and/or incision), treatment sites such as superficial and/or deep layers, a suitable device for administration of the cold solution, and which additional modality/modalities to be included in the subject’s treatment.
  • the cold solution properties for example, ingredients, tonicity and/or ice content, amount of cold solution to be delivered
  • delivery method(s) e.g., ingestion, inhalation, injection, topical/contact, and/or incision
  • treatment sites such as superficial and/or deep layers
  • a suitable device for administration of the cold solution e.g., a suitable device for administration of the cold solution, and which additional modality/modalities to be included in the subject’s treatment.
  • Factors considered in creating a treatment plan for a subject may comprise one or more of gender, height, body weight, body fat percentage, anatomy such as septae rigidity, lifestyle, vitals, medical history, lipid profiles, skin elasticity, medication, nutrition, supplements, demographic, vascularity of fat tissue, fat saturation, fat metabolism, and the like.
  • Fat saturation may be characterized by one or more of imaging, biopsy, and impedance measurement.
  • Fat metabolism may be characterized by imaging.
  • the amount of cold solution to be administered can be adjusted based on one or more of the area or areas to be treated, the subcutaneous fat layers to be treated, the depth of injection, and the injection pattern to be used, and which additional modality/modalities are to be incorporated.
  • Imaging may also be utilized during creation of a treatment plan for a subject by collecting pre-, peri-, and/or post-injection data from one or more subjects.
  • Information may be obtained through any suitable procedure, including but not limited to Magnetic Resonance Imaging (MRI), Computed Topography (CT), ultrasound, Positron Emission Tomography (PET), and combinations thereof. Utilizing images of the treatment site, surrounding areas, and/or other areas of interest, may provide detailed information regarding the most suitable treatment plan.
  • MRI Magnetic Resonance Imaging
  • CT Computed Topography
  • PET Positron Emission Tomography
  • a computer or artificial intelligence system may be utilized to create a treatment plan and/or a post-procedure plan for a subject by collecting pre-, peri-, and/or post-injection data from multiple subjects. It is appreciated that the more data points, the more effective the artificial intelligence system will be in creating a treatment plan for a subject.
  • pre-, peri-, and/or post- injection data may be collected for each subject comprising one or more of gender, height, body weight, body fat percentage, the subject's anatomy, lifestyle, the subject's vitals, medical history, lipid profiles, skin elasticity, medication, nutrition, supplements, demographic, fat saturation, imaging data, treatment data and fat loss data. Data may be measured by any suitable means.
  • fat loss data may be measured by calipers or any imaging methods such as ultrasound, MRI, 3D photography, visual assessment, and the like.
  • the system can be used to determine treatment eligibility, to order pre-treatment diagnostics/health screening, provide cost estimates, simulate results, provide information for subjects about the procedure, assist with patient intake, provide connectivity to service providers and Telehealth options, and provide an option for a subject to share individual treatment goals with a provider.
  • pre-procedure monitoring .e.g, to assist in creation of a treatment plan, and/or post-procedure monitoring, and/or a treatment modality can be performed via one or more monitoring devices including but not limited to a wearable physiological monitoring device, a sleep monitoring device, a metabolic monitoring device, a glucose monitoring device, monitoring of various biomarkers associated with health/disease such as markers associated with inflammatory and oxidative stress, blood work monitoring, hormone monitoring, body waste monitoring, white to brown fat conversion rate monitoring, mental well being monitoring, taking physical measurements, e.g., using measuring tape, muscle mass measurement, 3D Image Scan, bioelectric impedance measuring, e.g., a scale, a handheld device, whole body measuring device, a direct segmental whole body composition measuring device, hydrostatic weighing centers, measurement of rate of healing of tom muscle fibers from exercise, indirect calorimetry, and a wearable to passively measure oxygen intake and carbon dioxide output, e.g., an RBC measurement
  • Pre- or post- treatment steps may be utilized to optimize treatment results.
  • a massaging step may be utilized to increase fat cell damage and/or the mechanical force of the ice in the cold solution.
  • the massaging is performed to puncture one or more cell membranes.
  • the massaging step may be used to position or shape the cold solution post injection.
  • Massaging can be performed by any mechanical means, for example by hand, vibration, an applicator, or by acoustic means.
  • Imaging pre-injection can be utilized to create a treatment plan and may further be used to develop the profile for the subject. For example, the septae of the subject may be disrupted prior to injection of the cold solution to allow the cold solution to flow more smoothly.
  • the septae is disrupted mechanically, e.g., by puncture, massage, cutting, using one or more ice particles, such as in a slurry as described herein.
  • the septae is disrupted chemically, e.g., pharmaceutical agents including but not limited to hyaluronidase, collagenases, or elastases.
  • the septae is disrupted thermally, e.g., a laser to warm the tissue.
  • disrupt can mean cut, sever, break, damage, make more flexible, or otherwise change the properties thereof.
  • Methods for reducing fat and improving the appearance of skin comprise administering a cold solution to a subject, in combination with one or more additional modalities.
  • the one or more additional modalities include, but are not limited to, energy, surgery, nutrition and/or wellness, exercise, and aesthetic, chemical and/or biological treatments.
  • a modality which utilizes energy may include thermal energy, radiant energy, chemical energy, electrical energy and/or mechanical energy.
  • the additional modality can be used to augment or supplement the treatment with cold solution.
  • thermal energy may be utilized to increase the temperature at or near the injection site and/or the treatment site.
  • Thermal energy may be administered by any method known in the art, including but not limited to, hot or warm cloth, hot or warm water bottle, hot or warm bath, ultrasound, heating pad, heat therapy wraps, hydrocollator heat packs, and injection of a warm solution.
  • the increase in temperature at or near the injection and/or treatment site may alter the physical characteristics of the tissue in and around the site, thus increasing fat reduction and improvement of the appearance of the skin.
  • the tissue may be thinned and/or have increased flexibility.
  • the blood flow at or near the site may increase, thus improving oxygenation and wound healing.
  • the administration of thermal energy may reduce pain and/or inflammation at or near the site.
  • the administration of thermal energy may activate a pharmacological agent which may be administered before, during, or after the administration of the cold solution.
  • radiant energy may be utilized through any device such as a laser and/or method known in the art, including but not limited to utilization of solar energy, visible light, infrared waves, radio waves such as radiofrequency, ultraviolet waves, X-rays, microwaves, and/or radium, in the treatment of the subject.
  • a photosensitizer and light source can be administered to the treatment area, for example to improve the appearance of skin such as to reduce stretch marks.
  • photosensitizers include but are not limited to 5-aminolevulinate, porphyrins, chlorins, bacteriochlorins, phthalocyanines, phenothiazinium salts, rose Bengal, squarines, BODIPY dyes, phenalenones, ruthenium compounds, rhodium compounds, hypericin, hypocrellin, riboflavin, and cur cumin.
  • light sources include but are not limited to light-emitting diodes, lasers and intense pulsed light. In some instances, the radiant energy may be utilized to treat an area of the subject, or to diagnose and study an area of the subject.
  • chemical energy may be utilized through any device and/or method known in the art, in the treatment of the subject.
  • chemical energy is administered by administering one or more substances to the treatment site, wherein the one or more substances cause an exothermic reaction thereby heating the treatment site.
  • one or more substances can be administered to the treatment site where the one or more substances cause an exothermic reaction thereby heating the treatment site.
  • fat cells when fat cells are subjected to cold, such as through the administration of a cold solution, the fat cells release energy as heat, thus further aiding in the reduction of fat.
  • electrical energy may be utilized through any device and/or method known in the art, including but not limited to electrical stimulation devices and electromagnetic devices, such as an electronic muscle stimulator or a transcutaneous electrical nerve stimulator, in the treatment of the subject.
  • electrical energy may be administered in order to increase muscle metabolism, increase muscle mass, relax and/or tone muscles, increase blood circulation, manage pain, improve wound healing, and/or assist with drug delivery, for example, in the process of iontophoresis.
  • mechanical energy may be utilized through any device and/or method known in the art, in the treatment of the subject.
  • mechanical energy may be administered through ultrasound, massage, vibration, pulsation and/or compression.
  • mechanical energy may be utilized through fractional wounding, wherein micro-holes are drilled in or around the treatment site, in order to stimulate collagen production and/or deliver the cold solution to the subject.
  • a device containing a pre-fabricated array for example, an array of needles or cannulas, may be utilized to drill the micro-holes in an appropriate pattern, wherein the pattern is in an appropriate shape for the size and shape of the administration site, and may include a grid, wherein the grid is a square- shape, a rectangular-shape, a circular-shape, or a triangular shape, a plow-shape, a fan-shape, a combination thereof, or a modification thereof.
  • mechanical energy may be utilized by administering filaments, wherein the filaments may be administered via a staple gun.
  • the filaments are biodegradable, and may optionally be loaded with a pharmacological agent.
  • mechanical energy may be utilized by administering resorbable sutures in combination with the cold solution to the subject.
  • a device is generated by placing one or more resorbable sutures in a mold, for example, a cannula, and placing a solution comprising water and optionally one or more additives in the mold, prior to cooling the mold and components therein.
  • the cold solution further comprising one or more resorbable sutures is removed from the mold in an appropriate manner, and administered to the desired treatment site through an appropriate method, for example, via injection.
  • the cold solution melts, through any suitable active or passive measure.
  • the one or more resorbable sutures remain at or near the treatment site until resorption acting as an irritant to the tissue surrounding the treatment site.
  • a cosmetic benefit occurs due to the increased collagen produced around the treatment site due to the presence of an unknown irritant, specifically the one or more resorbable sutures.
  • the increased collagen promotes cell renewal, which provides cosmetically appealing results.
  • the sutures may be provided in a pattern suitable to the treatment site. For example, when treating the chin and neck area, the sutures may be administered in an arc pattern just below the jawline, thus providing minimally visible suture sites.
  • mechanical energy may be utilized by administering ultrasound, for example via delivery device comprising a transducer.
  • an ultrasound needle or catheter can be used to deliver energy, for example, the ultrasound catheter disclosed in Burdette, Everette et ah, (2010), The ACUSITT Ultrasonic Ablator: The First Steerable Needle with an Integrated Interventional Tool, Proceedings of SPIE - The International Society for Optical Engineering, 7629. 10.1117/12.845972, the contents of which are incorporated by reference in its entirety.
  • a modality which utilizes surgery may include any appropriate surgical procedure known to those skilled in the art, including but not limited to fat transfer, implant placement, filler injection (including but not limited to fat, collagen, hyaluronic acid, and any compositions disclosed in U.S. Provisional Patent Application Ser. No. 63/001,889 filed on March 30, 2020 which is incorporated herein by reference in its entirety), liposuction, abdominoplasty, gluteoplasty, brachioplasty, thighplasty, lower rhytidectomy, mentoplasty and bariatric surgery.
  • Surgery may also include less invasive fat reduction procedures including but not limited to laser-assisted liposuction, laser lipolysis (e.g., the breakdown of lipids), radiofrequency lipolysis, ultrasound lipolysis, and injection lipolysis.
  • a modality which utilizes nutrition and/or wellness may include monitoring and/or adjusting daily food intake, type of food and/or supplements, and/or calorie consumption of the subject to reduce fat.
  • a nutrition and/or wellness modality may also include one or more of nutritional analysis, nutrition coaching, lifestyle coaching, weight loss, a personalized food plan/guide, personalized recipes, a personalized nutrition plan/guide, meal box service, grocery delivery, a farm/meat share subscription, regenerative medicine, traditional aesthetic medicine, mindfulness, sleep tracking, e.g., sleep cycle, assistance of a sleep coach, light-based smart-home technologies, e.g., hue-adjusted smart lights, smart-shades, integration with sleep data to optimize wake up and go to sleep timeframes, blue light management, obstructive sleep apnea therapy, indirect data metrics, including but not limited to meal purchase, use of refrigerator artificial intelligence, career planning and/or coaching, acupuncture, energy- based therapies, reiki, use of informational websites, use of smart technologies,
  • Headspace app MyFitnessPal, and Google Fit
  • use of a health cloud e.g., Sales Force 360 CRM
  • spiritual guidance e.g., participation in faith based/spiritual communities, participation in faith based/spiritual experiences, financial planning, retirement planning, finance tracking, e.g., earnings and spending, and travel planning.
  • a modality which utilizes exercise may include implementing, or adding to, an exercise regimen to reduce fat, increase muscle and/or maintain weight and muscle content.
  • An exercise modality may also include one or more of personal training or coaching, physical therapy, at home workout, muscle stimulation, supplements, e.g., personalized supplements, meditation, yoga and tracking performance metrics.
  • a modality which utilizes self-optimization may include one or more of cosmetics including but not limited to hair products, skin products and nail products; aesthetic medicine approaches; a skin care regimen or treatment including but not limited to skin typing, personalized skin care regimen, topicals, skin tightening, cryangiogenesis, wrinkle management, treatment of dark spots, treatment of hyperpigmentation, texture, hydration, environmental stressor protection, e.g., sun care, pollution prevention, treatment of non-facial skin including but not limited to scars, striae, cellulite, skin laxity, keratosis pilaris, hyperhidrosis, folliculitis, and intertrigo; and a cosmetic procedure such as a non-invasive, minimally invasive or invasive procedure.
  • a chemical and/or biological modality may include treatment of the subject using small molecules, large molecules, mid-size molecules, protein degraders, antibody drug conjugates, gene therapy and/or molecular probes.
  • Such a treatment may include the administration of a pharmacological agent which may augment the reduction of fat and approving the appearance of skin.
  • the administration of the pharmacological agent may be in any suitable method.
  • the pharmacological agent includes, but is not limited to PPAR agonists, including but not limited to PPAR-gamma agonists such as thiazolidinediones, (e.g., pioglitazone, rosiglitazone, lobeglitazone), NSAIDs (e.g., ibuprofen, salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, selective COX-2 inhibitors), indole, fibrate drugs (e.g., clofibrate, gemifibrozil, ciprofibrate, bezafibrate), aleglitazar, muraglitazar, tesaglitazar, saroglitazar, caffeine, genistein, isoproterenol, theophylline, cysteine, gallic acid, rutin and catechin.
  • a biological treatment can include transplantation of brown and
  • the pharmacological agent includes exogenous agonists, including but not limited to BDNF, catecholamines (e.g., catechol, dopamine, norepinephrine, epinephrine, fenofibrate), IL-6 , PTHrP, Meteorin-like (METRNL), Irisin , Prostaglandins, VEGF, ANP/BNP, GDF5, FGF (FGF19, FGF21), BMPs (BMP4, BMP7, BMP8b).
  • exogenous agonists including but not limited to BDNF, catecholamines (e.g., catechol, dopamine, norepinephrine, epinephrine, fenofibrate), IL-6 , PTHrP, Meteorin-like (METRNL), Irisin , Prostaglandins, VEGF, ANP/BNP, GDF5, FGF (FGF19, FGF21),
  • the pharmacological agent includes drug agonists to promote endogenous signaling, including but not limited to BDNF, including but not limited to SSRI’s (e.g., citalopram, escitalopram, fluoxetine, fluvxamine, paroxetine, sertraline, dapoxetine) and SNRI’s (e.g., atomoxetine, desvenlafaxine, duloxetine, levomilnacipram, milnacipran, sibutramine, tramadol, venlafaxine); catecholamines (e.g, amitriptyline, imipramine, nortriptyline, phenoxybenzamine, doxazosin, terazosin, prazosin, atenolol, metroprolol, propanolol, labetolol, nifedipine, amlopdipine, diltiazem, verapamil
  • SSRI e.g.
  • GDF5 Guanethidine, Xylazine,Tizanidine, Medetomidine, Methyldopa, Methylnorepinephrine, Norepin ephrine, Lofexidine, Medetomidine, Xylometazoline, Oxymetazoline, Cirazoline, Epinephrine, e rgotamine, etilefrine, indanidine, mephentermine, metaraminol, methoxamine, mivazerol, naphaz oline, norfenefrine, octopamine, phenylpropanolamine, propylhexedrine, rilmenidine, romifidine, synephrine, talipexole); GDF5; FGF (e.g., FGF19, FGF21, e.g., SIRT1 activators polyphenols such as reservatrol, methylene blue, metformin, NAD+); BMPs (
  • the pharmacological agent includes drug agonists, including but not limited to TGF-B, TNF-alpha and Retinoid Acid.
  • more than one pharmacological agent may be administered.
  • the one or more pharmacological agents may be administered prior to, concurrently with, or subsequent to administration of the cold solution.
  • the one or more pharmacological agents may be administered independently from the cold solution, or may be present in the cold solution.
  • a modality that augments or supplements the treatment using a cold solution can enhance the cold solution treatment, reduce side effects of the cold solution treatment and/or improve the outcome of the cold solution treatment.
  • Modalities to enhance the cold solution treatment include but are not limited to administering an anesthetic prior to the cold slurry treatment; a modality to prevent leakage of the melted slurry, e.g., a dressing such as a superabsorbent polymer/water-absorbing polymer dressing such as a hydrogel dressing, gauze dressing, alginate dressing, hydrofiber dressing, foam dressing, medical bandage or adhesive; a modality to keep the subject warm before, during or after the treatment, e.g.
  • a warming blanket e.g., a non-contact thermal light source such as an infrared mask, hot water bottle, heating pad, heated treatment table, and a mild capsaicin cream (to increase blood flow and thus the perception of warmth); and a modality to minimize any noise created by the device during treatment, e.g., ear plugs, noise cancelling headphones or a wearable such as a foam padded hat.
  • a non-contact thermal light source such as an infrared mask, hot water bottle, heating pad, heated treatment table, and a mild capsaicin cream (to increase blood flow and thus the perception of warmth); and a modality to minimize any noise created by the device during treatment, e.g., ear plugs, noise cancelling headphones or a wearable such as a foam padded hat.
  • Modalities to reduce side effects include but are not limited to modalities to decrease bruising and/or inflammation caused by an injection, e.g., a topical comprising arnica and/or menthol; and a modality to improve healing and/or reduce scarring at an injection site, e.g., a topical such as a retinoid, corticosteroid cream, onion extract cream, petrolatum ointment, a dressing such as a silicone dressing, and a mechanical modality such as a massage or vibration device to relieve tension at the injection site.
  • a topical such as a retinoid, corticosteroid cream, onion extract cream, petrolatum ointment
  • a dressing such as a silicone dressing
  • a mechanical modality such as a massage or vibration device to relieve tension at the injection site.
  • Modalities to improve outcomes include but are not limited to a modality to break up the fibrous septae in advance of a treatment, e.g., a mechanical, thermal or chemical device as described herein; a modality to heating the treatment site before the treatment (either at home or in the treatment room), e.g., a warming blanket or thermal energy described herein; a modality to enable visualization during the procedure as described herein, modality to further break up fibrous septae and/or ice crystals post-treatment as described herein; and a modality to ensure symmetry post treatment, e.g., a compression band.
  • a modality to break up the fibrous septae in advance of a treatment e.g., a mechanical, thermal or chemical device as described herein
  • a modality to heating the treatment site before the treatment e.g., a warming blanket or thermal energy described herein
  • An exemplary method of treatment according to the invention includes creating a treatment plan, followed by pre-treatment, treatment and post-treatment.
  • a pre-treatment comprises heating, disrupting and/or preparing the treatment site immediately prior to administration of the cold solution.
  • a sheath e.g., a cannula or needle, comprising a lumen is inserted into the treatment site, and a device, e.g., an energy device, is inserted through the sheath.
  • FIG. 38A demonstrates a sheath comprising a lumen, wherein an energy device is inserted into the lumen for administration to the treatment site.
  • FIG. 38B demonstrates the cold solution may also be administered to the treatment site via the sheath and/or lumen.
  • the energy device can be any device described herein.
  • the energy device comprises one or more of an ultrasonic cutting tip, a resistive heater or a light source.
  • a sheath comprising more than one lumen (a multi-lumen sheath) is inserted into the treatment site, wherein a device, e.g., an energy device and the cold solution are administered via the more than one lumen.
  • FIG. 38C demonstrates a sheath comprising a first lumen and a second lumen, wherein an energy device is inserted into the first lumen for administration to the treatment site, and the cold solution may be administered to the treatment site via the second lumen.
  • Any number of working channels (or lumens) can be included, for example, two, three, four, five or six lumens, each configured to receive a device.
  • a visualization device can be inserted in a lumen.
  • a system for the method described above comprises a sheath comprising a lumen, an energy device configured to supply energy to a subject, and a cold solution supply source configured to supply a cold solution comprising liquid water and/or solid ice particles, the cold solution to be administered to a treatment site of the subject via the lumen.
  • the sheath comprises a first lumen and a second lumen, wherein the energy device is configured to administer energy to the subject via the first lumen, and the cold solution is configured to be administered to the subject via the second lumen.
  • the cold solution supply source is any suitable supply source, including but not limited to a pump system that generates flow of the cold solution through the sheath, for example, via a syringe.
  • an energy device is inserted into the treatment site through the lumen in the sheath, and directed toward the treatment site, in order to locally heat the treatment site, disrupt fascia between septae, cut tissue, provide illumination, provide imaging, collect data, and/or maximize the temperature difference experienced by the treatment site (contrast cryolipolysis) before and after administration of the cold solution.
  • an energy device is administered directly into the treatment site.
  • the energy device can comprise any of the energy devices described herein.
  • the energy device is an ultrasonic device, a resistive heater, an ultrasonically actuated cutting tip, a light guide or an optical fiber.
  • the energy device may be removed from the sheath or cannula, followed by administration of the cold solution through the open lumen.
  • the cold solution delivery device described above includes an ultrasound transducer which may generate heat and mechanical energy. In some aspects, generation of heat and mechanical energy will be located in a separate part of the delivery device, so as to avoid undesired heating of the cold solution.
  • the energy device When utilizing a multi-lumen sheath, the energy device may remain in place in the first lumen, and the cold solution may be administered through the second lumen.
  • radiant energy may be administered to the treatment site through the single lumen sheath or the multi-lumen sheath, or directly, in order to preheat the treatment site prior to administering the cold solution.
  • radiant energy may be administered to the treatment site prior to administering a cold solution, e.g., a slurry or a substantially solid solution, thus maximizing the temperature difference experienced by the tissue (contrast cryolipolysis), and augmenting the effects of the cold solution.
  • a cold solution is administered to the treatment site to provide cooling in order to increase the tolerability, and to limit thermal diffusion of radiant energy sources for skin treatment.
  • the cold solution may be administered to the treatment site via injection, followed by treatment of the skin at the administration site with a heat-based modality, in order to improve the appearance of the skin.
  • a cold solution delivery device may be coupled to the heating device. Such a method may enable treatment with higher levels of energy, because a cooling source is placed distal to the treatment area.
  • a substantially solid solution may be applied on the skin to actively cool the administration site and surrounding area, followed by administration of light.
  • the administration of the cold solution on the skin serves as a cooling source, e.g., numbing agent, to increase the tolerability of further administrations to the treatment site, e.g., laser treatment, and potentially increases the energy of traditional thermal methods of skin tightening and remodeling, including but not limited to laser, radio frequency, ultrasound skin tightening.
  • the cold solution and a secondary solution comprising a second agent are simultaneously delivered to the treatment site during administration, and the second agent is activated secondarily, for example, after the original administration and/or in a home environment.
  • FIG. 39 demonstrates an example of a multi-lumen sheath, wherein the cold solution is administered via a first lumen, and the secondary solution is administered via a second lumen.
  • a multi-lumen sheath is inserted into the treatment site, the cold solution is delivered through a first lumen, and a second agent, such as gold particles (e.g., gold microparticles or nanoparticles) in suspension, is delivered through a second lumen.
  • the second agent remains distributed over the area treated by the cold solution and may be externally activated, e.g., topically, to product combinatory effect.
  • light may be used to target heating of gold nanoparticles which were administered as the second agent.
  • the second agent can comprise silver particles (e.g., silver microparticles or nanoparticles) or microbubble enclosed particles.
  • the particles enclosed in microbubbles can be activated via an ultrasound device.
  • a system for the method described above comprises a sheath comprising a first lumen and a second lumen, a cold solution supply source configured to supply a cold solution comprising liquid water and/or solid ice particles, the cold solution to be administered to a treatment site of a subject via the first lumen, and a secondary solution supply source configured to supply a secondary solution comprising a second agent, the secondary solution to be administered to a treatment site of a subject via the second lumen.
  • the second solution supply source is any suitable supply source, including but not limited to a pump system that generates flow of the second solution through the sheath, for example via a syringe.
  • a cold solution is administered to a treatment site, followed by use of an additional modality, e.g., a laser, to topically heat the treatment site.
  • the additional modality may be selectively applied, such that the cold solution is melted in selected areas.
  • the melted areas may result in decreased therapeutic effect.
  • the use of selective melting may provide a desired contouring effect in or around the treatment site.
  • a pre-treatment comprises heating, disrupting and/or preparing the treatment site immediately prior to administration of the cold solution, wherein the pre-treatment utilizes a fenestrated needle.
  • a fenestrated needle For example, see FIG. 40A which demonstrates a fenestrated needle.
  • the fenestrated needle is inserted into the treatment site, followed by injection of a target molecule solution, such as gold particles, silver particles, microbubble enclosed particles, or another chemical component, into the treatment site. After injection of the target molecule solution, the fenestrated needle is removed.
  • energy is administered through the lumen of the fenestrated needle.
  • the energy source may be an ultrasonic device, a resistive heater, an ultrasonically actuated cutting tip, a light guide or an optical fiber, which may locally heat the treatment site, disrupt fascia between septae, cut tissue, provide illumination, provide imaging, collect data, and/or maximize the temperature difference experienced by the treatment site (contrast cryolipolysis).
  • FIG. 40B which demonstrates a target molecule solution being light activated through the fenestrations of the fenestrated needle.
  • the energy device Prior to administration of the cold solution, the energy device is removed.
  • the cold solution is administered via a delivery device attached to the fenestrated needle.
  • the fenestrated needle is withdrawn, and the cold solution is delivered via a delivery device.
  • pre-treatment includes obtaining measurements of the treatment site and/or the surrounding area through imaging, including but not limited to Magnetic Resonance Imaging (MRI), Computed Topography (CT), ultrasound, Positron Emission Tomography (PET), 3D imaging, and combinations thereof. Imaging may be used in the absence of, or together with, an incision near or at the treatment site.
  • measurements of the treatment site and/or the surrounding area may be obtained through a computer or artificial intelligence system, which contains data obtained from the subject to be treated and/or data obtained from multiple subjects.
  • pre-treatment also include a heat application at or near the injection site, which may improve cryolipolysis due to the difference in temperature between the warmed injection site and the cold solution to be administered, i.e., contrast cryolipolysis.
  • pre-treatment also includes selective disruption of fibrous tissue at the treatment and/or injection site and the surrounding area, thus enabling a smoothing effect in addition to the fat reduction.
  • the selective disruption of fibrous tissue may occur through any suitable method, including but not limited to, mechanical vibration, application of heat, and/or topical or subcutaneous administration of energy activated nanoparticles, e.g., gold or silver.
  • the selective disruption of fibrous tissue may also occur by administration of a cold solution, which may be utilized to mechanically disrupt fibrous tissue to break up compartments found within the subcutaneous fat, allowing the subcutaneous fat to spread and create a visually smoother appearance, for example in the treatment of cellulite, as described in US Provisional Application No. 62/953,272, previously incorporated by reference, and in International Patent Application Ser. No. PCT/US2017/059947 filed on November 13, 2017, the entirety of which is incorporated herein by reference.
  • pre-treatment also includes fractional wounding by drilling holes at or near the treatment site, in order to disrupt fibrous tissue and/or stimulate collagen production.
  • treatment includes injection of a cold solution to the subject, in any suitable amount, in the methods described above, optionally together with one or more pharmacological agents, as described above, or energy activated nanoparticles, such as gold or silver.
  • the cold solution, one or more pharmacological agents, and/or energy activated nanoparticles may be administered simultaneously and/or separately. If the cold solution, one or more pharmacological agents and/or energy activated nanoparticles are administered separately, the cold solution may be administered before, after, or before and after the administration of the one or more pharmacological agents and/or energy activated nanoparticles.
  • treatment includes heat application in order to improve cryolipolysis, application of mechanical energy, such as vibration, massage, pulsation, and/or compression, to assist with cell death after cold solution is injected, fractional wounding to deliver cold solution, and/or administration of resorbable sutures.
  • mechanical energy such as vibration, massage, pulsation, and/or compression
  • post-treatment includes one or more of magnetic muscle stimulation (MMS) in order to develop/improve muscle tone, compression, thermal compression, cool/cold compression, activation of previously deposited energy activated nanoparticles, nutrition planning and monitoring, exercise, topical application of a microneedle patch to allow transdermal delivery of one or more pharmacological agents, as described above, and/or the collection of samples, including but not limited to blood and interstitial fluid, which may utilized for data collection and analysis, collection of data using a computer program or application, and/or fractional wounding in order to stimulate collagen production.
  • MMS magnetic muscle stimulation
  • Delivering a cold solution according to the present invention can be via any suitable means, for example, topically, via injection, ingestion, inhalation, incision, and any combination thereof. Any of the delivery methods described herein can be image guided.
  • delivering a cold solution can comprise injecting a cold solution via a delivery device.
  • Any suitable delivery device may be used to deliver the cold solution to a subject.
  • An exemplary device for delivering cold solution is generally shown in FIG. 2.
  • the delivery device 100 includes a cylindrical member 105 having a first end 110 and a second end 115 along a longitudinal axis LA.
  • the delivery device also includes an interior lumen 120 defined by the interior wall of the cylindrical member 105 and provided to receive and hold cold solution.
  • the cylindrical member also includes a ledge 150, or flange, extending around the first end 110 out from the cylindrical member 105 along a plane that is orthogonal to the longitudinal axis LA.
  • the ledge 150 also has an opening concentric with the interior lumen 120.
  • the delivery device 100 is a syringe-type device, for example, any suitable sterile syringe.
  • the syringe can include a gauge size ranging from 8-25G.
  • the delivery device comprises a fenestrated needle, for example, as shown in FIG. 40A.
  • the cylindrical member 105 can be made of any type of biocompatible pharmacologically inert material suitable for use in holding and supplying fluids to be provided within a human body.
  • Exemplary materials for the cylindrical member 105 include plastic, such as polyethylene or polypropylene, and glass.
  • the delivery device 100 can be any size that suitable to hold one or more aliquots (doses) of cold solution for delivery to the desired tissue.
  • the volume capacity of the delivery device 100 can be between 1 ml and 60 ml, although capacity outside of those volumes is also contemplated.
  • the delivery device 100 also includes a plunger 125 at least partially disposed within the interior lumen 120.
  • the plunger 125 is configured to move in and out of the cylindrical member 105 through the first end 110.
  • the plunger 125 includes a head 130, a plunging member 135, and a rod 140 extending between the head 130 and plunging member 135 along the longitudinal axis LA.
  • the plunging member 135 is disposed along the rod 140 at a predetermined distance from the head 130.
  • the delivery device 100 also includes at least one needle 145 extending from the second end 115.
  • the needle 145 can comprise a gauge between 8 gauge and 25 gauge and a length between 1/4 inch and 10 inches, such as about 1/4 inch, 1/2 inch, 1 inch, 2 inches, 3 inches, 4 inches, 5 inches, 6 inches, 7 inches, 8 inches, 9 inches, or 10 inches.
  • the cylindrical member 105 narrows or tapers to a small opening at the second end 115, where the small opening is configured to receive the needle 145.
  • the needle 145 is a hypodermic needle.
  • Exemplary needle materials include, but are not limited to, stainless steel and carbon steel, with or without nickel plating.
  • the plunger 125 can be any type of biocompatible, pharmacologically inert material suitable for coming in contact with fluids to be provided within a human body.
  • Exemplary materials for the plunger 125 include plastic, such as polyethylene or polypropylene, and glass.
  • a portion or all of the plunging member 135 can be a rubber material, such that a seal is formed between the sides of the plunging member 135 and the interior wall of the cylindrical member 105.
  • the rubber material can be any rubber suitable for coming in contact with fluids to be provided to the human body, such as natural rubber latex or a synthetic rubber.
  • the delivery device 100 can also include an agitator (not shown) disposed within the interior lumen 120 configured to mix the cold solution ingredients.
  • the needle 145 is used to pierce the skin. Once the needle 145 is through the skin and positioned at or near the target tissue, i.e., treatment site, the plunger 125 is forced downward toward the second end 115 of the cylindrical member 105. The force of the plunging member 135 on the cold solution forces the cold solution through the cylindrical member 105, out the needle 145, and into (or near) the treatment site.
  • more than one needle is provided at the second end 115 of the delivery device 100. The more than one needle can be provided in single row array, multiple row array, circular pattern, or any other conceivable arrangement.
  • the device 100 of FIG. 2 is used to deliver cold solution 200 to a treatment site, tissue 205, for example, subcutaneous fat in an abdomen.
  • cold solution can be delivered using a syringe-type device, a catheter or a cannula.
  • the needle 145 is inserted through the subject's skin and advanced to a location at or near the tissue 205 (shown in phantom line).
  • the cold solution 200 is then delivered and cools the tissue 205 to achieve a therapeutic effect.
  • an area affected by the cold solution 200 may expand to a size larger than the initial delivery site (shown in the figure as arrows radiating outwardly from the delivered cold solution 200 and dashed circles of increasing size).
  • the cooling effect of the cold solution 200 is localized to the tissue 205 and possibly surrounding tissue, such as adjacent tissue 210. Accordingly, the treatment is targeted and precise.
  • the cold solution 200 is sterile and biocompatible; and, as such, the cold solution 200 can be left in the body (e.g. no removal of the cold solution is necessary after cooling has been effected).
  • the cold solution can be removed from the after the cooling has been effected.
  • the cold solution can be removed by any suitable means, for example via absorbing, e.g., via a sponge-like material, or withdrawing, e.g., using a syringe or suction.
  • a cold solution containment device can be used in combination with the delivery device 100, for example, a device comprising a balloon configured for controlling the cooling effect of the cold solution, as shown in FIG. 4.
  • a balloon deployment device 115 having an application cannula 120 is inserted through the subject’s skin.
  • the deployment device 115 is advanced until the controlling end 125 is at a location between the treatment site or target tissue 105 and an adjacent (surrounding) tissue 135.
  • the controlling end 125 includes a balloon 130. While the balloon 130 is shown having a linear shape, it can have any shape, such as a ring that encircles the target tissue 105.
  • the balloon 130 is filled with air to create a barrier between the adjacent tissue 135 and the spreading cold solution 110.
  • the balloon 130 limits heat transferring from the adjacent tissue 135 to the cold solution 110.
  • the delivery device 100 comprises a cannula such as a needle.
  • the balloon deployment device is the delivery device, for example, balloon 130 can be filled with cold solution so as to deliver and contain the solution to a particular area.
  • delivering a cold solution to one or more treatment sites can include topically contacting the cold solution to the one or more sites.
  • the delivering of the cold solution can include contacting the treatment site and circulating the cold solution through a delivery device, for example, the delivery device described in FIG. 4 having a balloon.
  • the cold solution can be circulated through a tubular member such as a catheter.
  • the delivering of the cold solution can include contacting the site and directly applying cold to the target tissue, for example, via a patch comprising the cold solution.
  • the patch can include an adhesive configured to adhere to the treatment site.
  • a cold solution can be delivered via an ice pack or a cooling blanket.
  • delivering a cold solution to one or more treatment sites can include creating an incision and positioning the cold solution at or near the one or more sites.
  • the cold solution is a substantially solid composition
  • an incision can be made proximate to the site and the substantially solid composition can be positioned at or near the site.
  • FIG. 5 shows an example of a point of delivery generation device 100 for making a cold solution inside a subject’s body.
  • the device 100 includes an application cannula 105 having a shape and size configured to be inserted through a subject’s skin.
  • the device 100 is fluidly coupled to a supply 110 providing components for making a cold solution.
  • a generating end 115 for forming a cold solution from the components.
  • the point of delivery generation device 100 is used by inserting the application cannula 105 through the subject’s skin and advancing the generating end 115 to a location at or near a target tissue or treatment site 120 (shown in phantom line).
  • the target tissue 120 can, for example be subcutaneous adipose tissue.
  • the solution ingredients, such as water and optionally one or more additives, are pumped or otherwise conveyed, separately, from the supply 110, through the application cannula 105, and out the generating end 115.
  • the components interact with each other and form the cold solution 125 at or near the treatment site or target tissue 120.
  • the cooling effect of the cold solution 125 is localized to the target tissue 120 and possibly surrounding tissue, such as adjacent tissue 130. Accordingly, the treatment is targeted and precise.
  • the cold solution is sterile and biocompatible; and, as such, the cold solution 125 can be advantageously left in the body (e.g. no removal of the cold solution is necessary after cooling has been effected).
  • FIG. 6 shows an example of the generating end 115 for making a cold solution from mixing a solution comprising water and optionally one or more additives and water in a solid state, i.e., solid water.
  • the cannula 105 houses a first delivery cannula 205 for supplying liquid water and optionally one or more additives 210 and a second delivery cannula 215 for supplying solid water (ice) 220.
  • the distal end of the first delivery cannula 205 is open and forms a first outlet 230 for the liquid water and optionally one or more additives 210 to exit.
  • the distal end of the second delivery cannula 215 is open and forms a second outlet 235 for the solid water 220 to exit.
  • FIG. 7A shows an example of the generating end 115 for making a cold solution from mixing liquid water and optionally one or more additives, and solid water. This example is similar to the one described above with reference to FIG. 6 with the addition of a grinder 240 located in front of the second outlet 235.
  • the arrangement of the grinder 240 with respect to the second outlet 235 is better seen in the cross-sectional view of FIG. 7B.
  • the grinder 240 breaks the solid water 220 into particles 245.
  • the solution comprising liquid water and optionally one or more additives 210 exiting from the first delivery cannula 205 mixes with the particles 245 to form a cold solution.
  • a vibrator can break the solid water into particles to combine with the solution comprising water and optionally one or more additives to form a cold solution at the point of delivery.
  • second delivery cannula 215 can supply liquid water to generate a substantially liquid cold solution.
  • FIG. 8 shows another example of the generating end 115 for making a cold solution from mixing liquid water and optionally one or more additives, and solid water.
  • the application cannula 105 houses a first delivery cannula 305 for providing a first supply of liquid water and optionally one or more additives 310, and a second delivery cannula 315 for providing a second supply of liquid water 320. As shown, the application cannula 105 further includes a gas line 325 for spraying a cooling gas 330 and freezing the second supply of water 320 into solid water 335.
  • the distal end of the first delivery cannula 305 is open forming a first outlet 340 for the first supply of liquid water and optionally one or more additives 310 to exit.
  • the distal end of the second delivery cannula 315 is open forming a second outlet 345 for the solid water 335 to exit.
  • a grinder (or vibrator) 350 to break the solid water 335 into particles as it emerges from the second delivery cannula 315.
  • the outlets 340, 345 are arranged so that the first supply of liquid water and optionally one or more additives 310 and the particles of solid water mix together to form a cold solution.
  • gas line 325 is configured to spray a cooling gas 330 and cool the second supply of water 320 and reduce the temperature of water 320 without freezing water 320 to generate a substantially liquid cold solution.
  • FIG. 9 shows an example of the generating end 115 for making a cold solution from crystalizing a supercooled solution comprising water and optionally one or more additives.
  • the application cannula 105 houses a first delivery cannula 405 for supplying a supercooled solution comprising water and optionally one or more additives 410.
  • Water normally freezes at 273.15 K (0 °C or 32 °F), but it can be “supercooled” at standard pressure down to its crystal homogeneous nucleation at almost 224.8 K (-48.3 °C/-55 °F).
  • the freezing point of the solution may vary depending upon the presence of one or more additives.
  • the supercooling process requires that water be pure and free of nucleation sites.
  • the application cannula 105 further houses a second delivery cannula 415 for supplying ice pellets 420, which serves as nucleation sites for the crystallization process.
  • the distal end of the first delivery cannula 405 is open and forms a first outlet 430 for the supercooled water 410 to exit.
  • the distal end of the second delivery cannula 415 is open and forms a second outlet 435 for the ice pellets 420 to exit.
  • the outlets 430, 435 are arranged so that the supercooled water 410 interacts with the ice pellets 420 causing it to crystalize and form a cold solution.
  • second delivery cannula 414 supplies liquid water to generate a substantially liquid cold solution.
  • FIG. 10A shows another example of the point of delivery generation device.
  • the device includes an application cannula 605 that is open at its distal end defining an outlet 610.
  • a generating end 615 includes an outer balloon 620 disposed around the outlet 610.
  • the application cannula 605 is in fluid communication with the interior volume of the outer balloon 620.
  • the application cannula 605 includes a fluid delivery cannula 625.
  • the application cannula 605 and the fluid delivery cannula 625 share a common longitudinal axis and can be said to be coaxially aligned.
  • the fluid delivery cannula 625 is open at its distal end defining a fluid outlet 630.
  • the generating end 615 further includes an inner balloon 635 disposed around the fluid outlet 630.
  • the fluid delivery cannula 625 is in fluid communication with an interior volume of the inner balloon 635, which is labeled 640 in the figure.
  • the inner balloon 635 is located inside the outer balloon 620. As shown, the inner balloon 635 occupies a portion of the interior volume of the outer balloon 620 leaving a space or gap 645 between an outer wall of the inner balloon 635 (which is labeled 650 in the figure) and an inner wall of the outer balloon 620 (which is labeled 655 in the figure).
  • the application cannula 605 is inserted through a subject’s skin and the generating end 615 is advanced to a location at or near a target tissue in much the same manner as described above with reference to FIG. 5.
  • the outer balloon 620 and the inner balloon 635 are inserted into the subject’s body in their uninflated state.
  • the inner balloon 635 is then filled or inflated with a cool solution comprising cold water and optionally one or more additives that is supplied through the fluid delivery cannula 625.
  • the outer balloon 620 is filled with a cooling gas or fluid, such as liquid nitrogen.
  • the cooling gas fills the gap 645 between the inner balloon 635 and the outer balloon 620. This causes the cool solution in the inner balloon 635 to partially freeze and form a cold solution 660, as shown in FIG. 10B. (For clarity the outer balloon 620 is not shown in FIG. 10B.)
  • the cold solution-filled inner balloon 635 can then be used to cool a target tissue.
  • the inner balloon 635 can be ruptured by a retractable puncture needle 665 that extends beyond the application cannula 605 when extended as shown. Rupturing the inner balloon 635 releases the cold solution 660 at or near the target tissue.
  • the cooling gas fills the gap between the inner balloon 635 and the outer balloon 620 to cool the solution in the inner balloon 635 to reduce the temperature of the solution without freezing the solution to generate a substantially liquid cold solution.
  • FIG. 11 shows another example of the point of delivery generation device for generating and replenishing a cold solution.
  • This example is similar to the one described above with reference to FIG. 10 with the addition of a fluid return cannula 670.
  • the fluid return cannula 670 is housed within the application cannula 605 together with the fluid delivery cannula 625, as shown.
  • the fluid return cannula 670 removes cold solution from the inner balloon 635 that is no longer at the desired temperature. Replenishing the “old” cold solution with “fresh” cold solution in this manner can accommodate for the eventually melting of cold solution.
  • FIG. 12 shows an example point of delivery generation device having multiple cannulas or “working channels” to control the functions described above with reference to FIGS. 10A, 10B, and 11.
  • the device includes an application cannula 705.
  • the application cannula 705 houses a gas delivery cannula 710, a fluid delivery cannula 715, and a fluid return cannula 720, to continuously generate and replenish cold solution, as described above with reference to FIGS. 10A and 11.
  • the application cannula 705 can also include a retractable puncture needle 725 to rupture a balloon filled with cold solution, as described above with reference to FIG. 10B.
  • the application cannula 705 can further have a cold solution temperature monitor 730 for measuring the temperature of the cold solution.
  • a working channel can be used to deliver a cold solution, and one or more additional working channels can be used to deliver another type of energy, for example, a laser device can be positioned at or near a target tissue to deliver energy to the target tissue.
  • one or more working channels can be used to provide image guided treatment.
  • FIGs. 5-12 describe on-demand or point of delivery cold solution generator devices that are combined with the delivery device.
  • the on-demand cold solution generator device can be separate from the delivery device.
  • the on- demand cold solution generator can include a port configured to dispense into a container or a delivery device such as a syringe.
  • the on-demand system can cool a solution via compressed gas, endothermic reaction or a standard refrigeration cycle. Additional systems and methods for on-demand cooling are described in US Publication No. 20180344074 which is
  • the one or more additional modalities may be delivered via a cold solution delivery device, as described in detail above, or via a second, distinct delivery device.
  • the cold solution delivery device is configured to provide fractionated delivery of the cold solution, and/or one or more additional modalities.
  • the cold solution delivery device is fenestrated, for example, a fenestrated needle as described above, thus providing for fractionated delivery of the cold solution and/or the one or more additional modalities.
  • a separate delivery device is provided for the administration of the one or more additional modalities, wherein the separate delivery device is configured to provide fractioned delivery of the one or more additional modalities, including but not limited to energy. Examples of fractional delivery devices are described below, and in International Patent Application Ser. No. PCT/US2017/048995 filed on August 29, 2017 which is incorporated by reference in its entirety herein.
  • FIGS. 13 and 14 illustrate a cooling treatment system 100 according to one non-limiting example of the present disclosure.
  • the cooling treatment system 100 includes a cooling device 102, an interface 104, and a delivery device 106.
  • the cooling device 102 is configured to provide cooling through the interface 104 and to the delivery device 106.
  • the cooling device 102 may be in the form of a thermoelectric cooler, cryogen gas, liquid nitrogen, liquid argon, cooled liquids, a Joule-Thomson refrigerator, nitrous oxide, and carbon dioxide, to name a few.
  • the interface 104 may be fabricated from a material with a high thermal conductivity to facilitate efficient heat transfer between the cooling device 102 and the delivery device 106.
  • the interface 104 may be coupled to the cooling device 102 (e.g., via an adhesive or a mechanical coupling mechanism) and may be detachably coupled to the delivery device 106.
  • the interface 104 may include one or more temperature sensors 108 and a controller 110.
  • the temperature sensors 108 are configured to measure a temperature at one or more locations on the delivery device 106 and communicate the measured temperatures to the controller 110.
  • the controller 110 is in communication with the cooling device 102 and may be configured to control a temperature output by the cooling device 102, thereby controlling a temperature of the delivery device 106.
  • a desired temperature of the delivery device 106 may be input to the controller 110 and the controller 110 may be configured to control the cooling device 102 to achieve the desired temperature of the delivery device 106, as measured by the temperature sensors 108.
  • the controller 110 may in communication with a display 112 and configured to instruct the display 112 to display, for example, a temperature of the delivery device 106, a time to administer the delivery device 106, a depth of the delivery device 106, and/or a temperature of the surface of a desired tissue region.
  • the delivery device 106 includes a base 114 and a plurality of protrusions 116 extending from the base 114.
  • the plurality of protrusions 116 may be in the form of a needle array configured to penetrate to a desired depth within a tissue region of a subject.
  • the needle array may be configured to enable the injection of a cold solution.
  • the plurality of protrusions 116 may be in the form of a plurality of conductive posts, or pins, configured to engage a surface of a tissue region of a subject to provide topical cooling.
  • the illustrated delivery device 106 includes a plurality of protrusions 116, in other non-limiting example, the delivery device 106 may include one or more protrusions 116.
  • a distance D defined between adjacent pairs of the plurality of protrusions 116 may be dimensioned to ensure that a fractional cooling pattern may be achieved in or on a desired tissue region. That is, the distance D can be dimensioned such that discrete zones of cooling are achieved when the delivery device 106 is administered.
  • a time that the delivery device 106 is engaged with the desired tissue region can also define the resulting cooling pattern, as will be described below.
  • FIGS. 15 and 16 illustrate another non-limiting example of the cooling treatment system 100 according to the present disclosure.
  • the cooling treatment system 100 may include a warming unit 300, a depth imaging device 302, and a thermal imaging device 304 each in communication with the controller 110.
  • the warming unit 300 may be configured to provide selectively controlled warming, for example, to a proximal end of the plurality of protrusions 116. Selectively warming the proximal end of the plurality of protrusions 116 can enable only a distal end, or tip, of the plurality of protrusions 116 to provide cooling to a desired tissue area.
  • the warming unit 300 may be configured to provide selective warming to a tissue surface (e.g., epidermis), and/or configured to provide selective warming to deeper tissue below a tissue surface (e.g., subcutaneous fat) via radio-frequency (RF) heating or laser heat.
  • a tissue surface e.g., epidermis
  • RF radio-frequency
  • the depth imaging device 302 may be configured to measure and image a depth that the plurality of protrusions 116 penetrate into a desired tissue region.
  • the depth imaging device 302 may be configured to provide a measured depth of the plurality of protrusions 116 to the controller 110.
  • the controller 110 may relay an image to the display 112 of the plurality of protrusions 116 penetrating into a desired tissue region to provide active feedback to a user of the cooling treatment system 100.
  • the depth imaging device 302 may be in the form of an OCT imaging device, magnetic resonance imaging (MRI) device, an ultrasound device, or an X-ray device.
  • the thermal imaging device 304 may be configured to measure and image a temperature at a surface of a desired tissue region. That is, when the plurality of protrusions 116 are applying cooling on or in a desired tissue region, the thermal imaging device 304 may enable a user to visually inspect a temperature at a surface of the desired tissue region. This can enable a user to ensure a desired cooling pattering is achieved (i.e., fractionated vs. bulk cooling) and/or verify a desired temperature is applied (i.e., ablative vs. cryostimulatory/cryotherapy) to the desired tissue region.
  • the thermal imaging device 304 may be integrated into the cooling treatment system 100 and may be in communication with the controller 110. The controller may relay a thermal image acquired by the thermal imaging device 304 to the display 112 to provide active feedback to a user of the cooling treatment system 100.
  • the thermal imaging device 304 may be a separate component used or worn by a user of the cooling treatment system 100 while providing cooling on or in a desired tissue region.
  • the thermal imaging device 304 may be in the form of an infrared camera, thermal imaging glasses, or a mobile device with a thermal imaging add-on.
  • the thermal imaging device 304 may comprise one or more thermocouples (or other thermal sensors), or infrared temperature sensing device.
  • the delivery device 106 and the plurality of protrusions 116 arranged thereon may define alternative shapes and sizes for a given tissue application.
  • the delivery device 106 and the corresponding interface 104 may define different treatment areas and/or different depths of treatment.
  • the base 114 of the delivery device 106 and the corresponding interface 104 may define a width Wi.
  • the base 114 of the delivery device 106 and the corresponding interface 104 may define a width W2, where W2 is greater than WI.
  • the plurality of protrusions 116 may each define a length Li.
  • the plurality of protrusions 116 may each define a length L2, where L2 is greater than Li. It should also be appreciated that a density (i.e., the number of the plurality of protrusions 116 extending from the delivery device 106) may be varied, for example, by altering the distance D between adjacent pairs of the plurality of protrusions 116 and accordingly adding or subtracting protrusions to the delivery device 106. These alternative geometric configurations may be tailored to provide desired treatment parameters for a given application of the cooling treatment system 100.
  • the illustrated base 114 of the delivery device 106 of FIGS. 13, 15, and 17-20 defines a generally flat profile, which results in the plurality of protrusions defining a generally flat treatment profile.
  • the delivery device 106 may define alternative shapes and profiles to accommodate various anatomical locations on a subject.
  • the base 114 of the delivery device 106 may define a generally arcuate shape, which thereby arranges the plurality of protrusions 116 in a corresponding arcuate treatment profile.
  • the delivery device 106 may be in the form of a wand, or rod, shape with the plurality of protrusions 116 extending from a distal end thereof.
  • the plurality of protrusions 116 may extend radially outward from the distal end of the delivery device 106.
  • the plurality of protrusions 116 may be arranged partially circumferentially around a periphery of the delivery device 106. That is, the plurality of protrusions 116 may be arranged circumferentially around approximately half (e.g., between 0 degrees and 180 degrees) of the delivery device 106.
  • the plurality of protrusions 116 may extend radially from the distal end of the delivery device 106, and may be arranged circumferentially around an entirety of the periphery of the delivery device 106 in approximately equal increments. Alternatively or additionally, the plurality of protrusions 116 may be arranged circumferentially around the periphery of the delivery device 106 in non equal increments. In the non-limiting examples of FIGS. 22A-23B, the plurality of protrusions 116 may be retractably received within the delivery device 106. For example, the delivery device 106 may be inserted into the target tissue with the plurality of protrusions 106 retracted into the delivery device 106 and then the plurality of protrusions 106 may be deployed from the delivery device 106 one within the target tissue.
  • FIG. 24 illustrates one non-limiting example of one of the plurality of the plurality of protrusions 116 according to one aspect of the present disclosure.
  • the illustrated protrusion 116 is in the form of a needle 1200 including a needle tip 1202 arranged at a distal end thereof.
  • the needle 1200 can be fabricated from a metal material and the entire axial length of the needle 1200 can be cooled via conduction from the cooling device 102.
  • the needle 1200 may be sized to be between approximately 15 gauge and approximately 35 gauge or smaller.
  • the needle 1200 may include insulation 1300 wrapped around a desired axial length of the needle 1200.
  • the insulation 1300 may extend axially along the needle 1200 while leaving the needle tip 1202 of the needle 1200 uninsulated. This, along with an axial length defined by the needle 1200, can control a depth within a desired tissue region that the cooling is applied. Further, only providing cooling at the needle tip 1202 can prevent healthy tissue from being damaged by the cooling applied at the needle tip 1202.
  • the insulation 1300 may be replaced by an active warming unit wrapped around the needle 1200. Similar to the insulation 1300, the active warming unit may not be arranged around the needle tip 1202 enabling the cooling to be applied to a desired tissue region at a target depth defined by the axial length of the needle 1200.
  • the entire axially length of the needle 1200 may be actively cooled by a circulated cryogen.
  • the illustrated needle 1200 may include an inlet passage 1400 and an outlet passage 1402 arranged within the needle 1200 and extending axially along the needle 1200.
  • a cryogen may be circulated into the inlet passage 1400 and out of the outlet passage 1402 to actively cool the entire axial length of the needle 1200.
  • a warming unit 1500 may be arranged adjacent to a proximal end of the needle 1200.
  • the warming unit 1500 may be configured to apply warming to a surface (e.g., epidermis) of a desired tissue region. This can prevent healthy tissue from being damaged by the cooling applied by the needle 1200.
  • the plurality of protrusions 116 may be configured to inject a desired volume of cold solution into a desired tissue region to apply cryotherapy or cryoablation.
  • FIG. 28A illustrates one nonlimiting example of the plurality of protrusions 116 in the form of a needle array 1600 configured to inject a cold solution 1602 into a desired tissue region.
  • the needles of the needle array 1600 may be sized to be between approximately 15 gauge and approximately 30 gauge.
  • the cold solution 1602 can be arranged in a cartridge 1604, which can be removably coupled to the delivery device 106.
  • the cold solution 1602 may be prepared to achieve a desired cooling temperature and to contain appropriately sized ice crystals to ensure fluid flow through the needle array 1600, as will be described below. Additionally, a volume of cold solution injected and/or the distance D between adjacent pairs of needles 1600 may be designed to ensure a desired cooling pattern is achieved (i.e., fractionated vs. bulk cooling).
  • the needle array 1600 may be removably coupled to a manifold 1610.
  • Each of the needles in the needle array 1600 may be removably coupled to the manifold 1610, for example, by a threaded engagement, a quick disconnect fitting, or a push-on fitting.
  • the removable coupling of the needle array 1600 to the manifold 1610 enables the number and/or arrangement of the needles in the needle array 1600 to be modified by the user, as desired.
  • the same manifold 1610 may be used to perform injections with needles of varying sizes (e.g., a 15 gauge needle array vs. a 30 gauge needle array).
  • a spacing between adjacent needles in the needle array 1600 may be controlled by the number and/or orientation of the needles that are coupled to the manifold 1610.
  • the manifold 1610 is coupled a needle array 1600 comprising four needles.
  • the manifold 1610 may be coupled to a needle array 1600 comprising more or less than four needles arranged in any pattern as desired.
  • the manifold 1610 includes an inlet port 1612 that is configured to be removably coupled to a cold solution injection device (not shown).
  • the manifold 1610 may include internal passageways that provide fluid communication between the inlet port 1612 and each of the needles in the needle array 1600.
  • the cold solution injection device may, for example, be in the form of a syringe-type device that includes a desired volume of cold solution to be injected into a desired tissue region.
  • the syringe-type device may be manually actuatable to facilitate the injection of the cold solution.
  • the syringe-type device may be electronically controlled (e.g., like a syringe pump) to facilitate the injection of the cold solution at a predetermined fluid flow rate.
  • a user may install the desired Size and arrangement of needle array onto the manifold 1610 and, subsequently, couple the cold solution injection device, which is filled with a desired volume of cold solution, to the inlet port 1612. With the delivery device 102 assembled, a user may inject the needle array 1600 into a desired tissue region to a desired depth within the desired tissue region, and inject the cold solution to achieve a fractional cooling pattern within the desired tissue region.
  • the fractional cold solution injection capabilities of the delivery device 102 of FIGS. 28 A and 28B may be able to cover a larger area of target tissue when compared with a single injection of an equivalent cold solution volume.
  • a fractional cold solution injection device may be able to cover approximately double the area of target tissue with a single cold solution injection, when compared to bulk cooling with a single injection.
  • the fractional cold solution injection capabilities of the delivery device 102 may provide several other operational and functional advantages, when compared to a single bulk injection of an equivalent cold solution volume.
  • reduced injection force required to deliver the cold solution into the target tissue may translate to a more uniform reduction of fat within the target tissue thereby avoiding an unwanted side effect of forming dents or depressions in the target tissue.
  • a single injection within a large amount of cold solution may create a bulge/swelling and tension within the target tissue, which can lead to ruptured blood vessels and bruising.
  • a large single injection may also stretch subcutaneous nerves and cause pain.
  • the cooling treatment system 100 may implement a single needle 1700, as shown in FIG. 29.
  • the needle 1700 may be sized to be between approximately 15 gauge and approximately 35 gauge or smaller.
  • the cooling treatment system 100 may be configured to provide bulk cooling to a desired tissue region.
  • the delivery device 106 may comprise an expandable needle 1800 as opposed, or in addition with, to the plurality of protrusions 116.
  • the expandable needle 1800 may be cooled by the cooling device 102 and subsequently be advanced by a user of the cooling treatment system 100 to a desired tissue region (e.g., lipid rich tissues in a subject's tongue/airway). Once the expandable needle 1800 reaches the desired tissue region, the user can expand a balloon 1802 attached to the expandable needle 1800. A cold solution at a desired temperature may then be delivered through the expandable needle 1800 to the balloon 1802 to provide cooling to the desired tissue region.
  • a desired tissue region e.g., lipid rich tissues in a subject's tongue/airway
  • the balloon 1802 may not need to be inflated prior to injection of the cold solution. Rather, injection of the cold solution may inflate the balloon 1802. Once the desired cooling treatment has been applied to the desired tissue region, the balloon 1802 may be retracted to in deflated state (FIG. 30).
  • FIGS. 32 and 33 illustrate two non-limiting examples of fractional delivery arrays 2000 and 2100, which may be implemented in the delivery device 106 as opposed to, or in addition with, the plurality of protrusions 116.
  • the fractional delivery array 2000 may be advanced by a user of the cooling treatment system 100 to a desired tissue region (e.g., lipid rich tissues in a subject's tongue/airway). Once the fractional delivery array 2000 is advanced to the desired tissue region, a cold solution may be delivered to the desired tissue region in a fractional pattern through a plurality of needles 2002.
  • the plurality of needles 2002 can extend outwardly from a distal end of an array tube 2004. As shown in FIGS. 32 and 33, the plurality of needles 2002 may be arranged in alternative patterns to define alternative fractional cooling patterns, as desired.
  • the cooling treatment system 100 may be designed to provide a desired cooling pattern. That is, in one non-limiting example, the cooling treatment system 100 may be designed to provide a fractional cooling pattern to a desired tissue region.
  • FIG. 34 illustrates one non-limiting example of a fractional cooling pattern 2200, which may be achieved via the injection of a cold solution, topical cooling, or the injection of actively cooled needles, as described above with reference to the delivery device 106. As shown in FIG. 34, discrete cooling zones 2202 are present with area of untreated tissue arranged between adjacent cooling zones in the fractional pattern 2200. It should be appreciated that the number of discrete cooling zones 2202 shown in FIG. 34 is meant for purposes of illustration and is not meant to be limiting in any way.
  • the cooling treatment system 100 may be configured to provide ablative cooling therapy (i.e., cryoablation) in a fractional pattern at a temperature between approximately -1S0°C and approximately -20°C. In some non-limiting examples, the cooling treatment system 100 may be configured to provide non-ablative cooling therapy (i.e., cryotherapy) in a fraction pattern at a temperature between approximately -20°C and 5°C.
  • ablative cooling therapy i.e., cryoablation
  • cryotherapy non-ablative cooling therapy
  • FIG. 35 illustrates an array bulk cooling pattern 2300 achievable by the cooling treatment system 100 according to one non-limiting example of the present disclosure.
  • the illustrated array bulk cooling pattern 2300 can be formed via application of a cooling array (e.g., the plurality of protrusions 116, the needle array 1600, the plurality of needles 2002, etc.), which may be achieved via the injection of a cold solution, topical cooling, or the injection of actively cooled needles, as described above with reference to the delivery device 106.
  • the array bulk cooling pattern 2300 defines a substantially uniform cooling profile over the desired tissue region.
  • the cooling treatment system 100 may be configured to provide non-ablative cooling therapy (i.e., cryotherapy) in an array bulk cooling pattern at a temperature between approximately -20°C and 5°C.
  • non-ablative cooling therapy i.e., cryotherapy
  • FIG. 36 illustrates a depot bulk cooling pattern 2400 achievable by the cooling treatment system 100 according to one non-limiting example of the present disclosure.
  • the illustrated depot bulk cooling pattern 2400 may by formed via injection of a cold solution from a single injection (e.g., the single needle 1700).
  • the depot bulk cooling pattern 2400 defines concentric zones of cooling decreasing in temperature as they extend radially outwards from a center of the depot bulk cooling pattern 2400.
  • alternative bulk cooling patterns are achievable by the cooling treatment system 100.
  • the single needle 1700 may be configured to provide a fanning bulk cooling pattern 2500 when injection a cold solution into a desired tissue region.
  • the cooling treatment system 100 is configured to provide bulk or fractionated cooling at either at very cold ablative temperatures or intermediary remodeling temperatures to promote tissue remodeling by inducing increased vasculature (i.e., angiogenesis) and the formation of new collagen (i.e., collagen remodeling).
  • angiogenesis vasculature
  • collagen remodeling new collagen
  • the cooling treatment system 100 can be implemented to induce the formation of collagen and angiogenesis and thereby promote healing or treatment of the specific malady.
  • the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -200°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -180°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -160°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -140°C and approximately 30°C.
  • the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -120°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -100°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -50°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -70°C and approximately 30°C.
  • the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -60°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -50°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -40°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -30°C and approximately 30°C.
  • the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -20°C and approximately 30°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -20°C and approximately 20°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -20°C and approximately 10°C. In some non-limiting examples, the cooling treatment system 100 may be configured to subject a desired tissue region of a subject to a temperature between approximately -20°C and approximately 5°C.
  • the fractionated delivery of the cold solution and/or one or more additional modalities encompasses delivery to more than one treatment site, or to numerous locations at a single treatment site, for example, through a needle array. In some aspects, the fractionated delivery of the cold solution and/or one or more additional modalities encompasses delivery in multiple directions during a single administration. In some aspects, the fractionated delivery of the cold solution and/or one or more additional modalities encompasses delivery using a fenestrated needle, wherein the fenestrated needle administers energy, including but not limited to optical energy, in order to warm the tissue at or around the treatment site, followed by administration of the cold solution. In some aspects, cold solution delivery device encompassing a fenestrated needle is configured to provide delivery of more than one type of energy at or near the treatment site.
  • the fractionated delivery of the cold solution and/or the one or more additional modalities encompass time-release delivery, wherein the cold solution may be administered in a time-release manner, and/or the one or more additional modalities may be administered in a time-release manner.
  • Determination of the specific time-release factors including but not limited to the delay in initial administration, the timing between multiple administrations, the timing between administration of the cold solution and/or the one or more additional modalities, and the timing between the administration of the one or more additional modalities and the administration of the cold solution, are determined based upon the specific treatment plan of the subject.
  • a delivery device for administering the one or more additional modalities may encompass an expendable needle, wherein the expendable needle is administered at or near the treatment site, prior to, during, or after the administration of the cold solution, in order to mechanically disrupt tissue at or near the treatment site.
  • the delivery device encompassing an expendable needle may be utilized to deliver energy at or near the treatment site, including but not limited to thermal or optical energy.
  • a delivery device for administering the one or more additional modalities may encompass a needle comprising a blade, wherein the needle comprising the blade is administered at or near the treatment site, prior to, during, or after the administration of the cold solution, in order to mechanically disrupt tissue at or near the treatment site.
  • a delivery device for administering the one or more additional modalities may encompass a smart needle, wherein optical energy is utilized to detect an artery in order to avoid injection or damage to an artery.
  • the invention includes a kit comprising one or more solutions comprising water and optionally one or more additives. When more than one solution is provided, the solutions may differ in their composition, including but not limited to the presence or absence of additives, the particular additives included and the amounts thereof, and the ice content.
  • the kit may also include one or more of a mold for generating a cold solution, a delivery device for the cold solution and/or one or more additional modalities, a point-of- delivery generating device, a guide device, a balloon, a coil, a sterile bag or container (empty or pre-filled with a solution comprising water and optionally one or more additives), and a coating material, for
  • the method may include one or more of pre-, peri- and post treatment monitoring such as imaging and/or performing one or more measurements.
  • the method can include determining one or more of the subject's core temperature, blood flow, stroke volume, heart rate, respiratory rate, central venous pressure, right ventricular pressure, pulmonary artery pressure, pulmonary capillary wedge pressure or left ventricular pressure.
  • An indication of success would be an observation of a decrease in the core body temperature and an improvement in the associated condition.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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Abstract

L'invention concerne des systèmes et des procédés pour réduire la graisse, une solution froide étant administrée à un sujet conjointement avec une ou plusieurs modalités supplémentaires. La solution froide comprend de l'eau liquide et/ou des particules de glace solides et comprend éventuellement un ou plusieurs additifs. La ou les modalités comprennent de l'énergie, y compris l'énergie thermique, rayonnante, chimique, électrique et/ou mécanique, la chirurgie, y compris la liposuccion, la nutrition et/ou le bien-être, l'exercice, l'auto-optimisation, les traitements chimiques et/ou les traitements biologiques. La ou les modalités peuvent être administrées séparément, ou en combinaison avec la solution froide.
PCT/US2021/035675 2020-06-05 2021-06-03 Systèmes de réduction de graisse et d'amélioration de l'aspect de la peau à l'aide de modalités multiples WO2021247843A1 (fr)

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