Devices for percutaneous cryolipolysis, kits for percutaneous cryolipolysis, and use of such devices or kits for percutaneous cryolipolysis.

Abstract

The present invention relates to a device for percutaneous cryolipolysis, a kit for percutaneous cryolipolysis, and the use of such a device or kit for percutaneous cryolipolysis, wherein the device comprises a body to which a cryofluid source can be coupled, and a cryoneadil assembly (11) coupled to or to the body, comprising at least one cryoneadil (12). The at least one cryoneadil (12) is configured to at least partially penetrate human or animal skin (D1, D2). The device is configured such that, when the cryofluid source and cryonedle assembly (11) are coupled to the main body, the cryofluid (G) from the cryofluid source cools at least one cryonedle (12) in at least a cryonedle cooling area (P1), and when the cooled cryonedle (12) has at least partially penetrated human or animal skin (D1, D2), the cooled cryonedle (12) forms a subcutaneous (F) tissue cooling zone (CZ) adjacent to the cryonedle cooling area (P1), and the device is configured to cool the subcutaneous (F) adipocytes (A, A1, A2) located in the tissue cooling zone (CZ) such that apoptosis (A1) and / or necrosis (A2) are initiated in at least some of the adipocytes (A, A1, A2) located in the tissue cooling zone (CZ).

Description

[Technical Field]

[0001] The present invention relates to a device for percutaneous cryolipolysis, the device comprising a body to which a cryofluid source can be coupled, and a cryoneadl assembly which is coupled to or can be coupled to the body and comprises at least one cryoneadl, the at least one cryoneadl is configured to penetrate at least partially into human or animal skin. The device is configured to cool at least one cryoneadl in at least a cryoneadl cooling area by using cryofluid from the cryofluid source when the cryofluid source and the cryoneadl assembly are coupled to the body, the device is configured to form a subcutaneous tissue cooling zone adjacent to the cryoneadl cooling area of ​​the cooled cryoneadl when the cooled cryoneadl is penetrating at least partially into human or animal skin.

[0002] The present invention further relates to a kit for transcutaneous cryolipolysis, comprising a device for transcutaneous cryolipolysis and a cryofluid source.

[0003] Furthermore, the present invention relates to the use of devices or kits for transcutaneous cryolipolysis for cosmetic, aesthetic, or therapeutic purposes, particularly for transcutaneous cryolipolysis for cosmetic, aesthetic, or therapeutic purposes. [Background technology]

[0004] Sometimes, the treatment of body tissue, particularly the destruction and / or removal of body tissue such as tumor tissue or adipose tissue, may be desired or necessary from a health perspective or for other reasons, such as cosmetic and / or aesthetic reasons.

[0005] One established therapy for treating tumor tissue, particularly for its destruction and / or removal, is so-called "cryosurgery," specifically cryoablation of tumor tissue, which is based on the application of extremely low temperatures to the tumor tissue to be treated. Several methods and devices for this purpose are known.

[0006] For example, WO2019 / 213205A1 discloses a handheld cryoprobe for use in invasive, percutaneous cryotherapy of tumorous masses. The handheld cryoprobe includes a probe attached to a CO2 gas distribution backend. The probe is made from a partially hollow, threaded aluminum rod with parameters specifically optimized for use with CO2 gas, providing maximum heat exchange. The system backend cools the gas coolant by restricting the flow of compressed CO2 gas to the cytotoxic low temperature required to kill target tumor cells, while regulating the flow of compressed CO2 gas. In addition, the initial incoming CO2 gas flow is restricted by a Joule-Thomson nozzle on the backend. The low-temperature exhaust gas is then used to pre-cool all subsequent incoming gas, resulting in a further decrease in the temperature of the probe tip and a positive feedback loop that continuously lowers the gas temperature. The temperature decrease is caused by the Joule-Thomson effect.

[0007] US2021 / 244457A1 describes a device for the invasive treatment of tumors of the breast, prostate, or kidney, comprising a probe having a distal end configured to contact the tissue of a living subject, and containing a lumen. A temperature sensor is located at the distal end, and a pump having a pump motor is coupled to supply cryogenic fluid to the distal end of the probe through the lumen and to receive the cryogenic fluid returning from the probe. A separator is coupled to separate the returning cryogenic fluid into the returning cryogenic liquid and the returning cryogenic gas, and a flow meter is coupled to measure the flow rate of the returning cryogenic gas. A processor is configured to control the pumping rate of the pump motor in response to the temperature measured by the temperature sensor and the flow rate of the returning cryogenic gas.

[0008] IceCure offers the ProSense® cryoablation device for the treatment of multiple cancer types of tumor tissue, particularly breast, prostate, lung, and bone cancer, which uses liquid nitrogen for cooling. See https: / / icecure-medical.com / and https: / / youtu.be / TfhQJ3SN6wQ, last accessed June 14, 2023.

[0009] Boston Scientific also offers cryoablation devices for the invasive treatment of tumor cells by applying extremely low temperatures, which can be cooled to -20°C to -40°C. See, for example, https: / / www.bostonscientific.com / en-US / products / cryoablation / icefx.html#, last accessed June 14, 2023.

[0010] Unlike tumor cells, fat cells have different characteristics and respond differently to treatment, and are often removed by liposuction. Fat cells are separated from the surrounding tissue and then aspirated. However, liposuction is an invasive procedure with several undesirable side effects.

[0011] For improved liposuction, WO98 / 41157 proposes combining cryosurgery and liposuction, where first, cryosurgery destroys the adipose tissue to be removed by controlled freezing of the tissue. This makes the removal of the adipose tissue easier. Subsequently, liposuction removes the destroyed adipose tissue by suction.

[0012] Other methods for reducing adipose tissue, particularly its volume, are based on the destruction of adipocytes by lipolysis, and different methods for triggering / initiating lipolysis are known.

[0013] Lipolysis of adipocytes can be triggered, for example, by injecting a defined composition into adipose tissue that induces adipocyte cell death.

[0014] Such compositions include, for example, Kybella® from Allergan Pharmaceuticals International Limited, which contains deoxycholic acid as a lipolysis initiator. However, undesirable side effects can occur.

[0015] Another method based on the injection of a composition that triggers lipolysis is described in Ni P, Farinelli WA, Cheng LL, Farrar CT, Motamarry A, Moradi Tuchayi S, Wang Y, Anderson RR, Garibyan L. Total ice content and lipid saturation determine adipose tissue cryolipolysis by injection of ice-slurry. Lasers Surg Med. 2023 Jan;55(1):116-125. doi:10.1002 / lsm.23557. Epub 2022 May 21. PMID:35598082;PMCID:PMC9676409, available under https: / / pubmed.ncbi.nlm.nih.gov / 35598082 / , last accessed June 14, 2023. This method is based on the injection of a defined “ice slurry”.

[0016] One significant drawback of lipolysis methods based on the injection of compositions into adipose tissue is that once the composition is injected, the tissue's reaction can no longer be affected, and the process is no longer controllable.

[0017] Furthermore, it is known that non-invasive cryolipolysis can destroy fat cells, which is caused by freezing fat cells from the outside, in which case the cooling is applied through the skin. However, this method carries risks such as superficial frostbite of the skin. Devices for non-invasive cryolipolysis treatment of adipose tissue are offered by, for example, Allergan Aesthetics and ZELTIQ® Aesthetics, Inc., and these devices are marketed as "Coolsculpting" devices. See, for example, https: / / www.coolsculpting.com / , last accessed June 14, 2023. With these devices, body adipose tissue is frozen by cooling applied through the skin. One of the undesirable side effects known with this type of treatment is paradoxical adipose hyperplasia.

[0018] Furthermore, the use of cooling in treatment is also known in pain management. iovera®, for example, promotes pain management devices that use cryogenic temperatures to stop nerves from sending pain signals to the brain. See, for example, https: / / www.iovera.com / , last accessed June 14, 2023. [Overview of the project]

[0019] In view of the above, one object of the present invention is to provide a device that enables the treatment of improved adipose tissue, in particular improved destruction and / or improved removal of adipocytes, preferably with reduced or better controllable side effects.

[0020] Another object of the present invention is to provide a kit that enables the treatment of improved adipose tissue, in particular improved destruction and / or improved removal of adipocytes, preferably with reduced or better controllable side effects.

[0021] A further object of the present invention is to provide a method of use, in which improved treatment of adipose tissue, in particular improved destruction and / or improved removal of adipocytes, can be achieved, preferably with reduced or better controllable side effects.

[0022] These objects of the present invention are achieved by providing a device, a kit, and a method of use as defined in the independent claims.

[0023] Possible, particularly preferred embodiments of the objects of the present invention are described in the dependent claims. Further embodiments and other objects, advantages, and features of the present invention will become apparent from the following detailed description of the invention, the illustration of specific embodiments in the accompanying drawings, and the detailed description of the embodiments. By express reference, the language of the original claims is incorporated herein.

[0024] Some objects of the present invention are particularly achieved by a device for percutaneous cryolipolysis, the device comprising a body to which a cryogenic fluid source can be coupled, and a cryo-needle assembly coupled to or couplable to the body, the cryo-needle assembly comprising at least one cryo-needle. At least one cryo-needle of the device is configured to at least partially penetrate the skin of a human or an animal. The device is configured to cool at least one cryo-needle, at least in a cryo-needle cooling area, by using cryogenic fluid from the cryogenic fluid source when the cryogenic fluid source and the cryo-needle assembly are coupled to the body, and the device is configured to form a subcutaneous tissue cooling zone adjacent to the cryo-needle cooling area of the cooled cryo-needle when the cooled cryo-needle at least partially penetrates the skin of a human or an animal. The device is further configured to cool subcutaneous adipocytes located in the tissue cooling zone such that apoptosis and / or necrosis is initiated for at least a part of the adipocytes located in the tissue cooling zone.

[0025] Some of the objectives of the present invention are achieved, in particular, by a kit comprising such a device and a cryofluid source.

[0026] Some of the objectives of the present invention are achieved, in particular, by using such devices and / or such kits.

[0027] A device for percutaneous cryolipolysis according to the present invention may comprise a body to which a cryofluid source may be bound, and a cryoneadjustment assembly which is bound to or can be bound to the body and may comprise at least one cryoneadjustment. The device may be configured to at least partially penetrate human or animal skin. When the cryofluid source and the cryoneadjustment assembly are bound to the body, the device may be configured to cool at least one cryoneadjustment in at least a cryoneadjustment cooling area by using cryofluid from the cryofluid source, and when the cooled cryoneadjustment penetrates at least partially human or animal skin, to form a subcutaneous tissue cooling zone adjacent to the cryoneadjustment cooling area of ​​the cooled cryoneadjustment. The device may be further configured to cool subcutaneous adipocytes located in the tissue cooling zone such that apoptosis and / or necrosis is initiated in at least some of the adipocytes located in the tissue cooling zone.

[0028] The device according to the present invention appears to allow for the precise destruction and removal of subcutaneous adipose tissue with lower risk, higher safety, and fewer side effects in at least some cases and in at least some areas of the human body, compared to other methods such as liposuction, slurry injection, Kybella®, or CoolSculpting®. The device according to the present invention appears to enable precise lipolysis of subcutaneous adipocytes in a wide variety of indications, such as lipodysplasia and / or lipomas, and / or other reasons.

[0029] The device according to the present invention appears to enable the targeted use, and particularly advantageous use, of different cell death mechanisms, depending on the specific needs and / or use case. In particular, the device according to the present invention appears to make it possible to initiate the desired cell death mechanism against different cell layers in each case. With the device according to the present invention, lipomas can be treated, for example, by initiating apoptosis against the inner core structure and necrosis against the outer shell structure. Necrosis first, then apoptosis, or a combination of apoptosis and necrosis is also possible. This can be done in a single treatment session or over multiple sessions.

[0030] In the sense of the disclosure herein, the term “cryolipolysis” means inducing cell death in human or animal adipocytes by applying cooling to cells. The term “cryolipolysis” specifically means inducing cell death in so-called “white” adipocytes, which are often also called “adipocytes” and / or “mature adipocytes” and are configured to store large amounts of fat in the human or animal body.

[0031] In the context of this disclosure, the term “percutaneous” means, according to its general and established medical definition, “by puncturing the skin.”

[0032] In the context of this disclosure, the term “subcutaneous” means “below or beneath the skin” according to its general and established medical definition.

[0033] The main body may include a housing and may be ergonomically designed to allow for easy handling by the practitioner. The main body may, in particular, include a gripping zone. The main body may also include one or more control buttons for controlling the device, in particular a power button, and / or one or more switches for turning cooling on and / or off, and in particular the flow of cryofluid may be controlled via operating elements that may be located on or integrated into the main body. The main body may be made of lightweight material, or at least partially lightweight material, in particular to allow for precise handling for precise cryo application. As an addition or alternative, one or more control buttons and / or operating elements may be located on a separate terminal, which may be directly or indirectly coupled to the main body, as is known in dental devices.

[0034] In the sense of this disclosure, “cryofluid source” is a source of fluid, and the term “fluid” encompasses gaseous and liquid media, and the fluid provided by the source, when flowing through the cryonead, can cause cooling of the cryonead, particularly its outer surface. The cryofluid source may be, but is not limited to, a container or cartridge filled with, for example, liquid nitrogen (N2), carbon dioxide (CO2), nitrous oxide (N2O; laughing gas), or other fluids suitable as cryofluids. In principle, all fluids are suitable as cryofluids and can produce the desired cooling effect by appropriately inducing the so-called “Joule-Thomson effect.” Therefore, other fluids that are well known in other use cases can also be used as cryofluids in principle. Other fluids that may be used in principle include cooling fluids known in the automotive or air conditioning industry, such as R134a, R123yf, R1234ze(E), R404A / R507, R407A / R407F, R407C, R410A, R32, R23 / R508A / R508B, R600a, R290 / R1270, or R717. However, when using non-medical cryofluids, additional measures may be required to ensure safety.

[0035] In some embodiments, the cryofluid source may be integrated into the device. In other embodiments, the cryofluid source may not be integrated into the device, but may be located separately, for example, at a separate terminal, and configured to be connected or connectable to the device, in particular to the cryonedle, via a line, hose, or tube, and especially via the main body.

[0036] The cryofluid source may be configured for stationary placement, and in particular, it may be a stationary fluid reservoir capable of containing cryofluid in volumes of up to 1 liter, 5 liters, 10 liters, 15 liters, or up to 20 liters. However, other sizes are also possible.

[0037] In another embodiment, the cryofluid source may be configured to be portable. In one embodiment, the cryofluid source may be, for example, a cryofluid cartridge. Such a cryofluid cartridge may have a volume ranging from, for example, 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, or 0.9 ml to, for example, 1 l, 1.5 l, or 2 l. However, other sizes are also possible.

[0038] The cryofluid source can be coupled to the main body, as is known from cryosurgery devices for tumor treatment, for example.

[0039] In the sense of this disclosure, “cryo-needle assembly” is an assembly comprising a cryo-needle and one or more other components, in particular a cryo-needle assembly comprising, in addition to the cryo-needle, at least a needle hub for attaching the needle assembly to a body. The cryo-needle assembly may further comprise, for example, an end stop for limiting the penetration depth of the needle when puncturing the skin and positioning the needle and placing the cooling area at a desired location in the subcutaneous adipose tissue.

[0040] The term “needle” in this disclosure includes needles and cannulas, in particular sharp needles configured to puncture skin, as well as blunt cannulas which may require the skin to be punctured first by another means.

[0041] The cryoneed device according to the present invention preferably comprises at least one lumen through which a cryofluid can flow from an inlet toward the needle cooling area, particularly toward the needle tip, and the flow of the cryofluid through the lumen can cause cooling of the outer surface of the needle in the needle cooling area according to the so-called well-known "Joule-Thomson effect".

[0042] In a preferred embodiment, the cryonead is designed so that the cryofluid does not flow into the surrounding tissue. Therefore, in a preferred embodiment, the cryofluid flow can preferably be at least partially returned.

[0043] Cryonedle assemblies can generally be designed and configured similarly to known cryonedles, for example, from cryosurgery and cryotherapy in tumor treatment. However, the devices according to this disclosure can cool subcutaneous adipose tissue very specifically. In particular, they differ in their ability to generate a specific and advantageous tissue cooling zone for lipolysis of subcutaneous adipocytes.

[0044] In the context of this application, the term “adipose tissue” means, in particular, a type of tissue that can be found in humans and animals that can store energy in the form of fat, wherein “adipose tissue” means, in particular, a tissue that includes adipocytes (certain cells that can store energy in the form of fat) and / or preadipocytes (cells that have the potential to differentiate into (mature) adipocytes).

[0045] In one embodiment, the cryofluid can be at least partially recirculated and returned to the cryofluid circulation. This can significantly reduce the consumption of the cryofluid for cryolipolysis. In some cases, reprocessing of the recirculated cryofluid, such as filtration and / or compression, may be required. In one embodiment, the device may include additional means for reprocessing the recirculated cryofluid and may be configured to circulate the cryofluid at least partially.

[0046] The cold outer surface of the needle cools the surrounding tissue, especially the tissue adjacent to the needle's outer surface. Depending on the amount of cooling energy generated, the temperature of the needle's outer surface, and the size and shape of the needle cooling area, tissue that is not directly adjacent to the needle, i.e., not in direct contact with the needle, may also be cooled. In particular, so-called "tissue cooling zones" are created, as described below.

[0047] Preferably, the needle cooling zone is located somewhere along the needle between the needle tip and the connection to the body.

[0048] When a cryonedle is positioned and penetrates the skin such that the needle cooling area is at least partially surrounded by subcutaneous tissue, a subcutaneous tissue cooling zone is created. If the surrounding tissue is subcutaneous adipose tissue, a subcutaneous adipose tissue cooling zone is created.

[0049] In the sense of this disclosure, “subcutaneous tissue cooling zone” means a zone located beneath the skin in human or animal tissue, particularly subcutaneous adipose tissue, where throughout this zone, the temperature of tissue cells becomes at least temporarily below a defined temperature during cooling, and an isotherm of the defined temperature defines the boundary of the cooling zone relative to the surrounding subcutaneous tissue. The defined temperature is, in particular, lower than +15°C, +14°C, +13°C, +12°C, +11°C, +10°C, +9°C, +8°C, +7°C, +6°C, +5°C, +4°C, +3°C, +2°C, +1°C, or 0°C, but not below -50°C, -40°C, -39°C, -38°C, -37°C, -36°C, -35°C, -34°C, -33°C, -32°C, -31°C, or -30°C. Temperatures may not fall below -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, or -1°C.

[0050] In a preferred embodiment, the device may be configured to generate and / or form a tissue cooling zone having a defined size and / or shape. The shape of the subcutaneous tissue cooling zone that may be generated by the device, particularly within the subcutaneous tissue, may be at least partially or completely elliptical, spherical, oval, toroidal, conical, or a combination thereof. In one embodiment, the device may be configured to establish a tissue cooling zone having a shape that conforms to the area of ​​body to be treated by cryolipolysis. This may be achieved by a specific cryonewel design, particularly a specific design of the outer surface of the cryonewel, a specific design of the lumen through which the cryofluid flows, an appropriate cryofluid flow, and / or an appropriate cryofluid temperature, and / or appropriate insulating properties of the needle, particularly the needle wall.

[0051] The term "apoptosis" should be understood according to its usual understanding in a medical context, referring to the primary mechanism of cell death (controlled cell death). Whether cells, particularly adipocytes, have died by apoptosis can be determined, for example, with the help of one or more specific, well-known markers.

[0052] The term "necrosis" should be understood according to its usual understanding in a medical context, referring to a second mechanism of cell death (uncontrolled cell death). Whether cells, particularly adipocytes, have died by necrosis can also be determined, for example, with the help of one or more specific, well-known markers.

[0053] In one possible embodiment, the device may be configured to cool at least one cryonead in the cryonead cooling area, thereby initiating apoptosis in at least 1 Vol.-%, 2 Vol.-%, 3 Vol.-%, 4 Vol.-%, 5 Vol.-%, 10 Vol.-%, 15 Vol.-%, 20 Vol.-%, 25 Vol.-%, 30 Vol.-%, 35 Vol.-%, 40 Vol.-%, 45 Vol.-%, 50 Vol.-%, 55 Vol.-%, 60 Vol.-%, 65 Vol.-%, 70 Vol.-%, 75 Vol.-%, 80 Vol.-%, 85 Vol.-%, 90 Vol.-%, 95 Vol.-%, or up to 99 Vol.-% of adipocytes located in the tissue cooling zone.

[0054] In one embodiment, the device may be configured to avoid necrosis in at least a portion of the adipocytes, particularly in adipocytes from which apoptosis is initiated.

[0055] In one possible embodiment, particularly as an addition or alternative, the device may be configured to cool at least one cryonedle in the cryonedle cooling area, thereby initiating necrosis of at least 1 Vol.-%, 2 Vol.-%, 3 Vol.-%, 4 Vol.-%, 5 Vol.-%, 10 Vol.-%, 15 Vol.-%, 20 Vol.-%, 25 Vol.-%, 30 Vol.-%, 35 Vol.-%, 40 Vol.-%, 45 Vol.-%, 50 Vol.-%, 55 Vol.-%, 60 Vol.-%, 65 Vol.-%, 70 Vol.-%, 75 Vol.-%, 80 Vol.-%, 85 Vol.-%, 90 Vol.-%, 95 Vol.-%, or up to 99 Vol.-% of adipocytes located in the tissue cooling zone.

[0056] In one embodiment, the device may be configured to prevent apoptosis in at least a portion of the adipocytes, particularly those adipocytes in which necrosis is initiated.

[0057] Different cell death mechanisms can lead to different cryolipolysis outcomes, particularly different long-term outcomes. Side effects can be influenced by the type of cell death that occurs. The type of cell death can, in particular, affect further mechanisms in the human and / or animal body, such as the processes of breakdown and / or removal of dead adipocytes. However, the outcomes of cryolipolysis appear to depend not only on the type of cell death, but rather on several further parameters, such as tissue composition in general, cooling process parameters, and especially cooling temperature and temperature gradient. By making the type and extent of adipocyte death that occurs controllable, the devices of the present invention can minimize undesirable side effects.

[0058] In one embodiment, the device may be particularly configured to induce defined cell death, i.e., apoptosis and / or necrosis, in a defined ratio, preferably a predetermined, desired ratio between the volume of adipocytes killed by apoptosis and the volume of adipocytes killed by necrosis. In some cases, apoptosis may be preferred; in other cases, necrosis. A device configured such that the type of cell death induced by cooling is adjustable within at least a defined boundary can cover a wide range of possible cryolipolysis treatments for different adipocytes at different tissue locations.

[0059] In one possible embodiment, the device may be configured to cool at least one cryonead in the cryoneadil cooling area such that apoptosis is initiated in some adipocytes located in the tissue cooling zone and necrosis is initiated in some adipocytes located in the tissue cooling zone, in particular, the ratio of the volume of adipocytes located in the tissue cooling zone where necrosis is initiated to the volume of adipocytes located in the tissue cooling zone where apoptosis is initiated is in the range of 0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 to 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1. This ratio may vary depending on the treatment site.

[0060] The device, particularly in a single cooling cycle, showed that the ratio of the volume of dead adipocytes in the cooling zone where apoptosis was initiated and therefore adipocytes died by apoptosis to the volume of dead adipocytes in the tissue cooling zone where necrosis was initiated and therefore adipocytes died by necrosis was 1:99, 2:98, 3:97, 4:96, 5:95, 6:94, 7:93, 8:92, 9:91, 10: 90, 11:89, 12:88, 13:87, 14:86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80, 21:79, 22:78, 23:77, 24:76, 25:75, 26:74, 27:73, 28:72, 29:71, 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, 60:40, 61:39, 62:38, 63:37, 64:36, 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 71 It can be specifically configured to achieve :29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or 99:1.

[0061] In one embodiment, and in a particularly preferred embodiment, the device may be configured so that a target ratio can be adjusted or set between the volume of adipocytes in the cooling zone in which apoptosis is to be initiated and the volume of adipocytes in the cooling zone in which necrosis is to be initiated.

[0062] In one embodiment, and in a particularly preferred embodiment, the device may be configured such that the size and / or shape of the cooling zone can be adapted. One important parameter that appears to significantly influence the type of cell death initiated (apoptosis and / or necrosis) is the cooling temperature.

[0063] In one possible embodiment, the device may be configured to cool at least one cryonead in a cryonead cooling area, so that the subcutaneous tissue in the resulting tissue cooling zone is cooled to at least +15°C, +14°C, +13°C, +12°C, +11°C, +10°C, +9°C, +8°C, +7°C, +6°C, +5°C, +4°C, +3°C, +2°C, +1°C, or 0°C, but not to -50°C, -40°C, -39°C, -38°C, -37°C, -36°C, -35°C, -34°C, -33°C, -32°C, -31°C, or -30°C. The tissue is not cooled to below -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, or below -1°C. The subcutaneous tissue within the tissue cooling zone is preferably cooled to a tissue temperature in the range of -50°C to +15°C, -40°C to +10°C, -35°C to +5°C, -30°C to 0°C, or -20°C to -5°C.

[0064] In one embodiment, the device may be configured to cool at least one cryonead in a cryonead cooling area, thereby generating a resulting tissue cooling zone, particularly in subcutaneous (white) adipose tissue, where the temperature is lower than a first temperature everywhere, and the first temperature can be, in particular, +15°C, +14°C, +13°C, +12°C, +11°C, +10°C, +9°C, +8°C, +7°C, +6°C, +5°C, +4°C, +3°C, +2°C, +1°C, or 0°C. However, temperatures are not lower than -50°C, -40°C, -39°C, -38°C, -37°C, -36°C, -35°C, -34°C, -33°C, -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, or -1°C.

[0065] In a preferred embodiment, the device may be configured to generate different tissue cooling zones, in particular, with different shapes, sizes, and / or temperature distributions within the tissue cooling zones, depending on the location and / or amount of adipose tissue to be treated by cryolipolysis in the device.

[0066] In advantageous embodiments, the device can be configured to establish a tissue cooling zone in subcutaneous adipose tissue, in particular, where adipocytes are cooled to tissue temperatures in the range of -50°C to +15°C, -40°C to +10°C, -35°C to 5°C, -30°C to 0°C, or -20°C to -5°C.

[0067] In order to form a suitable tissue cooling zone, a particularly advantageous tissue cooling zone, preferably such a tissue cooling zone, in at least one embodiment the device according to the present invention may be configured to apply a defined amount of cooling to the target tissue cooling zone.

[0068] In one possible embodiment, the device according to the present invention may be configured to apply a defined cooling in the range of +4°C to -30°C for a defined time to the tissue volume surrounding the tip of the cryoneedle of the device, and the device may preferably be configured to apply cooling in the range of 0°C to -25°C or 0°C to -20°C. The device may be configured to apply the defined cooling for a time ranging from 10 seconds to 10 minutes, 15 minutes, or 20 minutes.

[0069] In one possible embodiment, the device according to the present invention may be configured to apply cooling defined in particular within a range between a first temperature and a second temperature, the first temperature being, in particular, 4°C, 3°C, 2°C, 1°C, 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, -6°C, -7°C, -8°C, -9°C, -10°C, -11°C, -12°C, -13°C, -14°C, or -15°C. The second temperature could be, for example, -1°C, -2°C, -3°C, -4°C, -5°C, -6°C, -7°C, -8°C, -9°C, -10°C, -11°C, -12°C, -13°C, -14°C, -15°C, -16°C, -17°C, -18°C, -19°C, -20°C, -21°C, -22°C, -23°C, -24°C, or -25°C, and in particular, the second temperature could be at least 1K, 2K, 3K, 4K, or 5K lower than the first temperature, i.e., 1°C, 2°C, 3°C, 4°C, or 5°C lower, respectively.

[0070] In one embodiment of the device according to the present invention, the device may be configured to apply defined cooling to the tissue surrounding the cryonead within the temperature range described above, preferably from +4°C or 0°C to -20°C, -25°C, or -30°C, and the device may more preferably be configured to adjust the defined cooling within this range in increments of 1°C or 2°C.

[0071] In one possible embodiment, the device according to the present invention may be configured to apply cooling in particular in the range between a first application time and a second application time, where the first application time is in particular 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, 11s, 12s, 13s, 14s, 15s, 16s, 17s, 18s, 19s, 20s, 21s, 22s, 23s, 24s, 25s, 26s, 27s, 28s, 29s, 30s, 31s, 32s, 33s, 34s, 35s, 36s, 37s, 38s, 39s, 40s, 41s, 42s, 43s, 44s, 45s, 46s, 47s, 4 8s, 49s, 50s, 51s, 52s, 53s, 54s, 55s, 56s, 57s, 58s, 59s, 60s (=1 minute), 75s, 90s, 1 05s, 120s (=2 minutes), 135s, 150s, 165s, 180s (=3 minutes), 195s, 210s, 225s, 240s (=4 minutes), 25 It could be 5s, 270s, 285s, 300s (=5 minutes), 330s, 360s (=6 minutes), 390s, 420s (=7 minutes), 450s, 480s (=8 minutes), 510s, 540s (=9 minutes), 570s or 600s (=10 minutes), or 11 minutes, 12 minutes, 13 minutes, 14 minutes or 15 minutes.

[0072] The second application time is, for example, 7s, 8s, 9s, 10s, 11s, 12s, 13s, 14s, 15s, 16s, 17s, 18s, 19s, 20s, 21s, 22s, 23s, 24s, 25s, 26s, 27s, 28s, 29s, 30s, 31s, 32s, 33s, 34s, 35s, 36s, 37s, 38s, 39s, 40s, 41s, 42s, 43s, 44s, 45s, 46s, 47s, 48s, 49s, 50s, 51s, 52s, 53s, 54s, 55s, 56s, 57s, 58s, 59s, 60s (=1 minute), 75s, 90s, 105s, 1 The duration may be 20s (=2 minutes), 135s, 150s, 165s, 180s (=3 minutes), 195s, 210s, 225s, 240s (=4 minutes), 255s, 270s, 285s, 300s (=5 minutes), 330s, 360s (=6 minutes), 390s, 420s (=7 minutes), 450s, 480s (=8 minutes), 510s, 540s (=9 minutes), 570s or 600s (=10 minutes) or 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, or 20 minutes, and in particular, the second temperature may be at least 5s higher than the first application time.

[0073] In one embodiment of the device according to the present invention, the device may be configured to apply a defined cooling to the tissue surrounding the tip of the cryoneadyl within the time range described above, preferably from 2s, 5s, or 10s to 10 minutes, 15 minutes, or 20 minutes, and the device may be more preferably configured to allow the defined application time to be adjusted within this range in increments of 1s, 2s, 5s, 10s, 20s, or 30s.

[0074] In a preferred embodiment of the device according to the present invention, the device is configured to apply defined cooling to the tissue surrounding the cryoprobe within the temperature range as described above, preferably within the range from +4°C or 0°C to -20°C, -25°C or -30°C. The device may be more preferably configured such that the defined cooling can be adjusted in steps of 1°C or 2°C within this range. Also, the device is for applying defined cooling within the time range as described above, preferably within the range from 2 s, 5 s or 10 s to 10 minutes, 15 minutes or 20 minutes. The device may be more preferably configured such that the application time can be adjusted in steps of 1 s, 2 s, 5 s, 10 s, 20 s or 30 s within this range.

[0075] In an advantageous embodiment, the device may be configured to establish a tissue cooling zone of a defined size, particularly at least a first size, in the subcutaneous adipose tissue. For example, the device may be configured to establish a subcutaneous cooling zone of a first size having a volume in the range from 0.5 cm 3 to 10 cm 3 . In particular, the device may be at least 0.5 cm 3 , 1 cm 3 , 1.5 cm 3 , 2 cm 3 , 2.5 cm 3 , 3 cm 3 , 3.5 cm 3 , 4 cm 3 , 4.5 cm 3 , 5 cm 3 , 6 cm 3 , 7 cm 3 , 8 cm 3 , 9 cm 3 , or 10 cm 3 and may be configured to generate a tissue cooling zone in the subcutaneous adipose tissue of the first size.

[0076] In one embodiment, the device may be configured to generate subcutaneous cooling zones of different sizes and / or shapes, particularly depending on the respective use case, for cryolipolysis of subcutaneous adipose tissue at different locations on the human body (face, abdomen / stomach, legs, arms, back, buttocks, calves) and / or penetration depths. The device may be configured, for example, to generate a tissue cooling zone of a first size and shape in a first cooling cycle and a tissue cooling zone of a second size and / or shape in a second cooling cycle.

[0077] In one embodiment, the shape, size, and / or temperature distribution within the tissue cooling zone can be specifically adjusted to suit each use case for favorable cryolipolysis results. In particular, the defined temperature and the course of the isotherm of said defined temperature, which define the boundary of the cooling zone relative to the surrounding subcutaneous tissue, can be adjusted or set, in particular with respect to the location of the subcutaneous tissue to be treated by cryolipolysis using the device.

[0078] In one possible embodiment, at least one cryonedle may be thermally insulated and / or comprise a thermally insulating material, or be fabricated at least partially from a thermally insulating material. Such a thermally insulating material may influence and be particularly adaptable to the design and location of the cooled and uncooled areas along the needle, as well as the shape of the needle cooling zone, and / or the amount of cooling introduced into the surrounding tissue and the tissue cooling zone. By varying the thermal insulating properties and / or thickness of the insulating material, its arrangement and / or shape, the location, shape and size of the resulting needle cooling zone and / or the resulting temperature distribution within the needle cooling zone, and consequently the location, shape and size of the resulting tissue cooling zone, and / or the resulting temperature distribution within the tissue cooling zone, can also be adapted.

[0079] In one embodiment, to reduce the cooling of the outer surface of the needle in this area during the cryolipolysis process in which the needle penetrates the skin, and to avoid low-temperature burns in the penetration area of ​​the skin or other tissue in contact with the outer surface of the needle, a layer of thermal insulating material can be placed, for example, beneath the outer surface of the cooling needle, particularly in the proximal portion of the needle.

[0080] In one embodiment, to allow for maximum cooling of the subcutaneous tissue, particularly subcutaneous adipocytes, surrounding the needle tip area during the cryolipolysis process, thermal insulating material may not be placed in the area around the distal needle end. However, if the creation of a lower temperature needle and / or tissue cooling zone is desired, the presence of thermal insulating material at the distal end of the needle may be advantageous. In addition, or as an alternative, needle materials with different thermal insulating properties may be selected and / or used.

[0081] For a defined application of a defined amount of cooling, the device according to the present invention may be configured in particular to generate a defined needle cooling temperature, i.e., a defined temperature of the outer surface of the cooling needle, in particular in at least one zone of the cryoneadyl cooling area, in particular in particular the defined temperature of the outer surface of the cryoneadyl cooling area over the entire cryoneadyl cooling area.

[0082] The device cools the outer surface of the cryoneedle to +14°C, +13°C, +12°C, +11°C, +10°C, +9°C, +8°C, +7°C, +6°C, +5°C, +4°C, +3°C, +2°C, +1°C, or 0°C, but not to -51°C, -50°C, -40°C, -39°C, -38°C, -37°C, -36°C, -35°C, -34°C, -33°C The temperature can be configured so that it does not fall below -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, or -1°C.

[0083] In one embodiment of the device according to the present invention, the device may be configured to cool the outer surface of the cryoneedle at at least one point or portion of the needle cooling area to an outer surface temperature in the range of +4°C or 0°C to -20°C, -25°C or -30°C, and the device may be configured to adjust the outer surface temperature within this range in increments of 1°C or 2°C.

[0084] In one embodiment of the device according to the present invention, the device may be configured to apply defined cooling to the tissue surrounding the tip of the cryoneadyl within the time range described above, preferably from 2s, 5s, or 10s to 10 minutes, 15 minutes, or 20 minutes, and the device may be more preferably configured to allow adjustment of the application time (cooling application time) within this range in increments of 1s, 2s, 5s, 10s, 20s, or 30s.

[0085] In a preferred embodiment of the device according to the present invention, the device may be configured to apply defined cooling to the tissue surrounding a cryonead within the temperature range described above, preferably from +4°C or 0°C to -20°C, -25°C, or -30°C, and more preferably the device may be configured so that the defined cooling can be adjusted in 1°C or 2°C increments within this range, and also for applying defined cooling within the time range described above, preferably from 2s, 5s, or 10s to 10 minutes, 15 minutes, or 20 minutes, and more preferably the device may be configured so that the application time (of cooling) can be adjusted in 1s, 2s, 5s, 10s, 20s, or 30s increments within this range.

[0086] In a preferred embodiment, the cooling of the outer surface of the needle in the needle cooling area may be limited, for example, to a defined temperature limit and / or a defined application time limit, which may be adjusted and / or set by the practitioner, in particular, for example, by appropriate adjustment of one or more control parameters and / or by the selection of a particular cryonewine assembly. In at least one embodiment of the device according to the present invention, the limit may depend on one or more parameters. For example, the limit may depend on the cooling or cooling temperature applied so far and / or the application time elapsed and / or a combination thereof. This allows for precise control of subcutaneous tissue cooling. Precise control and adjustment of subcutaneous tissue cooling appears to be important, particularly for adipocytes, in order to achieve controlled cell death of adipocytes with as few side effects as possible.

[0087] In one possible embodiment, the device may include one or more valves for controlling, particularly restricting, and / or controlling the cooling flow of cryofluid to and / or through at least one cryonead. Such valves can significantly contribute to the control of the cooling process. Using precise and fast-responding valves that open and close precisely and instantly in response to user commands can achieve precise cooling of subcutaneous tissue, particularly subcutaneous adipose tissue.

[0088] In one embodiment, at least one valve may be configured to mix the cooling flow with ambient air for improved control and / or regulation of the cooling flow and / or favorable adjustment of the cooling temperature, in particular for improved control of the cooling temperature that occurs on the outer surface of the needle as the cryofluid flows through the cryoneedle.

[0089] In one possible embodiment, the device may be a handheld device similar to a dental device. In a preferred embodiment, the weight of the handheld device is less than 0.5 kg, 0.4 kg, 0.3 kg, or 0.2 kg. The lighter the device, the less tiring it is for the practitioner to use. For accurate treatment, it seems important that the device is well-balanced and can be held in the hand without any counteracting moment being applied by the holder. In particular, for comfortable and accurate use, the device should not be top-heavy, i.e., it should not tend to tilt away from the needle tip during use, nor should it be "tail-heavy," i.e., it should not tend to tilt downward with its end pointing away from the needle tip. To provide a well-balanced handheld device that is neither top-heavy nor tail-heavy, the device may have one or more countermass or countermass concentration areas. For example, a countermass may be useful, in particular, if the device includes a cryofluid cartridge located at the proximal end ("tail end") of the device.

[0090] To achieve a comfortable and well-balanced handheld device, the heaviest components may preferably be located in or near the central area of ​​the body, particularly within the grip area. In one embodiment of a handheld device configured to hold a cryofluid cartridge, the cartridge may be located in the central area of ​​the body and / or near the center of gravity of the handheld device.

[0091] In one possible embodiment, the body can be coupled to a stationary cryofluid reservoir as a cryofluid source, preferably CO2, N2, N2O, or a combination thereof, particularly via at least one supply line. In particular, the body may be coupled to the cryofluid source by one or more supply lines, hoses, or tubes. The device may include at least a first hose or tube or supply line for flowing cryofluid, particularly cryogas, from the cryofluid source to the body, preferably through the body, and further into a cryoneed needle. In one embodiment, the device may also include a second hose or tube or return line for flowing cryofluid, particularly cryogas, backward from the cryoneed needle. The return flow may be directed into the environment or at least partially recirculated and returned to the cryofluid circulation. The return flow may be directed through the body.

[0092] The rigidity of such supply or return lines and / or hoses and / or tubes can be as low as necessary, especially to minimize any impact on handling. Ideally, the supply lines should be barely noticeable during use, and the device should feel as if it were using a tubeless mobile device.

[0093] As an addition or alternative, the device, in particular the main body, may be coupled to a cryofluid cartridge, especially one filled with CO2, N2, N2O, or a combination thereof, as a cryofluid source. Methods for realizing such coupling are known, for example, from iovera® devices.

[0094] Cryofluids are particularly suitable for medical use and may be medical fluids possessing sufficient purity, especially sufficient medical purity.

[0095] In one possible embodiment, the cryoneadyl assembly is interchangeably and detachably coupled to or can be coupled to the body, and in particular, the body and / or the cryoneadyl assembly may include an adapter through which the cryoneadyl assembly and the body are coupled to or can be coupled to each other. The adapter allows different cryoneadyl assemblies to be easily and flexibly coupled to the body. This makes it very easy to increase the flexibility of the device. Furthermore, the adapter makes it very easy to achieve different orientations of the longitudinal axis of the cryoneadyl relative to the body. This allows for adaptation of the handling characteristics of the device, and in at least some cases, improved and / or more precise handling of the device can be achieved. In particular, in some cases, by using an appropriate adapter, access to specific parts of the body can be improved.

[0096] In one possible embodiment, at least one cryonead may be a needle or cannula of 15G, 16G, 17G, 18G, 19G, 20G, 21G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G, 30G, 31G, 32G, 33G, 34G, or 35G. The only important thing is that sufficient cooling can be achieved, particularly sufficient cooling based on the Joule-Thomson effect known from cryosurgery.

[0097] In one embodiment, the device may be configured to be used with different cryonews and / or different cryonews and / or assemblies, particularly with different cryonews and / or assemblies adapted to different treatment areas, such as percutaneous cryolipolysis of subcutaneous fat cells (adipocytes and / or preadipocytes) in the face (jaw, cheeks), thighs, calves, waist, abdomen, buttocks, arms, chest, upper back and / or upper back. This allows for the use of larger cryonews in areas with a large amount of subcutaneous fat tissue, for example, thereby improving the efficiency of cryolipolysis treatment by allowing more fat tissue to be destroyed in the same or a shorter time. Smaller cryonews may be used for more accurate and safer cryolipolysis in areas with a small amount of subcutaneous fat tissue, or in areas where very precise puncture and cryonews placement are important to avoid damage to surrounding structures such as blood vessels, nerves, organs, muscles and / or lymphatic vessels.

[0098] In one possible embodiment, the needle assembly may comprise at least two cryoneadils, in particular a group of needles, in particular an array of cryoneadils. Alternatively or additionally, the needle assembly may comprise one or more microneedles, in particular at least one array of microneedles.

[0099] In the sense of this disclosure, “needle array” means a group of needles arranged in a geometrically defined, particularly defined or regular pattern relative to one another.

[0100] A "needle group" means that one or more cryoneeds are arranged in a geometrically undefined manner relative to each other.

[0101] A "microneedle" refers to a needle that is shorter and / or thinner than a regular needle of the same size.

[0102] The use of cryoneedle groups or arrays may be advantageous, particularly in areas with a large amount of subcutaneous adipose tissue, while the use of cryoneedle assemblies, which consist of microneedles and / or single cryoneedles only, appears to be advantageous in areas with a small amount of subcutaneous adipose tissue, or in areas where very precise puncture and placement of the cryoneedle is important to avoid damage to surrounding structures such as blood vessels, nerves, organs, muscles, and / or lymphatic vessels.

[0103] In one embodiment, the device may be configured to generate subcutaneous cooling zones of different sizes and / or shapes for different needles in a group of needles, particularly depending on the use case, for cryolipolysis of subcutaneous adipose tissue at different locations on the human body (face, abdomen / stomach, legs, arms, back, buttocks, calves) and / or penetration depths. The device may be configured, for example, to generate a tissue cooling zone of a first size and shape adjacent to a first needle, and a tissue cooling zone of a second size and / or shape adjacent to a second needle.

[0104] To maintain sufficient distance from organs, as well as other structures such as muscles and major blood vessels and nerves, one or more markers (similar to a scale) may be provided on the outer surface of the needle to indicate the penetration / insertion depth.

[0105] In one embodiment, alternatively and / or additionally, the cryoneadyl assembly, in particular the cryoneadyl, may include an end stop that contacts the skin surface as soon as it reaches an acceptable penetration depth, preventing deeper penetration.

[0106] In one possible embodiment, the device may include a control unit configured for controlling, adjusting, and / or setting the cooling of the cryoneedle cooling area, in particular for controlling, adjusting, and / or setting the cooling temperature of the cryoneedle cooling area, in order to control the cooling temperature of the tissue cooling zone. In a preferred embodiment, the device may be configured so that a desired tissue cooling zone can be generated, in particular, one or more parameters may be set and / or adjusted before or during the cryolipolysis process to adapt the characteristics of the tissue cooling zone to a particular treatment.

[0107] In one embodiment, one or more parameters may be adjusted and / or set depending, in particular, on the location of the subcutaneous adipose tissue to be treated by cryolipolysis, the volume of the adipose tissue to be treated, the average size of the adipocytes to be treated, and the indication for treatment (lipedema, lipoma, cosmetic reasons, aesthetic reasons).

[0108] In one embodiment, the device may be configured to adjust, in particular, the cooling temperature of the needle cooling zone, especially the temperature of a defined point on the outer surface of the needle, preferably the cooling temperature distribution on the outer surface of the needle in the needle cooling area, and cooling may be induced in a preferably adjusted manner. This makes it possible to optimally adapt the needle cooling area to the requirements of several different use cases.

[0109] The device may include at least one temperature sensor, in particular a temperature sensor for detecting tissue temperature and / or a temperature sensor for detecting the surface temperature of the cryoneedle.

[0110] In one embodiment, the device may include a display unit for presenting the practitioner with the surface temperature of the cryoneed, and / or the elapsed time, and / or the remaining application time, and / or at least one other relevant parameter. The device may, for example, sound an alarm when the temperature exceeds a suitable range or a predetermined threshold, and / or when a defined application time has been reached. The device may indicate the start and / or end of cooling, and / or that the needle can be removed from the subcutaneous adipose tissue.

[0111] In one embodiment, the device may be configured so that the cooling temperature of the tissue cooling zone, a particularly defined temperature, preferably the cooling temperature distribution in the tissue cooling zone, and / or the needle cooling temperature (cooling temperature on the outer surface of the cryoneedle), and / or a defined application time can be adjusted, and cooling may be induced in a preferably adjusted manner. This makes it possible to optimally adapt the tissue cooling zone to the requirements of several different use cases.

[0112] In one embodiment, the device may be configured to set, in particular, a target volume of adipose tissue in which apoptosis and / or necrosis should be initiated, and / or a defined target volume ratio of cell death caused by apoptosis to cell death caused by necrosis.

[0113] In one embodiment, a defined application time and / or a defined tissue cooling temperature and / or a defined tissue cooling volume and / or a defined needle cooling temperature (needle outer surface temperature) may be set.

[0114] The device may include one or more displays, in particular, to indicate the status of the device and / or the status of the cooling process, or, for example, tissue temperature, and / or the time passed and / or remaining application time, and / or at least one other relevant parameter to the practitioner. In one embodiment, the device may be configured to visualize the adjusted / set tissue cooling zone and / or the generated tissue cooling zone.

[0115] The device may be programmable. The device may be configured to store predefined treatment programs for cryolipolysis therapy for different use cases, including appropriate default parameters and / or treatment schemes or patterns. The device may be configured to guide the practitioner through the treatment process.

[0116] The device may include a timer, in particular for precisely controlling the cooling time. In a preferred embodiment, the device may be configured so that the cooling temperature can be adjusted and / or controlled over time. In particular, one or more time-dependent cooling temperature profiles may be set.

[0117] In one embodiment, the device is particularly cooled at any combination of the cooling temperatures and / or temperature ranges described herein, such as 1s, 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, 11s, 12s, 13s, 14s, 15s, 16s, 17s, 18s, 19s, 20s, 21s, 22s, 23s, 24s, 25s, 26s, 27s, 28s, 29s, 30s, 31s, 32s, 33s, 34s, 35s, 36s, 37s, 38s, 39s, 40s, 41s, 42s, 43s, 44s, 45s, 46s, 47s, 48s, 49s, 50s, 51s , 52s, 53s, 54s, 55s, 56s, 57s, 58s, 59s, 60s (=1 minute), 75s, 90s, 105s, 120s (=2 minutes), 135s, 150s, 165s, 180s (=3 minutes), 195s, 210s, 225s, 240s (=4 minutes), 255s, 270s , 285s, 300s (=5 minutes), 330s, 360s (=6 minutes), 390s, 420s (=7 minutes), 450s, 480s (=8 minutes), 510s, 540s (=9 minutes), 570s or 600s (=10 minutes) to 20 minutes, 19 minutes, 18 minutes, 17 minutes, 16 minutes, 900s (=15 minutes), 870s, 840s (=14 minutes), 810s, 780s (=13 minutes), 750s, 720s (=12 minutes), 690s, 660s (=11 minutes), 600s (=10 minutes), 570s, 540s (=9 minutes), 510s, 480s (=8 minutes), 450s, 420s (=7 minutes), 3 90s, 360s (=6 minutes), 330s, 300s (=5 minutes), 285s, 270s, 255s, 240s (=4 minutes), 225s, 210 s, 195s, 180s (=3 minutes), 165s, 150s, 135s, 120s (=2 minutes), 105s, 90s, 75s, 60s (=1 minute It can be configured to cool subcutaneous adipose tissue with cooling times ranging from 59s, 58s, 57s, 56s, 55s, 54s, 53s, 52s, 51s, 50s, 49s, 48s, 47s, 46s, 45s, 44s, 43s, 42s, 41s, 40s, 39s, 38s, 37s, 36s, 35s, 34s, 33s, 32s, 31s, 30s, 29s, 28s, 27s, 26s, 25s, 24s, 23s, 22s, 21s, 20s, 19s, 18s, 17s, 16s, 15s, 14s, 13s, 12s, 11s, 10s, 9s, 8s, 7s, 6s, or 5s.

[0118] A kit for percutaneous cryolipolysis according to the present invention comprises a device and a cryofluid source, the device comprising a body to which the cryofluid source can be bound, and a cryoneadyl assembly that is bound to or can be bound to the body. The cryoneadyl assembly comprises at least one cryoneadyl, the at least one cryoneadyl configured to penetrate at least partially into human or animal skin. The device is configured to cool at least one cryoneadyl in at least a cryoneadyl cooling area by using cryofluid from the cryofluid source when the cryofluid source and the cryoneadyl assembly are bound to the body, and to form a subcutaneous tissue cooling zone adjacent to the cryoneadyl cooling area of ​​the cooled cryoneadyl when the cooled cryoneadyl penetrates at least partially into human or animal skin. The device is further configured to cool subcutaneous adipocytes located in the tissue cooling zone so that apoptosis and / or necrosis is initiated in at least some of the adipocytes located in the tissue cooling zone.

[0119] The device in the kit may be, in particular, a device according to the present invention as described above. The device and the cryofluid source may be coupled in a fluid communication manner, in particular, so that the cryofluid from the cryofluid source may flow into and / or through the cryoneadil.

[0120] According to the present invention, a device or kit configured for transcutaneous cryolipolysis as described above may be used in particular for cosmetic, aesthetic, or therapeutic applications, especially for transcutaneous cryolipolysis.

[0121] The devices or kits according to the present invention may be used for subcutaneous cryolipolysis, in particular, in combination with one or more defined therapeutic schemes or patterns, and / or according to different instructions for use, and / or for different indications. Such schemes may define zones where treatment is permitted and zones where it is not permitted, for example, the direction of penetration, penetration depth, cooling temperature, and time.

[0122] The device or kit according to the present invention may be used, in particular, for percutaneous cryolipolysis of lipedema, lipoma, and / or for cosmetic, aesthetic or therapeutic applications of human or animal adipose tissue, for example, for percutaneous cryolipolysis of subcutaneous fat cells (adipocytes and / or preadipocytes) of the face (jaw, cheeks), thighs, calves, waist, abdomen, buttocks, arms, chest, upper back and / or upper back.

[0123] In one embodiment, the device and / or kit may be configured so that percutaneous cryolipolysis can be performed under image control (e.g., ultrasound, MRT, CT).

[0124] In some cases, to make the treatment more comfortable for the patient, it may be advantageous to first apply a local anesthetic composition to the area to be punctured before puncturing the skin. For example, a cream containing lidocaine or other local anesthetic compositions may be applied first. In some cases, other means may be used to puncture the skin, especially if the cryonewydle is a blunt needle or cannula. In other words, this means that after the application of an optional local anesthetic, the skin is first punctured with the puncture device, and then the cryonewydle is inserted through the punctured skin, and its cooling area may be positioned in the subcutaneous adipose tissue.

[0125] Instead of liposuction, a device or kit according to the present invention may also be used. Using percutaneous cryolipolysis is expected to enable a safer and less risky reduction of body adipose tissue for the patient. However, it should be noted that the amount of subcutaneous adipose tissue that undergoes apoptosis and / or necrosis by percutaneous cryolipolysis may be limited by the body's ability to break down dead fat cells.

[0126] Next, the present invention described above will be further illustrated by the following non-limiting embodiments and examples, and further optional features of the present invention are disclosed in the drawings and their descriptions. All features and all combinations of features described above and / or schematically described below and / or shown only in the drawings can be realized in embodiments of the present invention in the described combinations, individually, or in at least one other combination not expressly described herein, as such combinations are technically reasonable.

[0127] The accompanying drawings incorporated herein and constituting part thereof schematically illustrate the invention described above, in particular preferred embodiments of the invention, and together with this specification, help to illustrate at least some of the principles and features of the invention described herein, and the same reference numerals are used for the same parts. [Brief explanation of the drawing]

[0128] [Figure 1] This is a perspective view of an example of a kit for percutaneous cryolipolysis according to the present invention, which has a first example of a device for percutaneous cryolipolysis according to the present invention. [Figure 2] This is a perspective view of a second example of a device for percutaneous cryolipolysis according to the present invention. [Figure 3]Figure 1 shows a schematic diagram of a portion of the cryoneedle assembly of the kit device during use, when it penetrates human skin and cools subcutaneous adipocytes to induce adipocyte death by subcutaneous cryolipolysis and apoptosis and / or necrosis. [Figure 4] Figures 1-3 are enlarged schematic diagrams of the first exemplary internal design within the cooling area at the tip of the cryoneedle. [Figure 5] Figures 1-4 show enlarged schematic diagrams of a second exemplary internal design within the cooling area at the tip of the cryoneedle. [Figure 6] This is an exemplary body area where the kit or device for percutaneous cryolipolysis according to the present invention can be used. [Figure 7] This is a side view of a third example of a device for percutaneous cryolipolysis according to the present invention. [Figure 8] This is a perspective view of a fourth example of a device for percutaneous cryolipolysis according to the present invention. [Figure 9] Figures 1-4 show another enlarged schematic of a further exemplary design within the cooling area at the tip of the cryoneedle. [Figure 10] These are bright-field microscope images of experimental results from adipocytes under defined conditions, for defined duration, and with defined cooling applied. [Figure 11] This is a fluorescence imaging analysis of the nuclei of blue-stained adipocytic cells, under defined conditions, for a defined duration, and with defined cooling applied. [Figure 12] Figure 11 shows the number of nuclei as a result of fluorescence image analysis of adipocytes, depending on the cooling temperature to which the cells were exposed. [Figure 13] , [Figure 14] These are the results of lactate dehydrogenase (LDH) assay tests to evaluate the cytotoxicity of temperature treatments applied to adipocytes under different conditions. [Modes for carrying out the invention]

[0129] Figure 1 is a perspective view of a first example of a device 10 for percutaneous cryolipolysis according to the present invention and an example of a kit 100 for percutaneous cryolipolysis according to the present invention, which has a cryofluid source 15.

[0130] The device 10 is an elongated handheld device 10 similar to a typical dental device, comprising a torpedo-shaped body 13 and a cryoneedle assembly 11 that includes a needle hub 20 and a cryoneedle 12.

[0131] The body 13 includes a proximal end and a distal end (not indicated by reference numerals), and a cryoneadyl assembly 11 is detachably attached to the proximal end of the body 13. The body 13 is configured to support a number of different cryoneadyl assemblies 11. The distal end of the body 13 is connected to the first end of a supply line 14 for supplying cryofluid to the cryoneadyl assemblies 11. The second end of the supply line 14 is connected to a cryofluid source 15, specifically a stationary cryogas container 15 with a capacity of 25 liters filled with carbon dioxide (CO2) as cryogas, and is particularly fluidically coupled.

[0132] Device 10 further comprises a control unit 16 integrated into the housing, which also contains a cryofluid source 15, a gas container filled with carbon dioxide (CO2). The housing and control unit 16 are part of an operating terminal for the operator to operate and control the kit 100, in particular the device 13. This is similar to a dental device. The operating terminal includes a number of operating buttons 17 and may further include one or more displays (not shown) that indicate the status of the kit 100 and / or the device 13. Control of the operating terminal by a foot switch (not shown) is also possible instead of control by the buttons 17.

[0133] In the illustrated example, the cryoneedle assembly 11 comprises a linear needle hub 20 and a 25G linear cryoneedle 12, wherein the needle hub 20 and the cryoneedle 12 are positioned along a common axis whose longitudinal axes coincide with the longitudinal axis of the main body 13.

[0134] The main body 13 is configured such that cryofluid from the cryo-gas source 15 is guided through the supply line 14 through the main body 13 into the cryo-needle assembly 11, particularly to the needle tip of the cryo-needle 12, and, based on the Joule-Thomson effect, can cause cooling of the outer surface of the cryo-needle 12 in the needle cooling area P1 (see Figures 3-5), as is commonly known from cryosurgery devices for cryotherapy of tumor tissue.

[0135] Device 10 may further include a gripping area on the main body for comfortable and ergonomic handling and secure gripping by the practitioner. For precise treatment of subcutaneous adipose tissue by percutaneous cryolipolysis, device 10 is also particularly well-balanced to avoid tilting in the practitioner's hand.

[0136] In other embodiments, the needle hub 20 and / or cryoneedle 12 may be angled or angled relative to the longitudinal axis of the body 13, for example, as shown in Figure 2, which shows a perspective view of a second example of the device 10A for transcutaneous cryolipolysis according to the present invention. Designs such as those shown in Figure 2 may be advantageous in some use cases because they offer different accessibility compared to the linear design shown in Figure 1.

[0137] Another difference between device 10 in Figure 1 and device 10A in Figure 2 is that, compared to device 10 in Figure 1, device 10A in Figure 2 additionally includes an adapter 19 between the main body 13 and the needle hub 20. The angle between the longitudinal axis of the cryoneadyl 12 and the longitudinal axis of the main body 13 is specifically caused by this adapter 19. By changing the adapter 19, multiple configurations to accommodate different use cases can be easily realized. This makes device 10A very flexible, especially more flexible than the device in Figure 1, and suitable for transcutaneous cryolipolysis in multiple body regions. With respect to the supply line 14, the device in Figure 2 further includes a supply line connector 18 that has a similar function to the adapter 19 between the main body and the needle hub 20.

[0138] According to the present invention, both devices 10 and 10A shown in Figures 1 and 2 are configured for percutaneous cryolipolysis of subcutaneous adipocytes (adipocytes and / or preadipocytes).

[0139] Figure 3 shows a schematic diagram of a portion of the cryoneedle assembly 11 of the device 10 of Kit 100 shown in Figure 1 during use. As shown in Figure 3, the cryoneedle 12 penetrates the dermis layers D1 and D2 of the skin and is configured to place at least partially, particularly its tip region and its needle cooling area P1, in the subcutaneous adipose tissue layer F, and to cool the adipocytes A (adipocytes and / or preadipocytes) surrounding the needle cooling area P1.

[0140] By using cryofluid G from a cryofluid source 15 and directing the cryofluid flow into the cryoneedle 12 (flow G1) and returning it (return flow G2), the outer surface of the needle 12 can be cooled in the needle cooling area or portion P1. This creates a cooling zone CZ in the surrounding subcutaneous adipose tissue F, which is elliptical or egg-shaped in the illustrated example.

[0141] In particular, to protect the dermis layers D1 and D2 of the skin above the subcutaneous adipose tissue F, portion P2 of the cryonewrench 12 is a non-cooled area P2 in which cooling of the outer surface of the needle is not caused, in order to avoid low-temperature burns of the tissue adjacent to and / or surrounding portion P2 of the needle. Cooling of the outer surface of the needle is caused only in portion P1 (needle cooling area) of the needle tip area.

[0142] The cryoneed needle 12 can cool subcutaneous adipocytes A, which can induce cell death. The device 13 is configured such that apoptosis is initiated in at least some of the adipocytes A located in the tissue cooling zone CZ, and necrosis is initiated in other adipocytes, with apoptotic cell death indicated by a white cross symbol labeled A1, and necrotic cell death indicated by a black cross symbol labeled A2. Other structures or deeper layers, such as muscle M, are preferably not affected by the cooling.

[0143] The tissue cooling zone (CZ), particularly its size, shape, and / or dimensions, is defined by an isotherm of a first temperature T1, where T1 may be, for example, T1 = -1°C. Throughout the tissue cooling zone, the tissue temperature is below -1°C. For visualization of the temperature distribution, isotherms of a second temperature (e.g., T2 = -5°C) and a third temperature (e.g., T3 = -10°C) are also schematically shown.

[0144] In the cooling zone (CZ) shown in Figure 3, a 1:1 cell death ratio was achieved, resulting in the death of 100% of adipocytes within the cooling zone. 50% of adipocytes died by apoptosis A1, and 50% died by necrosis A2.

[0145] The flow of the cryofluid G inside the needle 12 is illustrated in more detail in Figure 4, which shows an enlarged schematic diagram of the first exemplary internal design of the cryoneedle shown in Figures 1-3, in the cooling area at its tip region 21.

[0146] In this example of the cryoneedle 12, the cryofluid flow G1 from the cryofluid source 15 is directed into the lumen 12A and flows along the central axis of the cryoneedle 12 through the lumen 12A to a nearly closed needle tip 21. The tip 21 is closed to avoid leakage or transfer to surrounding tissue. At the end of the lumen 12A, the cryofluid flow is returned and flows back through the lumen 12B as flow G2, thereby cooling the cryofluid on the outer surface of the cryoneedle 12 and within the lumen 12A, increasing the overall cooling.

[0147] In other embodiments of the device according to the present invention, the flow direction may be reversed. In another embodiment, half of the entire lumen of the cryonead may be used for the feed flow G1 and the other half for the return flow G2. Further embodiments are also possible.

[0148] In the cooling zone CZ according to Figure 4, based on different device adjustments compared to Figure 3, a cell death ratio of 70:30 could be achieved, with 100% of adipocytes in the cooling zone CZ being killed. As adjusted before initiating cryolipolysis treatment, 70% of adipocytes by volume were killed by apoptosis A1 and 30% by necrosis A2.

[0149] In this example, the cryoneedle 12 has a closed needle tip 21 but is still configured to puncture the skin for percutaneous cryolipolysis. Therefore, it is not necessary to perform another puncture step with another puncture device to first puncture the skin in order to allow the cryoneedle 12 to penetrate the skin before insertion of the cryoneedle 12.

[0150] Figure 5 shows an enlarged schematic diagram of a second exemplary internal design in the cooling area P1 at the tip region 21 of the cryoneedle 12 in Figures 1-4, in which the cryoneedle 12 includes an inner insulating layer 22 to avoid cooling of the outer surface of the needle in the uncooled area P2. This significantly reduces the risk of low-temperature burns to upper skin layers, such as the dermis layers D1 and D2 (see Figure 3).

[0151] In the cryolipolysis zone (CZ) shown in Figure 5, based on the same adjustments as in Figure 3, a 50:50 cell death ratio could be achieved, resulting in 100% death of adipocytes within the cryolipolysis zone. As adjusted before initiating the cryolipolysis treatment, 50% of adipocytes by volume were killed by apoptosis A1 and 50% by necrosis A2.

[0152] Figure 6 shows exemplary body regions L1-L13 in which the kit 100 or device 10 for percutaneous cryolipolysis according to the present invention can be used (L1: face, especially cheeks; L2: chin; L3: neck; L4: chest; L5: arms; L6: abdomen; L7: waist; L8: thighs; L9: calves; L10: ankles; L11: upper back, shoulders; L12: lower back; L13: buttocks). The kit 100 and / or device 10, 10A may be adjusted or adapted according to the region of percutaneous cryolipolysis, a particularly suitable needle assembly 11 may be selected, and / or suitable cooling parameters, particularly the cooling temperature, may be adjusted and / or set, preferably over time.

[0153] Figure 7 is a side view of a third example of device 10B for percutaneous cryolipolysis according to the present invention, which has a pistol shape and is not a longitudinal device, and does not have a longitudinal body 13. However, this device 10B also has an adapter 19. The size of the cryoneadhesive 12 is larger than that of devices 10 and 10A in Figures 1 and 2. The flow of cryofluid can be controlled by a lever 23. This device can process particularly large amounts of subcutaneous adipose tissue A in, for example, body region L6 (abdomen), body region L8 (thigh), and / or body region L13 (buttocks). However, this device 10B, 20 is less precise than devices 10 and 10A in Figures 1 and 2.

[0154] Figure 8 is a perspective view of a fourth example of device 10C for percutaneous cryolipolysis according to the present invention, which is tubeless and comprises a single 0.25L cartridge 24 filled with cryo-gas, in this case N2O. A counterweight 26 is incorporated within the body 13 to achieve good balanced handling. Device 10C further comprises an end stop 25 on the needle hub to prevent over-insertion. Device 27 further comprises status LEDs and indicator means for displaying one or more cooling parameters such as tissue cooling temperature, outer needle temperature and / or cooling time.

[0155] Figure 9 shows another enlarged schematic diagram of a further exemplary design within the cooling area at the tip of the cryoneedle shown in Figures 1-4, in which the device is equipped with a temperature sensor 29 in the needle tip area, in addition to the device shown in Figure 5. Furthermore, the device shown in Figure 9 is configured to allow for precise adjustment and control of the needle surface temperature TN on the outer surface of the needle, in particular in 1°C increments within a range of +4°C to -25°C, and the application time / cooling time in 20-second increments within a range of 10 seconds to 15 minutes, depending on the specific needs of different treatments, for example, to achieve a defined desired cell death ratio of approximately 78:12 (cells killed by apoptosis:cells killed by necrosis).

[0156] Figure 10 shows bright-field microscopy images of experimental results after exposure to adipocytes prepared by the defined method (differentiated from pre-adipocytes to mature adipocytes within 14 days under defined conditions), with most images taken 12 hours after the end of treatment.

[0157] The image in the upper left shows the first control sample of mature adipocytes prepared as described above, which was treated at 37°C for 10 minutes instead of undergoing defined cooling, and the image was taken 12 hours after the end of treatment.

[0158] The image in the upper center shows a second control sample of mature adipocytes prepared as described above, treated for 10 minutes with staurosporine (a chemical structure capable of initiating or inducing apoptosis in a defined manner in various cell types). The image was taken 16 hours after the end of treatment.

[0159] The image in the upper right shows a sample of mature adipocytes prepared as described above, which underwent a defined cooling period of +4°C for 10 minutes. The image was taken 12 hours after the end of treatment.

[0160] To cool the cells in a defined manner, each cell was supplied in a defined state within a special cell culture carrier, in this case a plastic so-called "multiwell plate" well-known from the prior art. Each cell culture carrier containing the cells was placed on a cooling plate for a desired defined cooling time, and the surface of the cooling plate was cooled to a desired defined cooling temperature.

[0161] The image in the lower left shows a sample of mature adipocytes prepared as described above, which underwent a defined cooling period of +0°C for 10 minutes. The image was taken 12 hours after the end of treatment.

[0162] The image in the lower center shows a sample of mature adipocytes prepared as described above, which underwent a defined cooling period of -20°C for 10 minutes and was taken 12 hours after the end of treatment.

[0163] The image in the lower right shows a sample of mature adipocytes prepared as described above, which underwent a defined cooling period of -80°C for 10 minutes. The image was taken 12 hours after the end of treatment.

[0164] Figure 11 shows fluorescence imaging analysis of the cell nuclei of blue-stained preadipocytes from different samples to which the same defined cooling as described in Figure 10 had been previously applied.

[0165] The leftmost image shows the fluorescence image of the first control sample. The image to the right (labeled STS) shows the second sample treated with staurosporine. The next image to the right shows the stained cell nuclei of a sample treated at +4°C for 10 minutes. The next image to the right shows the stained cell nuclei of a sample treated at +0°C for 10 minutes. The next image to the right shows the stained cell nuclei of a sample treated at -20°C for 10 minutes, and the next image to the right shows the stained cell nuclei of a sample treated at -80°C for 10 minutes.

[0166] The lower the applied temperature, i.e., the greater the amount of cooling applied, the more preadipocytes were killed, resulting in a smaller number of cells. At -80°C, all cells died, and any released cells were washed away.

[0167] Figure 12 shows the number of nuclei as a result of fluorescence image analysis of the preadipocytes shown in Figure 11, depending on the cooling temperature to which the cells were exposed.

[0168] This figure clearly shows that the lower the applied temperature, i.e., the greater the amount of cooling applied, the more pleadiocytes are killed and the greater the reduction in cell number. At -80°C, all cells died, and any freed cells were washed away. Cell viability (cell number) may decrease linearly with decreasing applied cooling temperature. Controlled cell death can be achieved in the temperature range from +4°C to -20°C, especially in the 0°C to -20°C range.

[0169] Figures 13 and 14 show the results of lactate dehydrogenase (LDH) assay tests performed to evaluate the cytotoxicity of temperature treatments applied to adipocytes under different conditions. In these tests, mature adipocytes prepared as described above were used and analyzed by LDH assays as is commonly known.

[0170] LDH assays are biochemical assays used to quantify the activity of the enzyme lactate dehydrogenase (LDH) in various biological samples, including blood, serum, plasma, and cell cultures. A characteristic feature of this type of assay is that LDH is released extracellularly when cells are damaged or lysed. The amount of released LDH can be detected, and the determined LDH level can serve as a marker of cell death or cytotoxicity.

[0171] Figures 13 and 14 show the response results of different samples of adipocytes exposed to different conditions. Figure 13 shows the resulting cell response after cells were stored in an incubator for 4 hours following a defined (cooling) treatment. Figure 14 shows the resulting cell response after cells were stored in an incubator for 24 hours following the (cooling) treatment.

[0172] The samples labeled “ctrl.I,” “ctrl.II,” and “ctrl.III” are control samples, with the first control sample, “ctrl.I,” being the corresponding positive control sample related to the assay. It was analyzed solely to check the functionality of the assay kit but was not subjected to defined temperatures and / or cooling.

[0173] Control sample II ("ctrl.II") was exposed to a temperature of 37°C, i.e., body temperature, for 15 minutes and was therefore not subjected to cooling.

[0174] To prevent the sample from freezing during cooling and losing the functionality of the assay, the adiposites being cooled in the test needed to be preserved, and a 35% glycerol solution was used for this purpose. The behavior of adiposites preserved in 35% glycerol after exposure to 37°C for 15 minutes is shown by the results for control sample III ("ctrl.III").

[0175] Samples marked 4°C* were stored in 35% glycerol and exposed to +4°C for 15 minutes; samples marked 0°C* were stored in 35% glycerol and exposed to 0°C for 15 minutes; and samples marked -20°C* were stored in 35% glycerol and exposed to -20°C for 15 minutes.

[0176] Consistent with the results mentioned above, cytotoxicity, the inverse of cell viability, decreases with increasing cooling or decreasing cooling temperature. Furthermore, the experimental data shows that cytotoxicity increased even further after being left in the incubator for more than 20 hours (i.e., after 24 hours compared to 4 hours of storage in the incubator) without any additional cooling treatment. This indicates that, at the very least, the additional cells that died during the additional 20 hours of storage in the incubator died due to apoptosis, which generally occurs with a time delay after the event that causes cell death, and not due to necrosis, which generally occurs immediately after the event that causes cell death.

[0177] Cooling temperatures ranging from +4°C to -25°C, particularly 0°C to -20°C, applied to adipocytes and / or preadipocytes, appear suitable for initiating controlled apoptosis in each cell. By varying the cooling temperature and / or cooling time, the cooling energy introduced into the cells / tissues can be controlled.

[0178] If there is no insulating material between the cells and the cooling surface, for example, if there is no cell culture carrier plastic material, it will result in direct contact between the cells (adipocytes and / or preadipocytes) and the cooling surface, for example, direct contact with the outer surface of the cryoneed needle (needle cooling surface), which may require less cooling energy, and in particular, may result in higher temperatures and / or shorter application (cooling) times.

[0179] These results also indicate that adipocytes do not respond as strongly to staurosporine and / or LDH assay tests as other cell types. This highlights the specific nature of adipocytes, which are particularly incomparable to tumor cells, and therefore require different treatments to initiate controlled cell death, especially apoptosis.

[0180] Further examples are described below. Example 1 (face):

[0181] In a first example of percutaneous cryolipolysis of the facial, particularly subcutaneous adipose tissue of the cheek, the device 10 according to the present invention is used, first a suitable needle assembly 11 is selected and attached to the main body. CO2 is used as the cryofluid, and a cryofluid source containing CO2 is coupled to the main body. The cryofluid container 15 may also be replaced. In the next step, cryolipolysis parameters are set, and the needle cooling temperature (temperature of the outer cooling needle surface in the cooling area P1) is adjusted to -10°C for a cooling time of 2 minutes in order to initiate sufficient apoptosis A1 and necrosis A2. In particular, the A1 / A2 ratio is adjusted to 1:1, and the volume is 3 cm³. 3 A cooling zone (CZ) is established. Next, the patient is prepared. After cleaning and disinfecting the skin surface, especially around the cheek area, a local anesthetic cream containing lidocaine is applied. After the device is set up, the skin is sterilized in the puncture zone. In the next step, the skin is punctured with the cryoneadil 12, which is placed in the subcutaneous tissue beneath the skin along with its needle cooling area. Once the needle is in place, the cooling process can be initiated by starting a cooling flow through the cryoneadil 12 as adjusted. After 2 minutes, the cryolipolysis cycle is complete, and the needle 12 is removed from the tissue. At least several steps can be repeated to confirm the success of the treatment. Example 2 (abdomen):

[0182] In a second example of percutaneous cryolipolysis according to the present invention, device 10B is used, and first a suitable needle assembly 11 is selected and attached to the main body. Since a large amount of subcutaneous adipose tissue needs to be treated in the patient's abdomen, a needle assembly including a needle array is selected and attached to the main body. CO2 is used as the cryofluid, and a cryofluid source 15 containing CO2 is attached to the main body. Cryolipolysis parameters are set, and the needle cooling temperature (temperature of the outer cooling needle surface in the cooling area P1) is adjusted to -40°C for a cooling time of 3 minutes in order to initiate sufficient apoptosis A1 and necrosis A2. In particular, the A1 / A2 ratio is adjusted to 1:1, and the volume is 7.5 cm³. 3 A cooling zone (CZ) is established. Next, the patient is prepared. After washing and disinfecting the skin surface, a local anesthetic cream containing lidocaine is applied. In the next step, the skin is punctured with a cryoneadil 12, which is positioned in the subcutaneous tissue beneath the skin along with its needle cooling area. Once the needle is in place, the cooling process can be initiated by starting a cooling flow through the cryoneadil 12 as adjusted. After 3 minutes, the cryolipolysis cycle is complete, and the needle 12 is removed from the tissue. At least several steps can be repeated to confirm the success of the treatment.

[0183] All features described herein in relation to one aspect of the present invention can be implemented, individually or in combination, in any other aspect of the present invention to any other subject, to the extent that it is technically possible. [Explanation of symbols]

[0184] 10, 10A, 10B, 10C Device for transcutaneous cryolipolysis according to the present invention 100 Kit for percutaneous cryolipolysis according to the present invention 11 Needle Assembly 12 Cryo Needles 12A Lumen for directing cold cryofluid towards the needle tip 12B Lumen for cryofluid backflow 13. The main body of the device 14. Cryofluid supply and backflow hose 15. Cryofluid source (cryofluid container, etc.) 16 Control Unit 17. Operating elements for controlling cryo-application parameters 18. Supply Connector 19 Adapters 20 Needle Hub 21 Closed needle tip 22 Thermal insulating materials 23. Lever for controlling cryofluid flow 24 Cartridges filled with cryofluid 25 End stop for limiting penetration depth 26 Counterweights 27 Status LEDs 28 displays 29. Temperature sensor for detecting needle cooling temperature A. Adipocytes (fat cells) A1 Adipocytes (fat cells) that have died by apoptosis in the cooling zone. A2 Adipocytes (fat cells) that have died due to necrosis within the cooling zone. CZ (Cold Zone) - Subcutaneous Cooling Zone ("Ice Ball") D1 outer dermal layer D2 Inner dermal layer F Subcutaneous layer of body adipose tissue G Cryofluid Flow G1 Cooling flow of cryofluid G2 Cryofluid backflow M Body tissue (muscles, etc.) L1...L13 Possible body parts for percutaneous cryolipolysis P1 Cryoneedle cooling section P2 Uncooled portion of the cryoneedle T1 First isotherm of the cooling zone (defining the boundary between the cooling zone and surrounding tissue) T2 isotherm, second isotherm T3 isotherm, the third isotherm TN needle cooling temperature (cooling temperature on the outer surface of the cooling needle)

Claims

1. A device for percutaneous cryolipolysis (10, 10A, 10B, 10C), - A main body (13) to which cryofluid sources (15, 24) can be connected, - A cryoneedle assembly (11) which is coupled to or can be coupled to the main body (13), comprising at least one cryoneedle (12), the cryoneedle assembly (11), At least one cryonedle (12) is configured to at least partially penetrate human or animal skin (D1, D2), The aforementioned devices (10, 10A, 10B, 10C) - When the cryofluid sources (15, 24) and the cryoneadl assembly (11) are coupled to the main body (13), the cryofluid (G) from the cryofluid sources (15, 24) is used to cool at least one cryoneadl (12) in at least the cryoneadl cooling area (P1), - When the cooled cryoneadil (12) penetrates at least partially the skin (D1, D2) of a human or animal, it is configured to form a subcutaneous tissue cooling zone (CZ) adjacent to the cryoneadil cooling area (P1) of the cooled cryoneadil (12), The devices (10, 10A, 10B, 10C) are configured to cool the subcutaneous adipocytes (A, A1, A2) located in the tissue cooling zone (CZ) such that apoptosis (A1) and / or necrosis (A2) are initiated in at least some of the adipocytes (A, A1, A2) located in the tissue cooling zone (CZ). device.

2. The devices (10, 10A, 10B, 10C) cool the adipocytes (A, A1, A2) located in the tissue cooling zone (CZ) to at least 5 Vol. -%, 10 Vol. -%, 15 Vol. -%, 20 Vol. -%, 25 Vol. -%, 30 Vol. -%, 35 Vol. -%, 40 Vol. -%, 45 Vol. -%, 50 Vol. -%, 55 Vol. -%, 60 Vol. -%, 65 Vol. -%, 70 Vol. -%, 75 Vol. -%, 80 Vol. -%, 85 Vol. -%, 90 Vol. -%, or 95 Vol. The device (10, 10A, 10B, 10C) according to claim 1, configured to cool at least one cryonedle (12) in the cryonedle cooling area (P1) such that apoptosis (A1) is initiated for -%.

3. The devices (10, 10A, 10B, 10C) cool the adipocytes (A, A1, A2) located in the tissue cooling zone (CZ) to at least 5 Vol. -%, 10 Vol. -%, 15 Vol. -%, 20 Vol. -%, 25 Vol. -%, 30 Vol. -%, 35 Vol. -%, 40 Vol. -%, 45 Vol. -%, 50 Vol. -%, 55 Vol. -%, 60 Vol. -%, 65 Vol. -%, 70 Vol. -%, 75 Vol. -%, 80 Vol. -%, 85 Vol. -%, 90 Vol. -%, or 95 Vol. The device (10, 10A, 10B, 10C) according to claim 1, configured to cool the at least one cryonead (12) in the cryonead cooling area (P1) such that necrosis (A2) is initiated for -%.

4. The devices (10, 10A, 10B, 10C) are configured to cool at least one cryonedle (12) in the cryonedle cooling area (P1) such that apoptosis (A1) is initiated in some adipocytes located in the tissue cooling zone (CZ), and necrosis (A2) is initiated in some adipocytes (A, A1, A2) located in the tissue cooling zone (CZ), in particular the tissue cooling zone (CZ) where necrosis (A2) is initiated. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 3, wherein the ratio (A1:A2) of the volume of adipocytes (A, A1, A2) located in the tissue cooling zone (CZ) where apoptosis (A1) is initiated to the volume of adipocytes (A, A1, A2) located in the CZ is in the range of 0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 to 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.

1.

5. The devices (10, 10A, 10B, 10C) are designed such that the subcutaneous tissue (F) in the formed tissue cooling zone (CZ) is cooled to at least +10°C, +5°C, +4°C, +3°C, +2°C, +1°C, or 0°C, but not to below -50°C, -40°C, -30°C, -20°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, or -1°C, according to the cryony The device (10, 10A, 10B, 10C) according to any one of claims 1 to 4, configured to cool the at least one cryonedle (12) in a cryonil cooling area (P1), such that the subcutaneous tissue (F) in the tissue cooling zone (CZ) is cooled to a tissue temperature (T1, T2, T3) preferably in the range of -50°C to +10°C, -40°C to +5°C, -30°C to 0°C, or -20°C to -5°C.

6. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 5, wherein at least one cryonead (12) comprises a thermal insulator (22) and / or a thermal insulating material (22), or is made at least partially of a thermal insulating material (22).

7. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 6, wherein the device (10, 10A, 10B, 10C) comprises a valve for controlling and particularly restricting the cooling flow (G) of the cryofluid in and / or through at least one cryoneadil (12).

8. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 7, wherein the device (10, 10A, 10B, 10C) is a handheld device (10, 10A, 10B, 10C).

9. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 8, wherein the main body (13) can be coupled to a stationary cryofluid storage unit (15) as a cryofluid source (15), preferably CO2, N2, N2O, or a combination thereof, particularly via at least one supply line (14).

10. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 9, wherein the cryoneedle assembly (11) is interchangeably and detachably coupled to or can be coupled to the body (13), and in particular the body (13) and / or the cryoneedle assembly (11) are provided with an adapter (19) through which the cryoneedle assembly (11) and the body (13) are coupled to or can be coupled to each other.

11. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 10, wherein at least one cryonead (12) is a needle or cannula of 15G, 16G, 17G, 18G, 19G, 20G, 21G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G, 30G, 31G, 32G, 33G, 34G, or 35G.

12. The device (10, 10A, 10B, 10C) according to any one of claims 1 to 11, wherein the needle assembly (11) comprises at least two cryoneedle (12), in particular a group of needles (12), in particular an array of cryoneedle (12), and / or the needle assembly (11) comprises at least one microneedle, in particular at least one microneedle array.

13. The device according to any one of claims 1 to 12, comprising a control unit (16) configured to control the cooling of the cryoneadyl cooling area (P1) in order to control the cooling temperature (T1, T2, T3) in the tissue cooling zone (CZ), and in particular to control the cooling temperature in the cryoneadyl cooling area (P1).

14. A kit (100) for percutaneous cryolipolysis, - Devices (10, 10A, 10B, 10C), - A main body (13) to which cryofluid sources (15, 24) can be connected, - A cryoneedle assembly (11) which is coupled to or can be coupled to the main body (13), comprising at least one cryoneedle (12), the cryoneedle assembly (11), At least one cryonedle (12) is configured to at least partially penetrate human or animal skin (D1, D2), The aforementioned devices (10, 10A, 10B, 10C) - When the cryofluid sources (15, 24) and the cryoneadl assembly (11) are coupled to the main body (13), the cryofluid (G) from the cryofluid sources (15, 24) is used to cool at least one cryoneadl (12) in at least the cryoneadl cooling area (P1), - When the cooled cryoneadil (12) penetrates at least partially the skin (D1, D2) of a human or animal, it is configured to form a subcutaneous tissue cooling zone (CZ) adjacent to the cryoneadil cooling area (P1) of the cooled cryoneadil (12), A device (10, 10A, 10B, 10C) configured to cool the subcutaneous adipocytes (A) located in the tissue cooling zone (CZ) such that apoptosis (A1) and / or necrosis (A2) are initiated in at least some of the adipocytes (A, A1, A2) located in the tissue cooling zone (CZ), - Cryofluid source (15, 24) and A kit (100) equipped with [the following].

15. The use of a device (10, 10A, 10B, 10C) or a kit (100) configured for transcutaneous cryolipolysis for cosmetic, aesthetic, or therapeutic purposes, particularly for transcutaneous cryolipolysis, wherein the device (10, 10A, 10B, 10C) for transcutaneous cryolipolysis is - A main body (13) to which a cryofluid source (13, 24) can be connected, - A cryoneedle assembly (11) which is coupled to or can be coupled to the main body (13), comprising at least one cryoneedle (12), the cryoneedle assembly (11), At least one cryonedle (12) is configured to at least partially penetrate human or animal skin (D1, D2), The aforementioned devices (10, 10A, 10B, 10C) - When the cryofluid sources (15, 24) and the cryoneadl assembly (11) are coupled to the main body (13), the cryofluid (G) from the cryofluid sources (15, 24) is used to cool at least one cryoneadl (12) in at least the cryoneadl cooling area (P1), - When the cooled cryoneadil (12) penetrates at least partially the skin (D1, D2) of a human or animal, it is configured to form a subcutaneous (F) tissue cooling zone (CZ) adjacent to the cryoneadil cooling area (P1) of the cooled cryoneadil (12), The devices (10, 10A, 10B, 10C) are configured to cool the subcutaneous (F) adipocytes (A) located in the tissue cooling zone (CZ) such that apoptosis (A1) and / or necrosis (A2) are initiated in at least some of the adipocytes (A, A1, A2) located in the tissue cooling zone (CZ). use.

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