Cryosurgery devices and materials therefor, and methods of use thereof

Abstract

In the present disclosure, materials, devices, systems, and methods are provided for performing cryo-surgery on a mammalian subject. More specifically, a cryo-slurry and a device, system, and method for subcutaneously injecting the cryo-slurry into a subject in need of body fat reduction treatment are presented. The slurry and the device, system, and method allow for highly effective subcutaneous ice-phase-lipolysis without the need for general anesthesia on the subject and without the need for significant new surgical training among practitioners.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 307,359, filed February 7, 2022, the entire disclosure of which is hereby incorporated by reference into this specification.

[0002] The present disclosure relates to the field of surgical devices, materials, and methods. More specifically, the present disclosure provides devices, materials, and methods for performing injection-based ice-phase lipolysis. [Background technology]

[0003] Body fat reduction procedures are extremely popular and represent a significant source of revenue for physicians and medical supply manufacturers. In 2019, the American Association of Plastic Surgeons reported that over 265,000 liposuction procedures were performed (American Association of Plastic Surgeons, Cosmetic Procedure Trends https: / / www.plasticsurgery.org / documents / News / Statistics / 2020 / cosmetic-procedure-trends-2020.pdf).

[0004] Treatments for body fat include dietary changes and modifications, exercise routine modifications, nutritional supplements, drugs, and micro / macro surgeries such as lap bands, intragastric balloons, liposuction and fat removal, etc. Each of these procedures carries certain drawbacks, such as high cost to the subject, pain, discomfort, unwanted side effects, health risks, inconvenience, time consuming, and less than expected results.

[0005] As a result, there is a large unmet need for safe and effective body fat reduction treatments that are affordable to perform. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides surgical materials, surgical devices, systems, and methods of their use. More specifically, the present disclosure provides devices, materials, and methods for performing injectable ice-phase lipolysis on a mammalian subject in need thereof.

[0007] In one aspect, the present disclosure provides a cryogenic slurry for use in mammalian surgery comprising a mixture of chilled aqueous solution and ice, the aqueous solution comprising dissolved simple carbohydrates and dissolved salts. In any embodiment of the cryogenic slurry, the simple carbohydrate may comprise any monosaccharide having 3-7 carbon atoms. In some embodiments, the simple carbohydrate may comprise any monosaccharide having 6 carbon atoms. In yet another embodiment, the simple carbohydrate comprises dextrose.

[0008] In any embodiment of the low temperature slurry, the salt may comprise a biocompatible salt. In some embodiments, the salt may be a chloride salt. In some embodiments, the salt comprises sodium chloride.

[0009] In some embodiments of the cold slurry, the simple carbohydrate is dextrose and the salt is sodium chloride, both of which are present in aqueous solution and at sufficient concentrations to allow the cold slurry to be supercooled while remaining a substantially freely flowable solution.

[0010] In any embodiment involving a cold slurry, the slurry may be sterilized.

[0011] In another aspect, the present disclosure provides a surgical injection device including a container operatively connected to a surgical pump, the container being operatively connected to or further including a mixing means. The mixing means may include one or more mixing pumps or internal augers. In any embodiment of the surgical injection device, the container contains a cryogenic slurry, the cryogenic slurry including a mixture of a chilled aqueous solution and ice, the aqueous solution including dissolved simple carbohydrates and dissolved salts. In some embodiments of the surgical injection device, the surgical pump may include a peristaltic roller pump.

[0012] In any of the embodiments of the surgical injection device, the device may further include a cannula / injection needle operably connected to the surgical pump. In some embodiments, the outer diameter of the needle is 2.7 mm.

[0013] In any of the embodiments of the surgical injection device, the hopper may further include a lid that covers and closes the container.

[0014] In another aspect, the present disclosure provides a surgical injection system comprising a container configured to receive and contain a cryogenic slurry, a surgical pump operatively connected to the container, and a cannula / injection needle operatively connected to the surgical pump, the cryogenic slurry comprising a chilled aqueous solution and ice, the aqueous solution comprising dissolved monosaccharides and dissolved salts. In any embodiment of the system, the container may comprise a mixing funnel. In any embodiment, the mixing funnel may comprise an upper portion and a lower tip. In such an embodiment, the mixing funnel may comprise one or more hook-ups for tubing at the upper portion. The mixing funnel is fluidly coupled to one or more mixing pumps to circulate and maintain the liquid to ice ratio and / or components of the cryogenic slurry.

[0015] In some embodiments of the surgical injection system, the monosaccharide is dextrose and the salt is sodium chloride. In some embodiments, the system is capable of operating effectively at supercooled temperatures. In some embodiments, the cryogenic slurry is at a temperature low enough to cause ice-phase lipolysis when contacted with living mammalian adipocytes upon injection.

[0016] In any of the embodiments of the surgical injection system, the container may be stored refrigerated. In some embodiments, the container may be refrigerated at about 0° C. Any of the embodiments of the surgical injection system may further comprise a holding chamber. In any of the embodiments, the holding chamber may be refrigerated. In some embodiments, the holding chamber may be refrigerated at about 0° C. The holding chamber may be configured to receive and hold a batch of the solution and / or a batch of the cold slurry. In some embodiments, the holding chamber may include one or more containers having sidewalls that include a Teflon material.

[0017] In another aspect, the disclosure provides a method of inducing ice-phase lipolysis by injection in a mammalian subject, the method comprising subcutaneously injecting a cold slurry comprising a mixture of chilled aqueous solution and ice, the aqueous solution comprising dissolved simple carbohydrates and dissolved salts, such that the slurry is in close proximity to adipocytes that are to be ice-phase lipolysis.

[0018] In some embodiments, the dissolved simple carbohydrate comprises dextrose and the dissolved salt comprises sodium chloride.

[0019] In any of the embodiments of the method, the method can be carried out using the devices and systems provided in the present disclosure. In any of the embodiments of the method, the method can be carried out using sterilized equipment and materials and aseptic techniques. [Brief description of the drawings]

[0020] Certain embodiments are herein described, by way of example only, with reference to the accompanying figures, in which it is emphasized that the specific matter shown is by way of example and is for the purpose of illustrating the embodiments, and in which, when read in conjunction with the drawings, it will become apparent to those skilled in the art how the embodiments may be practiced.

[0021] It will be readily understood from the context that certain terms or symbols may be interchangeable or synonymous, for example, a diagram showing an element labeled "jar" may also refer to a technical feature of the device of the present disclosure that may be described herein as a "hopper."

[0022] [Figure 1] FIG. 1 is a schematic diagram of an embodiment of a surgical device and system of the present invention. The device embodiment shown in the schematic diagram includes a "holding chamber" for maintaining one or more batches of slurry at a low operating temperature, e.g., 0° C., a mixing chamber that can accommodate a mixing means such as an auger for receiving and mixing a new batch of spent slurry, a cooling chamber surrounding the mixing chamber, a roller pump for advancing the slurry through tubing to an injection needle opening / cannula, and a cannula / needle configured for subcutaneous insertion into a surgical subject. The inclusion of a "holding chamber" along with the "mixing chamber" allows for a batch of slurry to be kept cooled while simultaneously mixing other batches of slurry. Using the embodiment of FIG. 1, each batch of slurry can take approximately 50 minutes to produce. [Diagram 2] 2 is a photograph of a mock-up of an embodiment of the surgical device and system of the present invention. The diagram (photograph) shows a container with a mixing means, such as an auger, operatively connected to an auger motor, which feeds into a tube that is operatively connected to a roller pump, which delivers the slurry through the tube and towards an injection needle / cannula to deliver a subcutaneous injection to a surgical subject. [Figure 3A]3A-3C are photographs showing steps in a method using an embodiment of the surgical device and system of the present invention. FIG. 3A is a photograph showing the insertion of an auger into a container. The auger rotates, for example driven by an electric motor, to mix the ice slurry in the jar and maintain the slurry in a quasi-liquid state, preventing the slurry from separating into ice and liquid. FIG. 3B is a photograph showing the container filled with sterilized ice slurry. FIG. 3C is a photograph showing the container being covered and sealed with a lid. [Figure 3B] 3A-3C are photographs showing steps in a method using an embodiment of the surgical device and system of the present invention. FIG. 3A is a photograph showing the insertion of an auger into a container. The auger rotates, driven, for example, by an electric motor, to mix the ice slurry in the jar and keep it in a quasi-liquid state, preventing the slurry from separating into ice and liquid. FIG. 3B is a photograph showing the container filled with sterilized ice slurry. FIG. 3C is a photograph showing the container being covered and sealed with a lid. [Figure 3C] 3A-3C are photographs showing steps in a method using an embodiment of the surgical device and system of the present invention. FIG. 3A is a photograph showing the insertion of an auger into a container. The auger rotates, driven, for example, by an electric motor, to mix the ice slurry in the jar and keep it in a quasi-liquid state, preventing the slurry from separating into ice and liquid. FIG. 3B is a photograph showing the container filled with sterilized ice slurry. FIG. 3C is a photograph showing the container being covered and sealed with a lid. [Figure 4A] Figures 4A-4B are photographs showing subcutaneous adipose tissue from the lower abdomen excised from a subject using the method of the present invention. Figure 4A shows excised untreated negative control adipose tissue. Figure 4B shows excised adipose tissue treated with 300cc-500cc of sterile ice slurry at about 0°C. [Figure 4B]Figures 4A-4B are photographs showing subcutaneous adipose tissue from the lower abdomen excised from a subject using the method of the present invention. Figure 4A shows excised untreated negative control adipose tissue. Figure 4B shows excised adipose tissue that was treated with 300cc-500cc of sterilized ice slurry at about 0°C. [Figure 5A] 5A-5B are exemplary perspective views of an injection device according to the present disclosure. Fig. 5A shows a view of an embodiment of the injection device without a touch screen. Fig. 5B shows a view of an alternative embodiment of the injection device with an interactive touch screen. [Figure 5B] 5A-5B are exemplary perspective views of an injection device according to the present disclosure. Fig. 5A shows a view of an embodiment of the injection device without a touch screen. Fig. 5B shows a view of an alternative embodiment of the injection device with an interactive touch screen. [Figure 6] 6 is an exemplary cross-sectional view of an injection device according to the present disclosure. Exemplary embodiments such as those shown in FIG. 6 are described in further detail in the Examples below. [Figure 7] FIG. 7 is an exemplary diagram showing a qualified medical practitioner pouring a slurry containing dissolved simple carbohydrates and dissolved salts into the mixing funnel of an exemplary embodiment of the disclosed apparatus and system (such as the apparatus shown in FIG. 6). The slurry may be prepared from a premixed aqueous solution by a third party manufacturer and supplied and stored in a liquid phase and under sterile conditions. The qualified medical practitioner may pour the solution into a receptacle of the disclosed apparatus and system or an accessory device that cools the solution and mixes it with ice, creating a slurry of, for example, about 60 percent solution and 40 percent solid ice. The disclosed apparatus and system may maintain the slurry at the proper temperature and composition, for example, by a cooling system and an auger mechanism. [Figure 8]8 shows an exemplary diagram of an embodiment of a mixing funnel for use in embodiments of the disclosed device and system. The illustrated mixing funnel is provided with three tube outlets that can be connected to tubing. The tubing can be in fluid communication with, for example, a mixing pump. The tubing can be in fluid communication with an outlet pump and can also be in fluid communication with a cannula or injection needle used to introduce the slurry into the subject's body. [Figure 9] 9 illustrates an exemplary embodiment of a holding chamber of an embodiment of the device and system of the present disclosure. The holding chamber may hold an aqueous solution and / or a slurry, or may hold one or more containers containing an aqueous solution and / or a slurry. The holding chamber may cool its contents, for example, to maintain aqueous solutions at low temperatures for storage or to maintain slurries at freezing temperatures to maintain ice content or consistency. [Figure 10] FIG. 10 is an exemplary diagram of an apparatus that can be used to prepare an ice slurry from a liquid aqueous solution. [Figure 11] FIG. 11 illustrates an exemplary embodiment of a reusable canister for holding and supplying ice slurry to the devices and systems of the present disclosure. [Figure 12] FIG. 12 is an overhead photograph of an exemplary cannula / injection needle that can be used to surgically inject an ice slurry into a subject's body after an incision is made. [Figure 13] FIG. 13 is a perspective view of an exemplary disposable sterile tube that can be used with the methods, systems, and devices of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The inventions described herein include surgical materials, surgical devices, surgical materials, and methods of use thereof. More specifically, the present disclosure provides devices, materials, systems, and methods for performing injectable ice-phase lipolysis in a mammalian subject in need thereof.

[0024] Body fat reduction procedures such as traditional liposuction are very popular, with surgeons performing approximately 265,000 liposuction procedures per year in recent years. Most liposuction procedures are performed under general anesthesia, which entails significant costs, equipment and staff complexity, and medical risks compared to local anesthesia methods, such as tumescent anesthesia. General anesthesia is the most dangerous aspect of surgery. A 2009 study found that approximately 1 in every 10,000 surgical subjects who received general anesthesia died from general anesthesia-related complications. See Leandro Gobbo Braz et al., "Mortality in Anesthesia: A Systematic Review," CLINICS 2009;64(10)999-1006 (2009). In other words, traditional liposuction carries all the risks and costs associated with any invasive surgery.

[0025] Meanwhile, non-surgical approaches have emerged that target the specific physical properties of lipids to selectively destroy fat as an alternative to traditional liposuction. Techniques in this field of technology include ultrasound, radio frequency, and laser-based devices (see, for example, Zocchi M., "Clinical Aspects of Ultrasonic Liposculpture," SEMIN PLAST SURG 1993 7(2):153-72). Since about 2010, cryolipolysis, which emerged from the observation that fatty tissues are more susceptible to cold injury than lean tissues, has become the most popular minimally invasive, or "non-invasive," alternative cosmetic surgery (see, for example, Zelickson B. et al., (2009) "Cryolipolysis for Non-invasive Fat Cell Destruction: Initial Results in a Pig Model," DERMA SURG, 35(10), 1462-70). The subcutaneous fat is cooled to a temperature that causes cell death, but the dermis and the underlying muscle and connective tissue are not damaged. The treated subject's body then simply expels the dead fat cells.

[0026] "Ice-phase lipolysis" as used throughout this disclosure (unless otherwise clearly specified or implied by the context) refers to any method of reducing the temperature and deliberately targeting and killing fat cells in a living animal using ice slurry injections. "Cryolipolysis" as used throughout this disclosure (unless otherwise clearly specified or implied by the context) may refer to the achievement of low temperatures by the transdermal application of cooling to deliberately target and kill fat cells in a living animal.

[0027] Traditional cryolipolysis non-surgically induces localized fat reduction by contacting an applicator with selected areas for a pre-determined period of time, usually 30-60 minute cycles. Traditional cryolipolysis typically involves lowering the subcutaneous temperature to around 8°C over a period of about 1 hour. See Gordon H. Sasaki, MD, FACS, et al., "Localized Natural Fat Reduction and Contouring by Noninvasive Selective Cryolipolysis and Reperfusion Recovery," AESTHETIC SURG J, 34(3)420-31 (2014). However, traditional cryolipolysis has so far been less effective than liposuction. This method is time consuming and limited in terms of the location and amount of fat that can be removed from the treated body.

[0028] Thus, subjects seeking fat reduction treatment are torn between traditional liposuction (which is effective, but expensive and requires extensive expertise and general anesthesia) and traditional cryolipolysis techniques (which are less expensive and do not require general anesthesia, but are less effective). The presently disclosed ice-phase lipolysis materials, devices, systems, and methods provide a unique solution to this dilemma without requiring significant new regulatory approvals or surgeon training.

[0029] To address this long-standing unmet need, the present disclosure provides materials, systems, and methods for the subcutaneous delivery of a sterile, soft, frozen ice slurry. The present disclosure provides systems and methods that utilize ice-phase lipolysis to achieve the destruction, absorption, and evacuation of fat cells, generally for the purpose of aesthetic body contouring (although the materials, systems, and methods can also be used for other medical purposes). The materials, systems, and methods of the present disclosure allow for the introduction of the slurry into the subcutaneous space of the subject to be treated in a process similar to the placement of tumescent fluid in traditional liposuction. The melted ice slurry absorbs energy to cool nearby fat cells, causing cell death. The contents of the fat cells are then absorbed and expelled into the subject's body. Such systems of the present disclosure can be used by medical personnel to produce frozen saline for localized cooling in appropriate surgical or emergency procedures, and for the transport of transplant organs. The systems of the present disclosure do not require general anesthesia and may be employed when the subject is awake. The systems and methods of the present disclosure are expected to reduce fat in the treatment area by about 25% to about 50%.

[0030] The present invention provides a cryo-slurry that can be gently injected under the dermis of a locally anesthetized treatment subject. The present disclosure further provides devices, systems, and methods for injecting the cryo-slurry to induce body fat loss. In 2021, the first pilot study was published concluding that subcutaneous ice slurry injection is feasible and observed a safety and tolerability profile comparable to local cryolipolysis (Kandula P. et al., Injection-Based Cryolipolysis: First-in-Human Study, PLAST RECONSTR SURG GLOB OPEN 2021, 9(9):e3818). The phase change of subcutaneously injected ice slurry can induce ice-phase lipolysis and is selective to the injection site. No significant changes were observed at the control site. Thus, the disclosed invention allows for deeper and more effective fat reduction than conventional cryolipolysis methods without the need for general anesthesia and without the need for extensive regulatory approval or practitioner training, as the disclosed method is within the routine training and knowledge and skill of most plastic surgeons. Additionally, the present invention allows for the treatment of difficult to reach areas within the subject's body.

[0031] The disclosed system and method can be employed to treat any localized subcutaneous fat deposit for aesthetic body contouring or other predetermined medical purposes. Examples of areas on the subject's body include the chin, arms, chest, abdomen, flanks, torso, back, thighs, and legs. No specific body mass index (BMI) or requirements are stated for use of the disclosed system and method. Treatment using the disclosed system and method is expected to take about 10 to about 20 minutes. The subject's body area that is initially treated can be treated again as desired. For example, a subject may treat the thighs and then re-treat the same area several months later.

[0032] In one aspect, the present disclosure provides a cold slurry for use in mammalian surgery comprising a mixture of chilled aqueous solution and ice, the aqueous solution comprising dissolved simple carbohydrates and dissolved salts.

[0033] In any embodiment of the cold slurry, the simple carbohydrate may include any monosaccharide having 3-7 carbon atoms. In some embodiments, the simple carbohydrate may include any monosaccharide having 6 carbon atoms. In yet other embodiments, the simple carbohydrate comprises dextrose.

[0034] In any embodiment of the low temperature slurry, the salt may comprise a biocompatible salt. In some embodiments, the salt may be a chloride salt. In some embodiments, the salt comprises sodium chloride.

[0035] Although internal cryolysis has been employed to treat tumors and other pathologies, such methods are not suitable for fat-specific treatments because the local temperature is significantly lower than 0°C. As mentioned above, the conventional cryolipolysis method, which involves applying low temperatures to the surface of the skin of the treatment subject, has been used since around 2010. Meanwhile, other groups have experimented with subcutaneous ice-phase lipolysis, but using ice slurries at -4.8°C to -3.5°C containing 0.9% sodium chloride and 10% glycerol. Based on knowledge and belief, as of January 2022, the U.S. Food and Drug Administration has approved only small amounts (i.e., less than 500 mg) of glycerol for subcutaneous injection. On the other hand, dextrose-sodium chloride solutions have been proven safe and have been used for subcutaneous injection procedures for decades. For example, subcutaneous injection of dextrose-sodium chloride solutions is required to rehydrate treatment subjects who have experienced acute dehydration. See, e.g., Paula A. Rochon et al., "A Systematic Review of the Evidence for Subcutaneous Injections to Treat Dehydration in the Elderly," J GERONTOL A, May 1997, 52(3):M169-76; and Tari Turner and Anne-Marie Cassano, "Subcutaneous Dextrose for Rehydration of Elderly Subjects-An Evidence-Based Review," BMC GERIATR 2004:4(2). The present disclosure provides a new and surprising improvement in that dextrose-sodium chloride solutions can be used to form safe and effective cold slurries.

[0036] In some embodiments of the cold slurry, the simple carbohydrate is dextrose and the salt is sodium chloride, both in aqueous solutions and at sufficient concentrations that the cold slurry is super-chilled (i.e., below 0° C.) while remaining a substantially freely flowable solution.

[0037] The cold slurry may include about 5% by weight ice, about 10% by weight ice, about 15% by weight ice, about 20% by weight ice, about 25% by weight ice, about 30% by weight ice, about 35% by weight ice, about 40% by weight ice, about 45% by weight ice, about 50% by weight ice, about 55% by weight ice, about 60% by weight ice, about 65% by weight ice, about 70% by weight ice. The cold slurry may include about 5% by volume ice, about 10% by volume ice, about 15% by volume ice, about 20% by volume ice, about 25% by volume ice, about 30% by volume ice, about 35% by volume ice, about 40% by volume ice, about 45% by volume ice, about 50% by volume ice, about 55% by volume ice, about 60% by volume ice, about 65% by volume ice, about 70% by volume ice. In some embodiments, the slurry contains about 40% ice by weight. By adjusting the ice to liquid ratio, any viscosity or latent heat of phase change can be achieved.

[0038] In any embodiment of the cold slurry, the slurry may be sterile. The liquid components of the cold slurry are manufactured under sterile conditions, sealed in sterile containers, and opened by medical personnel at and / or near the time of treatment. Similarly, any equipment, containers, surfaces, tubing, gloves, and / or skin that the cold slurry comes into contact with may also be sterile.

[0039] In one embodiment, the slurry comprises an aqueous solution of 12.2% dextrose and 0.18% sodium chloride in sterile water. In one embodiment, the slurry may not contain any drugs added to the slurry solution. Such a solution may be transformed into about 40% soft frozen ice slurry. The system of the present disclosure is employed to mix ice and about 60% liquid aqueous solution.

[0040] In another aspect, the present disclosure provides a surgical injection device comprising a container operatively connected to a surgical pump, the container operatively connected to a mixing means. In any embodiment, the container contains a cold slurry comprising a mixture of an aqueous liquid and ice, the aqueous solution may include a monosaccharide and a salt, the monosaccharide may be dextrose, and the salt may be sodium chloride. In one embodiment, the container may receive and contain a cold slurry comprising an aqueous solution of 12.2% dextrose and 0.18% sodium chloride in sterile water. In some embodiments, the slurry may not include a drug added to the slurry solution. The slurry may be a soft frozen ice slurry comprising about 40% ice and about 60% liquid aqueous solution.

[0041] In any embodiment of the surgical injection device, the container may include a bucket, bowl, pouch, screw-top container, or mixing funnel. The container may be open-topped, have a sealable lid, or may be permanently or semi-permanently sealed and have a fill valve. The container may be made of any suitable material. The container may be substantially rigid or substantially non-rigid. The container may be reusable, partially reusable, disposable, or partially disposable. The mixing means may include one or more mixing pumps or may include an auger. The mixing pump may be fluidly coupled to the container by tubing, and the pump may keep the slurry circulating and / or agitating to prevent the slurry from solidifying, thereby maintaining a desired liquid-to-ice ratio and consistency. In an embodiment having an auger, the auger rotates at a sufficient speed to agitate and continuously mix the cryogenic slurry, thereby allowing the slurry to be properly pumped. In some embodiments of the surgical injection device, the surgical pump may include a peristaltic roller pump.

[0042] In an exemplary embodiment, the surgical injection device may include components such as a main unit including a mixing chamber (mixing funnel, mixing pump head), output lines, treatment lines, mix funnel storage drawer, foot pedal, and holding chamber (FIG. 5A), as well as an optional electronic user interface, such as a touch screen (FIG. 5B). Specifically, the mixing chamber houses the funnel, mixing pump head, and output lines (FIG. 6). The funnel unit is a custom-designed, sterile, disposable mixing bag that can be connected to three tubes. Two tube lines pass through two peristaltic pumps (mixing pump heads) and one tube line passes through the output pump head, where the slurry solution pumps the slurry into the funnel unit (FIG. 8). The optional touch screen (FIG. 5B) is a user control interface for controlling the speed of the mixing pump and the output pump, and the foot pedal switches the output pump on and off. The holding chamber holds 6-12 liters of the slurry in a reusable sterile canister (FIGS. 9, 11). The aqueous solution used to form the slush (illustratively containing dextrose and sodium chloride) may be manufactured by a third party and provided to the end user. Upon addition of the sterile aqueous solution to the device, the device produces a soft, injectable frozen ice slurry for use in phase change lipolysis treatment (FIG. 7).

[0043] As previously mentioned, an exemplary embodiment includes a reusable canister (FIG. 11) that is filled with a sterile aqueous solution (e.g., including dextrose and sodium chloride). The canister may be filled and sealed at an off-site manufacturing facility or on-site at the same facility as the treatment site. The reusable canister and its contents may be stored at room temperature or above freezing temperatures, such as refrigeration. The canister may be opened / unsealed at or near the time and / or treatment site. The sterile aqueous solution may be converted to a low temperature ice slurry at the treatment site using a freezer. The freezer is a component of the surgical injection device that is fluidly coupled to the device's container, whereby the freezer freezes the aqueous solution into a soft frozen ice slurry and delivers the slurry to the surgical injection device container. Alternatively, the freezer is located external to the injection device, the freezer freezes the sterile aqueous solution, and the output sterile soft frozen ice slurry is manually transferred to the device's funnel unit (sterile disposable mixing bag) using procedures accepted in a sterile operating room (FIG. 7). The funnel unit may be manufactured according to a unique design compatible with the devices and systems of the present disclosure. In an exemplary embodiment, the funnel unit is connected to an output pump head (e.g., a peristaltic pump) via a smaller third tube (see FIG. 8). A disposable, sterile subject tube is connected between the funnel unit and a subject administration cannula (FIG. 6). The sterile cannula is used to inject the slurry into the subject. The surgical injection device maintains the temperature of the sterile slurry until it is injected (FIG. 7). (Once the slurry is injected into the subject, it melts, so there is no need to control the temperature of the slurry at this point.) This device may consist of a cannula / injection needle (FIG. 12) and a disposable tube (FIG. 13).

[0044] In any embodiment of the surgical injection device, the device may further include an injection needle operably connected to the surgical pump. In some embodiments, the needle is a 2.7 mm outer diameter needle.

[0045] In any of the embodiments of the surgical injection device, the container may further include a lid that covers and closes the container.

[0046] In another aspect, the present disclosure provides a surgical injection system comprising a container configured to receive and contain a cryogenic slurry, a surgical pump operably connected to the container, and an injection needle operably connected to the surgical pump, the cryogenic slurry comprising a chilled aqueous solution and ice, the aqueous solution comprising a dissolved monosaccharide and a dissolved salt.

[0047] In some embodiments, the vessel includes a mixing funnel (see, e.g., FIG. 6). The mixing funnel may further comprise a mixing means or may be operably connected to the mixing means. The mixing means may agitate the cryogenic slurry to maintain a preferred liquid to ice ratio or consistency. In some embodiments, the mixing funnel comprises an upper tip and a lower tip. In such embodiments, the upper portion of the mixing funnel may be fluidly coupled to the mixing means by one or more connections to tubing. The mixing means may include one or more mixing pumps. In some embodiments, the mixing funnel may further comprise an internal auger.

[0048] In some embodiments of the surgical injection system, the monosaccharide is dextrose and the salt is sodium chloride. In some embodiments, the system is capable of operating effectively at supercooled temperatures. In some embodiments, the cryogenic slurry is at a temperature low enough to cause ice-phase lipolysis upon contact with live mammalian adipocytes. In some embodiments, the live adipocytes of the mammalian subject may be cooled to 10° C. or lower. In some embodiments, the slurry may comprise an aqueous solution comprising 12.2% dextrose and 0.18% sodium chloride in sterile water. In some embodiments, the slurry may be free of added drugs. In some embodiments, the slurry may be comprised of an aqueous solution comprising 12.2% dextrose and 0.18% sodium chloride in sterile water without added drugs. The slurry may be a soft frozen ice slurry comprising about 40% ice and about 60% liquid aqueous solution.

[0049] In some embodiments, the vessel may be substantially surrounded by a cooling element configured to maintain the contents of the vessel at an operating temperature of the slurry. In any embodiment, the operating temperature of the slurry is about -10°C to slightly above 0°C. In any embodiment, the operating temperature of the slurry may be about 0°C, about -5°C, about -8°C, or about -10°C.

[0050] In some embodiments, the surgical injection system may further comprise a cooling chamber or "holding chamber." The holding chamber may or may not be operably or fluidly coupled to the container. In embodiments where the holding chamber is not operably or fluidly coupled to the container, a qualified medical personnel may transfer the solution and / or slurry to the holding chamber. In embodiments where the holding chamber is operably and / or fluidly coupled to the container, the system may transfer the solution and / or slurry to and from the holding chamber via a pumping means. The holding chamber may be configured to maintain the contents at a slurry operating temperature. The holding chamber may be configured to receive and contain ice slurry from the container, and to allow the container to be emptied and ingredients introduced for preparing another batch of cold slurry. Thus, a batch of cold slurry may be maintained in the cooling chamber while another batch of ice slurry is being prepared at the same time. In some embodiments, the holding chamber may comprise one or more containers for containing the slurry canisters, the sidewalls of which may be constructed of Teflon material. In any embodiment, preparation of a batch of cold slurry may take approximately 50 minutes. In any embodiment, the operating temperature of the slurry may range from about -10° C. to slightly above 0° C. In any embodiment, the operating temperature of the slurry may be about 0° C., about -1° C., about -2° C., about -3° C., about -4° C., about -5° C., about -6° C., about -7° C., about -8° C., about -9° C., or about -10° C. In any embodiment, the operating temperature of the slurry may be just 0° C., -1° C., -2° C., -3° C., -4° C., -5° C., -6° C., -7° C., -8° C., -9° C., -10° C., or even lower.

[0051] In another aspect, the disclosure provides a method of inducing ice-phase lipolysis in a mammalian subject, the method comprising the step of subcutaneously injecting a cold slurry to bring the slurry into proximity with adipocytes to be subjected to ice-phase lipolysis, wherein the cold slurry comprises a mixture of chilled aqueous solution and ice, wherein the aqueous solution comprises dissolved simple carbohydrates and dissolved salts.

[0052] In some embodiments, the dissolved simple carbohydrate comprises dextrose and the dissolved salt comprises sodium chloride. In some embodiments, the aqueous solution comprises 12.2% dissolved dextrose and 0.18% dissolved sodium chloride by weight. In some embodiments, the cold slurry comprises 60% liquid aqueous solution and 40% ice.

[0053] In any embodiment of the method, the method may be performed using the devices and systems provided in this disclosure above. In any embodiment of the method, the method may be performed using sterilized equipment and materials and aseptic techniques.

[0054] In any embodiment of the method, the subject may be awake and not under general anesthesia. In any embodiment, the subject may be an adult (i.e., 18 years of age or older) male or female.

[0055] example

[0056] 1. Exemplary Method Protocol

[0057] In an illustrative, non-limiting example of the use of the disclosed materials, systems, and methods, a licensed medical professional administers a sterile, soft-frozen ice slurry subcutaneously to an area of ​​localized adipose tissue of a human subject using a cannula. Cell death then occurs as the fat cells cool. Over time, the slurry and cells are then absorbed and expelled from the subject's body. The protocol employed in ice-phase lipolysis is substantially the same as the first step of traditional liposuction in that both processes begin with the injection of a solution subcutaneously. In the case of liposuction, a tumescent fluid (usually containing saline, epinephrine to constrict blood vessels, and lidocaine to reduce pain) is typically injected into the subject in an amount equal to the amount of fat removed (although this may vary) (see Ingargiola M. et al., "Cold Cryolipolysis for Fat Reduction and Body Contouring: Safety and Effectiveness of Current Treatment Paradigms," PLAST AND RECONST SURG, June 2015, 135(6)1581-90).

[0058] More specifically, the exemplary procedure follows the following steps:

[0059] (1) Prepare the skin to be treated as for surgery (e.g., with betadine, chlorhexidine, etc.).

[0060] (2) A local anesthetic is injected at the insertion site. The low temperature of the sterile slurry inactivates many local sensory nerves, but some nerves, especially those that sense pressure, may remain active during the procedure. Therefore, local anesthesia is recommended.

[0061] (3) Determine the injection rate of the sterilized slurry, usually 200 mL to 400 mL per minute.

[0062] (4) The insertion site is incised and the sterile slurry is injected through the anesthetized incision using a cannula to treat the desired area. Sterile slurry is added until the treatment site is swollen and hardened areas are visible. Typically, the amount of slurry injected is about 2 liters to about 4 liters.

[0063] (5) Suture the incision as necessary and place pads to absorb any leakage from the treated body.

[0064] Following such a procedure, the subject may experience fluid drainage from the insertion site for up to several days. The subject may also experience redness, bruising, or tenderness at the insertion site for up to several weeks.

[0065] 2. Operation mode of the device

[0066] As illustrative and non-limiting examples of user operation modes for the devices and systems of the present disclosure, the device has four modes of operation: "Startup," "Standby," "Active," and "Pump Only." When a user powers on the unit, it enters startup mode during which the interactive touch screen display lights up and the cooling system activates. Touch screen buttons on the controller allow the user to toggle between the various modes.

[0067] Start-up: When the unit is powered on, the temperature approaches 0°C in start-up mode.

[0068] Standby: In standby mode, the temperature is kept at 0°C to ensure optimal treatment for the subject.

[0069] Active: In active mode, when the physician presses the foot pedal, the mix pump head in the mix chamber is activated and the output pump head (also called the "treatment target pump") is primed for use (Figure 5A).

[0070] Pump Only: In pump only mode, the output pump head (also called the treatment target pump) is primed for use (Figure 5A).

[0071] 3. Clinical pilot study

[0072] The disclosed cryogenic slurries, devices, and systems were tested in a five-person study. All materials and methods met professional and ethical standards, and full informed consent of study subjects was given for the procedures.

[0073] The subjects consisted of five adult women seeking abdominal plastic surgery, each with excess fat in the subcutaneous space of the lower abdomen. The selection of subjects currently undergoing abdominal plastic surgery allowed for the removal of skin as part of the already scheduled cosmetic surgery, even if complications arose. Additionally, abdominal plastic surgery allowed for the removal of dermal tissue for histological examination. Preoperative ultrasound was performed to assess adipose tissue.

[0074] Using the apparatus and methods described in this disclosure, a sterile ice slurry containing dextrose and sodium chloride was prepared at approximately 0° C. The slurry was placed in a container and mixed with an auger. A roller pump was then used to deliver the slurry from the container to the cannula / infusion needle.

[0075] Subjects were given local anesthesia with nitrous oxide for analgesia. A surgeon inserted an injection needle into the subcutaneous space in the right lower quadrant and injected 300cc to 500cc of sterile ice slurry into the subcutaneous space in the right lower quadrant under sterile conditions. The left lower quadrant was intentionally left untreated as a negative control.

[0076] The surgery was performed as an outpatient procedure and was well tolerated by study subjects, who were able to return home shortly after the procedure.

[0077] Tissue specimens were taken 1 to 16 weeks after the scheduled control abdominoplasty. At that time, abdominal tissue was harvested and photographed (Figures 4A-4B). Specimens from the right lower quadrant (test site) and left lower quadrant (negative control) were sent for histology. Several cellular changes were observed in the treated subjects in the study. Specifically, treated adipose tissue had higher rates of cell death and volume loss than the untreated negative control.

[0078] 4. Clinical trial proposal

[0079] The following clinical study proposals are non-limiting prospective examples.

[0080] To further evaluate the safety and efficacy of the disclosed systems and methods in the minimally invasive treatment of excess fat in the submental area, arms, chest, abdomen, flanks, torso, back, thighs, and legs, the following study protocol is proposed.

[0081] This clinical trial will be conducted in compliance with Good Clinical Practice (GCP) and other requirements for investigational devices as set forth in 21 C.FR parts 50, 54, 56, and 812, to the extent applicable. At least 30 subjects will be enrolled at at least two different clinical sites. The study endpoints are not necessarily body site dependent, as injection of the slurry into the subcutaneous space of the fat reduction device is body site independent (i.e., all body sites are administered subcutaneously).

[0082] The primary safety endpoint is the incidence of unexpected adverse effects from the device. Expected adverse effects of the device of the disclosed method and system may include redness, bruising, or tenderness. The primary evaluation endpoint is fat layer reduction. Secondary endpoints are assessed by questionnaires administered 12 weeks after treatment, which assess comfort with the procedure, satisfaction with the results, and whether or not the patient would recommend the procedure to a friend.

[0083] A usability questionnaire will also be completed by clinical investigators (i.e., physicians) to evaluate the ease of use of the device interface and associated displays.

[0084] Those skilled in the art will appreciate that various modifications can be made to the disclosed aspects and embodiments without departing from the scope of the invention, which is defined solely by the appended claims.

Claims

1. a vessel configured to contain a slurry and including mixing means configured to agitate said slurry so as to maintain a predetermined liquid to ice ratio and / or consistency; a surgical pump operably connected to the container to facilitate administration of the slurry from the container through a subject tube to the subject.

2. The mixing means includes one or more mixing tubes attached to the container at both ends; 10. The surgical injection device of claim 1, further comprising: a mixing pump coupled to each tube and configured to circulate the slurry from the container through the mixing tube, thereby providing agitation.

3. Two or more of the mixing tubes; 3. The surgical injection device of claim 2, comprising two or more mixing pumps, each pump connected to one of the tubes.

4. The surgical injection device of claim 2 , wherein each mixing pump is configured to be a peristaltic pump.

5. The container has a tapered bottom, The surgical injection device of claim 2 , wherein one end of each mixing tube is attached at a lower end to the container.

6. The surgical injection device of claim 1 , wherein the mixing means includes an auger disposed within the container.

7. The surgical injection device of claim 1 , wherein the surgical pump is configured to be a peristaltic pump.

8. 10. The surgical injection device of claim 1, further comprising an injection needle operably coupled to said surgical pump via a subject tube.

9. The surgical injection device of claim 1 , further comprising a lid for closing the container.

10. The slurry is cooled and configured to be a mixture of an aqueous solution and water; The surgical injection device of claim 1 , wherein the aqueous solution comprises a dissolved monosaccharide and a dissolved salt.

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