Abstract:
A method and device for treating tissue with temperature-sensitizing adjuvants to enhance the effects of ablation therapy. The method may comprise identifying tissue to receive ablation therapy, treating the tissue with a temperature-sensitizing agent, and activating an ablation therapy device proximate the treated tissue. The device may comprise a cryo-sensitizing adjuvant operable in association with a cryotherapy device, the cryo-sensitizing adjuvant enhancing the effectiveness of tissue destruction upon application of temperatures below 0° C.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims priority to U.S. Provisional Application Ser. No. 61/591388, filed Jan. 27, 2012, entitled CRYO SENSITIZING AGENTS TO CATHETERS FOR THE ENHANCEMENT OF CRYOTHERAPY, the entirety of which is incorporated herein by reference. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    n/a 
       FIELD OF THE INVENTION 
       [0003]    The present invention relates to a method and system for enhancing the effects of cryoablation, such as increasing lesion size and reducing damage to non-target tissue. 
       BACKGROUND OF THE INVENTION 
       [0004]    Ablation therapy is a technique that uses temperature extremes to destroy or alter body tissue, for example cryoablation (which uses freezing temperatures) and radiofrequency ablation (“RFA,” which uses heat). Such undesirable tissue may be a tumor, cardiac tissue associated with arrhythmia, or diseased tissue. Ablation catheters are typically used to perform these techniques, and may generally include a power source, an energy and/or coolant source, and one or more ablation elements (such as a Peltier cooler, a balloon through which coolant circulates, or RF electrodes). 
         [0005]    Even though ablation may be effective for treating some conditions, techniques such as cryoablation are not always the preferred mode of treatment for some diseases. However, adoption of ablation therapy by the medical community would be enhanced by improving the visualization of the “kill zone” (for example, the treatment region within the imaged iceball edge), increasing the size of the kill zone, and/or minimizing the incursion of collateral damage to non-target surrounding tissue. The effectiveness of ablation therapy is largely dependent on the ability of the physician to predict the critical isotherm (temperature at which complete cell destruction occurs) based on the imaging feedback (for example, of the edge of the iceball), and thus the outcome of ablation can vary greatly. Further, it can be difficult to destroy target tissue at the periphery of the treatment area (such as the iceball) while avoiding damage to non-target cells. 
         [0006]    In an exemplary cryoablation procedure, the cryoablation elements are placed in contact with living body tissue to be ablated, and the temperature of the device at the cryoablation element is reduced to a temperature well below 0° C. After cooling of the cryoablation element begins, the temperature of the tissue in contact with the cryoablation element reaches the phase transition temperature and begins to freeze. As more heat is extracted, the temperature of the device continues to drop and the freezing interface (iceball) begins to propagate outward from the surface of the cryoablation element farther into the tissue, and this may result in a variable temperature distribution in both the frozen and unfrozen regions of the tissue. 
         [0007]    The freezing interface continues to penetrate into the tissue until either the temperature of the cryoablation element rises (for example, when the flow of coolant within the device stops) or until the heat of the living tissue surrounding the frozen lesion reaches a steady state condition (that is, the heat becomes equal to the amount of heat removable by the cryoablation element). At this point, the frozen tissue has a temperature distribution that ranges from a low cryogenic temperature at the tissue/cryoablation element interface to the phase transition temperature on the outer edge of the frozen lesion. The temperatures in the unfrozen tissue range from the phase transition temperature at the margin of the frozen lesion to the normal body temperature. In typical cryoablation protocols, the cooling system keeps the tissue frozen for a desired period of time, and then the tissue is allowed to passively heat and thaw. Depending on the procedure, the tissue may again be frozen after thawing. The application of multiple freeze-thaw (FT) cycles has been shown to beneficially impact lesion size. However, multiple FT cycles also increases treatment time and may increase the likelihood of damaging non-target tissue. 
         [0008]    Not only do temperature variations occur at and around the treatment site, but a variety of post-freezing effects occur in tissue that must be accounted for when optimizing the effects of cryoablation. When using a cryoablation device such as a cryoprobe at sub-zero temperatures to ablate an area of tissue, the thermal effects on each cell vary depending on its distance from the cryoprobe (closer cells experiencing lower temperatures and faster freezing rates). Complete tissue destruction may occur at temperatures below approximately −40° C., and temperatures at the edge of the iceball may be around −0.5° C. Uneven cell death rates may occur between −40° C. and −0.5° C. 
         [0009]    Damage to cells from cryoablation may be by several mechanisms, including cellular, vascular, and immunological. At higher cooling rates near the cryoprobe, direct cell damage occurs due to the presence of ice crystals both within the cell and in the extracellular space within the tissue, up to a temperature of −0.5° C. At low cooling rates, the presence of extracellular ice causes solutes concentration outside the cell to rise, which in turn causes an osmotic imbalance of the cell membrane and dehydration of the cell. Vascular mechanisms of destruction may involve the shutdown of microvasculature after freezing and resultant ischemia, direct endothelial injury, thrombosis, free-radical formation, and inflammation. Immunological mechanisms of injury, such as when treating a tumor, may include the release of proteins into the blood stream. These proteins function as antigens, which may induce an immune reaction against the remaining tumor by stimulating immune cells to produce antibodies against tumor cells. Cryoablation may also increase the level of serum cytokines and induce maturation of dendritic cells, which then stimulate T-cells against the antigen. 
         [0010]    Similarly, RFA destroys tissue instantaneously at temperatures greater than 60° C., with mechanisms of cell death including protein denaturation and destruction of blood vessels. Like cryoablation, the outcome of treatment is difficult to predict, which effectiveness being a function of treatment time, treatment temperature, and distance of tissue from the treatment element. 
         [0011]    Certain chemicals have been shown to increase tissue sensitivity to temperature extremes. For example, the application of temperature-sensitizing adjuvants (“TSAs”) may increase the likelihood that cells within the periphery of the iceball that would otherwise remain viable will be destroyed by ablation treatment. These adjuvants (also referred to as “agents”) may include thermophysical adjuvants, chemotherapeutic adjuvants, cytokines or vascular-based adjuvants, and immunomodulators. Additionally, the application of low-current energy as an adjuvant may enhance the effects of cryoablation by increasing salt ion movement through the cell membrane, thereby increasing the salt imbalance occurring during freezing. 
         [0012]    Sensitizing an area of target tissue before or during cryotherapy is therefore desired because an increase amount of damage may be incurred by the target tissue at higher temperatures, thus minimizing the energy requirements of the treatment device. Further, collateral damage may be mitigated. For example, cryotreatment of the heart may have unintended adverse consequences on the lungs, phrenic nerve, and other parts of the body because of the intense cold required to treat areas of the heart such as the pulmonary veins. 
         [0013]    However, a convenient method of applying these adjuvants to target tissue in vivo is needed. For example, although adjuvants such as antifreeze proteins increase tissue sensitivity to cold, such results have been obtained after soaking excised tissue in the adjuvant, not through precise adjuvant application on living target tissue during a cryoprocedure. 
       SUMMARY OF THE INVENTION 
       [0014]    The present invention advantageously provides a method, system, and device for treating tissue with temperature-sensitizing adjuvants to enhance the effects of ablation therapy. The method may comprise identifying tissue to receive ablation therapy, treating the tissue with a temperature-sensitizing agent, and activating an ablation therapy device proximate the treated tissue. The temperature-sensitizing agent may be applied to the tissue by an applicator, the applicator being at least one of: an applicator integrated with the ablation therapy device, and an applicator integrated with a second device that is not the ablation therapy device. The ablation therapy may be at least one of: cryoablation and the ablation therapy device is a cryoablation device; radiofrequency ablation and the ablation therapy device is a radiofrequency ablation device; and combination thereof. The temperature-sensitizing agent may be a temperature-sensitizing adjuvant selected from the group consisting of thermophysical adjuvants, chemotherapeutic adjuvants, vascular adjuvants, immunomodulator adjuvants, aquaporin inhibitors and combinations thereof. 
         [0015]    The applicator may be integrated with the ablation therapy device, the applicator being at least one of an ablation element having an outer surface, the outer surface being coated with a layer of temperature-sensitizing adjuvant, a distal end of the ablation therapy device, the distal end being coated with a layer of temperature-sensitizing adjuvant, a cannula slidably disposed within a lumen of the ablation therapy device and being in fluid communication with a reservoir for containing the temperature-sensitizing adjuvant; and a spray nozzle at the distal end of the ablation therapy device and being in fluid communication with a reservoir for containing the temperature-sensitizing adjuvant. Additionally or alternatively, the applicator may be integrated with the second device, the applicator being at least one of a distal end of the second device, the distal end being coated with a layer of temperature-sensitizing adjuvant, a distal end of the second device, the distal end being in fluid communication with a reservoir for containing the temperature-sensitizing adjuvant, a hypodermic needle and syringe for containing the temperature-sensitizing adjuvant; and a spray nozzle, the nozzle being in fluid communication with a reservoir for containing the temperature-sensitizing adjuvant. 
         [0016]    The ablation element may be an expandable element, and the distal end of the device may include a plurality of indentations each sized to contain a volume of temperature-sensitizing adjuvant. Further, the ablation element may be coated with a layer of temperature-sensitizing adjuvant further includes a layer of temperature-sensitive substrate material between the ablation element and layer of temperature-sensitizing adjuvant, the layer of substrate material readily separating from the ablation element when substrate material is within a certain temperature range. Further, the distal end of the ablation therapy device may be coated with a layer of temperature-sensitizing adjuvant further includes a layer of temperature-sensitive substrate material between the ablation therapy device and layer of temperature-sensitizing adjuvant, the layer of substrate material readily separating from the ablation therapy device when the substrate material is within a certain temperature range. 
         [0017]    The temperature-sensitizing agent may be delivered either before or after the application of ablation therapy to the tissue. The temperature-sensitizing agent is an electrode, and the electrode may be operable to emit a low current energy of between approximately 100 millivolt (mV) to approximately 500 mV for less than 1 millisecond (ms). 
         [0018]    In a further embodiment, the method may comprise identifying tissue to be ablated; treating the tissue with a cryo-sensitizing formulation; and activating a cryoablation device proximate the treated tissue, at least a portion of the cryoablation device being coated with a layer of the cryo-sensitizing formulation used to treat the tissue, the cryo-sensitizing formulation being selected from the group consisting of thermophysical adjuvants, chemotherapeutic adjuvants, vascular adjuvants, immunomodulator adjuvants, aquaporin inhibitors and combinations thereof. 
         [0019]    The device may comprise a cryo-sensitizing adjuvant operable in association with a cryotherapy device, the cryo-sensitizing adjuvant enhancing the effectiveness of tissue destruction upon application of temperatures below 0° C. The cryo-sensitizing adjuvant may be applied to the tissue by an applicator, the applicator being at least one of integrated with the cryotherapy device, integrated with a second device that is not the cryotherapy device. The cryo-sensitizing adjuvant may be a cryo-sensitizing adjuvant selected from the group consisting of: thermophysical adjuvants, chemotherapeutic adjuvants, vascular adjuvants, immunomodulator adjuvants, aquaporin inhibitors and combinations thereof. Alternatively, the cryo-sensitizing adjuvant may be an electrode that emits a low current energy of between approximately 100 mV to approximately 500 mV for less than 1 ms. 
         [0020]    The applicator is integrated with the cryotherapy device, the applicator being at least one of: a treatment element having an outer surface, the outer surface being coated with a layer of cryo-sensitizing adjuvant, a distal end of the cryotherapy device, the distal end being coated with a layer of cryo-sensitizing adjuvant, a cannula slidably disposed within the cryotherapy device and being in fluid communication with a reservoir for containing the cryo-sensitizing adjuvant; and a spray nozzle located at a distal end of the cryotherapy device and being in fluid communication with a reservoir for containing the cryo-sensitizing adjuvant. Alternatively, the applicator may be integrated with the second device, the applicator being at least one of a distal end of the second device, the distal end being coated with a layer of cryo-sensitizing adjuvant, a distal end of the second device, the distal end being in fluid communication with a reservoir for containing the cryo-sensitizing adjuvant, a hypodermic needle and syringe for containing the cryo-sensitizing adjuvant, and a spray nozzle, the nozzle being in fluid communication with a reservoir for containing the cryo-sensitizing adjuvant. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0021]    A more complete understanding of the present invention, and the attendant advantages and features thereof, will be more readily understood by reference to the following detailed description when considered in conjunction with the accompanying drawings wherein: 
           [0022]      FIGS. 1A-1C  show a method and exemplary results of ablating non-treated tissue, as known in the prior art; 
           [0023]      FIGS. 2A-2D  show a method and exemplary results of ablating tissue treated with thermo-sensitizing adjuvant; 
           [0024]      FIG. 3  shows an exemplary ablation system; 
           [0025]      FIG. 4A  shows a cross-sectional view of the distal end of a device, the device including a balloon coated with a layer of temperature-sensitizing adjuvant; 
           [0026]      FIG. 4B  shows the cross-sectional view of the distal end of a device, the device including a balloon coated with a substrate layer and layer of temperature-sensitizing adjuvant; 
           [0027]      FIG. 4C  shows the cross-sectional view of the distal end of a device, the device including a balloon with a layer of porous material containing temperature-sensitizing adjuvant; 
           [0028]      FIG. 5  shows the distal end of an ablation device, the distal tip coated with a layer of temperature-sensitizing adjuvant; 
           [0029]      FIG. 6  shows the distal end of an ablation device, the distal tip having a plurality of depressions and being coated with a layer of temperature-sensitizing adjuvant; 
           [0030]      FIG. 7  shows a cross-sectional view of the distal end of an ablation device, the distal tip having a spray nozzle for the application of temperature-sensitizing adjuvant to tissue; 
           [0031]      FIG. 8  shows the distal end of an ablation device, the device having a cannula for the application of temperature-sensitizing adjuvant to tissue; 
           [0032]      FIG. 9  shows the distal end of an ablation device, the device having an electrode; 
           [0033]      FIG. 10A  shows a cross-sectional view of the distal end of an ablation device, the device having both a balloon and one or more electrodes; 
           [0034]      FIG. 10B  shows a side view of the distal end of an ablation device, the device having both a balloon and one or more electrodes; 
           [0035]      FIG. 11A  shows a first exemplary embodiment of an ablation device used in association with a second device for the application of temperature-sensitizing adjuvant to tissue; 
           [0036]      FIG. 11B  shows a second exemplary embodiment of an ablation device used in association with a second device for the application of temperature-sensitizing adjuvant to tissue; and 
           [0037]      FIG. 12  shows the distal end of an ablation device, the device having a guidewire lumen for the application of temperature-sensitizing adjuvant to tissue. 
       
    
    
       [0038]    It should be noted that the drawings are not drawn to scale. 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0039]    As used herein, the term “enhancing the effects of ablation” refers to augmenting the vascular, immunologic, and/or direct cellular effects of cryoinjury, increasing the accuracy in predicting lesion dimensions, increasing the likelihood that cells within a viability zone will be destroyed by the ablation therapy, and/or reducing collateral damage to non-target tissue. 
         [0040]    As used herein, the term “ablation zone” refers to the area of tissue that is thermally affected by the ablation therapy. The ablation zone includes a “destruction zone” (area in which substantially all cells are irreversibly damaged or destroyed) and a “viability zone” (area in which fewer than substantially all cells are destroyed, with more cells remaining viable than destroyed). The ablation zone may correspond to an iceball created during cryoablation or the area of tissue thermally affected by RFA, with the destruction zone having a temperature of approximately −40° C. and below, and the viability zone having a temperature of between approximately −40° C. and approximately 0° C. Likewise, the destruction zone of an RFA zone, the zone at which tissue coagulation may occur, has a temperature of between approximately 60° C. and approximately 100° C. 
         [0041]    As used herein, the term “distal end” refers to the distal region of an ablation device and includes one or more ablation elements (such as electrodes or balloons) and adjuvant applicator elements (such as adjuvant coatings, spray nozzles, and applicator tubes). Additionally, the term “distal end” refers to the distal region of a second device and includes adjuvant applicator elements such as hypodermic needles, swabs, adjuvant coatings, spray nozzles, and applicator tubes). The term “distalmost tip” refers to the tip of an ablation or second device (for example, a tip of a balloon catheter that extends beyond the distal end of the balloon, as shown in  FIG. 10B ). The distalmost tip includes a smaller area than the distal end of an ablation or second device. 
         [0042]    Referring now to  FIGS. 1A-1C , a method and exemplary results of ablating non-treated tissue are shown, as is known in the prior art. Cryoablation is shown in  FIGS. 1A-1C , with  FIG. 1A  depicting target tissue  10  identified for ablation (the larger outer area being non-target tissue). When the cryoablation element  12  (such as an electrode, as shown in  FIG. 1A ) of an ablation device  14  is placed in contact with target tissue  10  and activated, an iceball  16  forms. An iceball  16  substantially corresponds to the ablation zone  18  and includes two temperature zones: a destruction zone  20  closer to the cryoablation element (approximately −40° C. and below) and a viability zone  22  closer to the iceball  16  edge (approximately −40° C. to approximately 0° C.). Therefore, the lesion (the area of tissue destroyed, corresponding to the destruction zone  20 ) is smaller than the ablation zone  18  (as shown in  FIG. 1C , with the ablation zone  18  being depicted with dashed lines), which makes it difficult to accurately predict the size and/or shape of the lesion created. Additional FT cycles may be used to increase the size of the iceball  16 , but this not only makes the procedure longer, but also increases the likelihood of damage to non-target tissue. For example, the border between target and non-target tissue may lie beneath the imaged iceball  16 , making it difficult to impossible to determine whether non-target tissue is being ablated. For simplicity, the area of the ablation zone  18  and the iceball  16  area are depicted as being the same in  FIG. 1B . As shown in  FIG. 1B , the ablation device  14  is an ablation catheter having a fixed diameter, but could also be an ablation catheter having an expandable element such as a balloon (as shown in  FIGS. 3 ,  4 A,  4 B,  10 A, and  10 B). 
         [0043]    Referring now to  FIGS. 2A-2D , a method and exemplary results of ablating tissue treated with thermo-sensitizing adjuvant are shown. Cryoablation is used as a non-limiting embodiment in  FIGS. 2A-2D , and similar results may be effected by other ablation techniques (such as RFA). In  FIG. 2A , the tissue that will receive ablation therapy (“target tissue”)  10  is identified. The target tissue  10  is then treated with a temperature-sensitizing agent  26  (as shown in  FIG. 2B ) using an applicator  28 , and the ablation therapy device  14  (such as a fixed-diameter ablation device as shown in  FIG. 2C ) is activated and applied to the treated target tissue  10 . When cryoablation is used, an iceball  16  will form (as shown in  FIG. 2C ), which substantially corresponds to the ablation zone  18  and includes a destruction zone  20  and viability zone  22 . For simplicity, the area of the ablation zone  18  and the iceball  16  area are depicted as being the same in  FIG. 2C . The applicator  28  may be a fixed-diameter applicator, as shown in  FIG. 2B ; however, the applicator could be of a different type, for example, as shown and described in FIGS,  3 ,  4 A, and  4 B. 
         [0044]    Continuing to refer to  FIGS. 2A-2D , the temperature-sensitizing agent  26  may be applied both before and after ablation therapy, or temperature-sensitizing agent  26  may be applied only before or only after ablation therapy. Whether before or after ablation therapy, the temperature-sensitizing agent  26  may be applied to an area  30  that substantially corresponds to the target tissue  10 , although the application area  30  may be larger than the area of target tissue  10 . However, the effects of ablation therapy may only be enhanced within the ablation zone  18  (that is, tissue thermally affected by the ablation therapy). For example, the lesion may substantially correspond to the ablation zone  18 , even though the application area  30  extended beyond the ablation zone  18 . Further, if the TSA  26  is considered toxic to non-target tissue, the TSA  26  is carefully applied onto to target tissue  10  using the applicator  28 . As shown in  FIG. 2D , the lesion (depicted as the destruction zone  20 ) may substantially correspond to the entire ablation zone  18 , effectively reducing the viability zone  22 . Additionally, the depth of the destruction zone  20  may be increased, depending on the absorption characteristics of the TSA  26  and the tissue  10  to which the TSA  26  is applied. 
         [0045]    The temperature-sensitizing agent  26  may have any of a variety of modes of action, and may be used with both cryoablation and RFA therapies. For example, the temperature-sensitizing agent  26  may be a thermophysical adjuvant, a chemotherapeutic adjuvant, a vascular adjuvant, an aquaporin inhibitor, or an immunomodulator adjuvant. However, some adjuvants may have multiple modes of action (such as TNF-a, which may be classified as both a vascular adjuvant and an immunomodulator adjuvant. Additionally, the temperature-sensitizing agent  26  may include one adjuvant, or may include a mixture of adjuvants having different modes of action. When used with cryoablation, a TSA (referred to as, in this case, a cryo-sensitizing adjuvant) may increase cell destruction within the viability zone  22  (such as at temperatures of between approximately −40° C. and approximately 0° C.), effectively increasing the destruction zone  20 . The controlled application of temperature-sensitizing agents as described herein may reduce any toxic effects to non-target tissue. 
         [0046]    Thermophysical adjuvants used as cryo-sensitizing adjuvants may include antifreeze proteins (AFPs), salts, amino acids, nucleic acids, peptides (including proteins and other polypeptides), although other thermophysical adjuvants may be used. Thermophysical cryo-sensitizing adjuvants may modify the crystalline ice phase during freezing, thereby increasing the amount of direct cell injury due to the presence of ice crystals. For example, AFPs may modify ice crystals to a spicular shape, which is effective to mechanically disrupt cell membranes and tissue connective structures. Salt solutions (such as NaCl and KCl) and amino acids (such as glycine) may induce secondary ice formation, which can enhance cell injury between −21° C. and −5° C. Additionally, thermophysical adjuvants may be effective when applied only a few minutes before cryoablation. 
         [0047]    Chemotherapeutic adjuvants used as cryo-sensitizing adjuvants may include adriamycin, peplomycin, 5-fluorouracil, cisplatin, bleomycin, and etoposide, although other chemotherapeutic cryo-sensitizing adjuvants may be used. The use of chemotherapeutic cryo-sensitizing adjuvants with cryoablation may enhance cell destruction at temperatures between, for example, −15° C. and −5° C. Some chemotherapeutic cryo-sensitizing adjuvants may be toxic to non-target cells (such as non-tumor, normal cells), and the controlled application of these adjuvants to target tissue (such as shown and described in  FIGS. 3-10 ) may reduce toxicity to non-target cells. 
         [0048]    Vascular-based adjuvants used as cryo-sensitizing adjuvants may include cytokines such as TNF-a, although other vascular cryo-sensitizing adjuvants may be used. Vascular cryo-sensitizing adjuvants may increase susceptibility of the microvasculature to the vascular mode of cryoinjury. Effects may include blood coagulation, vasoconstriction, inflammation, and free-radical formation. Like chemotherapeutic cryo-sensitizing adjuvants, the controlled application of vascular cryo-sensitizing adjuvants to target tissue (such as shown and described in  FIGS. 3-10 ) may reduce toxicity to non-target cells. 
         [0049]    Aquaporins are, generally, small integral membrane proteins that function as molecular water channels within the cellular membrane. Aquaporin inhibitors may be used to prevent water egress from within cells during freeze duration. Such trapping of water within the cell in a localized fashion would result in greater accumulation of intracellular ice in the targeted region. Intracellular ice damages organelles and membranes, causing irreversible damage that results in cell death. A small difference in solute concentration results in a very large osmotic pressure gradient across the cell membrane; however, animal cell membranes cannot withstand any appreciable pressure gradient. Water movement may eliminate differences in osmolality across the cell membrane, but not if the water is trapped inside the cell or impeded by aquaporin inhibitors. Human hearts express mRNA for AQP-1, -3, -4, -5, -7, -9, -10, and -11, but only express AQP-1 and possible AQP-3 protein. In addition, endothelial aquaporins, which move water either into or out of the interstitial space or capillaries, depending on the direction of the osmotic gradient, would likewise be inhibited in blood vessels within the ablation target treated with aquaporin inhibiting agents. This will cause further tissue destruction from the effects of coagulation necrosis. Aquaporin inhibitors may be based on metallic (for example, mercury, silver, or gold) reactive compounds, as well as new small-molecule or peptide aquaporin blockers. 
         [0050]    Immunomodulator adjuvants used as cryo-sensitizing adjuvants may enhance immunological cell injury by stimulating the cells of the immune system through the production of cytokines such as TNF-a and IFN-y. 
         [0051]    Referring now to  FIG. 3 , an exemplary ablation system  32  is shown. The system  32  generally includes a console  34  that houses various controls and an ablation device  14  for treating tissue. The system  32  may be adapted for cryoablation, RFA, or both. The console  34  may include one or more of a coolant reservoir  36 , an RF generator  38 , a TSA reservoir  40 , and may further include various displays, screens, user input controls, keyboards, buttons, valves, conduits, connectors, power sources, and computers for adjusting and monitoring system parameters. 
         [0052]    Continuing to refer to  FIG. 3 , the ablation device  14  may generally include a handle  42 , an elongate body  44  having a distal end  46  and an ablation element  12 . The handle  42  may include various knobs, levers, user control devices, input ports, outlet ports, connectors, lumens, and wires. The distal end  46  of the elongate body  44  may include one or more ablation elements  12 . The one or more ablation elements  12  may be a balloon (as shown in  FIG. 3 ), electrodes (as shown in  FIG. 2C ), a combination thereof, or any other type of ablation element  12 . In some embodiments, the ablation element  12  may also be the TSA applicator  28 , for example, a cryoablation balloon coated with a layer of TSA  26  (as shown in  FIG. 3 ). The elongate body  44  may further include a lumen  54  in fluid communication with the coolant reservoir  36  if the device  14  is used for cryoablation. If the device  14  is used for RFA, the elongate body  44  may include a lumen  54  in communication with an RF generator  38  and/or a power source. Alternatively, the device  14  may be used for both cryoablation and RFA, in which case the device  14  may include several lumens in communication with the one or more ablation elements  12 . 
         [0053]    Referring now to  FIGS. 4-12 , embodiments of TSA applicators  28  are shown. Generally, the applicator  28  may be either integrated with the ablation device  14  (as shown in  FIGS. 4A and 4B ), or integrated with a second device  56  having a distal end  58  (as shown in  FIGS. 11A ), or both (as shown in  FIG. 11B ). Further, as shown and described in  FIG. 3 , for example, the ablation element  12  of the ablation device  14  may be the applicator  28  (that is, the ablation element  12  may be coated with a layer of TSA  26 ), or the applicator  28  may be incorporated into another area of the device  14  (for example, the distalmost tip of a balloon catheter may be coated with a layer of TSA  26 , whereas the balloon is not coated). The distal end  46  of the ablation device  14  may be suited for cryoablation, RFA, or both, and may be coated with a layer of TSA  26  (as shown in  FIGS. 4A ,  10 A, and  10 B) or a substrate layer  60  and TSA layer  26  (as shown in  FIG. 4B ). Further, the ablation device  14  may be a fixed-diameter device (as shown in  FIGS. 11A and 11B ) or the ablation device  14  may have an expandable ablation element  12 , such as a balloon (as shown in  FIGS. 4A ,  4 B,  10 A, and  10 B). Although not shown in  FIGS. 4-10 , the ablation element  12  would be placed in contact with target tissue  10  during an ablation procedure, with the applicator  28  (either as part of the ablation device  14  or second device  56 ) being proximate or in contact with the tissue  10  to apply TSA  26 . 
         [0054]    Referring now to  FIGS. 4A-C , cross-sectional views of the distal end  46  of an ablation device  14  are shown, the ablation device  14  including an ablation element  12  (such as a balloon, as shown in  FIGS. 4A-C ) coated with a layer of TSA  26 . The balloon ablation element  12  may be suited for either cryoablation, RFA, or both (or neither, if the balloon functions as an applicator  28  that is part of a non-ablating second device  56 ), and is coated at least in part with a layer of TSA  26 . Additionally or alternatively, the balloon ablation element  12  may be coated with a layer of nano- or micro-porous material  50 , with small amounts of TSA  26  being contained within the nano- or micro-pores  52 . When the balloon ablation element  12  is pressed against the target tissue  10 , the TSA  26  may be released from the pores  52  to the tissue  10 . For example, the porous material  50  may be spongelike in that it contains a plurality of throughpores. Additionally or alternatively, the porous material may contain a plurality of surface indentations (as shown in  FIG. 4C ). The layer of TSA  26  may be between approximately 0.01 microns to approximately 200 microns (as shown in  FIG. 4A ). The ablation element  12  may be additionally coated with a substrate layer  60 , which may be located between the ablation element  12  and TSA layer  26  (as shown in  FIG. 4B ). The substrate layer  60  may include one or more temperature sensitive compounds that readily separate from the ablation element  12  when a certain threshold temperature is reached (for example, 0° C. or 60° C.). This substrate layer  60  thus facilitates movement of the TSA  26  from the distal end  46  of the ablation device  14  to the target tissue  10 . Additionally or alternatively, the substrate layer  60  may be separated from the ablation element  12  by mechanical stress, for example, as when created as a balloon ablation element  12  is inflated. 
         [0055]    Referring now to  FIGS. 5 and 6 , the distal end  46  of an ablation device  14  is shown, the distal end  46  being coated with a layer of TSA  26 . The coated area of the distal end  56  may include an ablation element  12  (as shown in  FIG. 5 ) suited for either cryoablation, RFA, or both (such as a focal catheter), or the coated area of the distal end  56  may not include an ablation element  12  (as shown in  FIG. 6 ), and is coated at least in part with a layer of TSA  26 . The layer of TSA  26  may be between approximately  0 . 01  microns to approximately 200 microns. The distal end  46  may be additionally coated with a temperature-sensitive substrate layer  60 , which may be located between the distal end  46  and TSA layer  26  (as shown and described in  FIG. 4B ). Additionally, as shown in  FIG. 6 , the surface of the distal end  46  of the device  14  may include a plurality of indentations or depressions  62  sized to contain a volume of TSA  26 . For example, each indentation  62  may contain as little as 0.1 μL and as much as 1 μL. The indentations  62  may either supplement or replace the TSA layer  26 . 
         [0056]    Referring now to  FIG. 7 , a cross-sectional view of the distal end  46  of an ablation device  14  is shown, the distal end  46  having a spray nozzle  64  for the application of TSA  26  to tissue  10 . The spray nozzle  64  includes a plurality of apertures  65  in the distal end  46  of the device  14  through which pressurized TSA  26  may pass and be atomized or broken into small droplets. Each droplet may be, for example, between approximately 0.5 μm and approximately 0.5 mm. The spray nozzle  64  may be in fluid communication with the device lumen  54  and TSA reservoir  40 . 
         [0057]    Referring now to  FIG. 8 , the distal end  46  of an ablation device  14  is shown, the ablation device  14  having a cannula or other element  66  for the application of TSA  26  to tissue  10 . The cannula  66  may be slidably movable within the device lumen  54 , and may be advanced beyond the distal end  46  of the device  14  to bring the outlet  68  of the cannula  66  in contact with or near the tissue  10 . Temperature-sensitizing adjuvant  26  is then either sprayed (as shown in  FIG. 7 ), dripped (as shown in  FIG. 8 ), or otherwise applied from the outlet  68  to the tissue  10 . The cannula  66  may further include a lumen  70 , in fluid communication with the outlet  68  and the TSA reservoir  40 . Alternatively, the device  14  may be as shown in  FIG. 12 , wherein the device  14  is an over-the-wire catheter having a guidewire lumen  54  with an outlet  71 . Temperature-sensitizing adjuvant  26  is then either dripped, squirted, or otherwise applied from the outlet  71  of the guidewire lumen  54 . Further, the device  14  may include an expandable ablation element  12 . 
         [0058]    Referring now to  FIG. 9 , the distal end  46  of an ablation device  14  is shown, the distal end  46  including an ablation element  12  (such as an electrode, as shown in  FIG. 9 ). The ablation element  12  may be suited for RF ablation, and is capable of emitting at least low-current energy (for example, 100 mV to approximately 500 mV), and may also be capable of emitting RFA-level energy. The application of low-current energy to target tissue  10  facilitates the creation of a salt-concentration gradient (such as the salt-concentration gradient that develops during slow freezing of tissue) and enhances water permeability of cell membranes. Cells of the tissue  10  respond to an increase in salt concentration by releasing water, resulting in cell dehydration and eventually death. The ablation element  12  may apply low-current energy to the tissue  10  either before, during, or after ablation. Alternatively, the same ablation element  12  may first apply low-current energy to the tissue  10  (“gradient generating mode”) and then apply RFA-level energy to the tissue  10  (“ablation mode”). Further, multiple cycles of gradient generating mode/ablation mode may be applied. 
         [0059]    Referring now to  FIGS. 10A and 10B , the distal end  46  of an ablation device  14  is shown, the device  14  having more than one treatment elements  12 . As shown in  FIGS. 10A and 10B , the ablation device  14  includes both a balloon  72  and one or more electrodes  74 . The electrodes  74  may be located on the distalmost point of the distal end  46 , on the balloon  72 , or both. For example, one electrode  74  at the distalmost point of the distal end  46  may be used in gradient generating mode, while other electrodes  74  on the balloon  72  may be used in ablation mode. The one or more electrodes  74  may be in any configuration, for example, discrete electrodes or bands that at least partially circumscribe the balloon  72  (as shown in  FIG. 10B ). Alternatively, the balloon  72  may be a cryoablation device, with a tip and/or balloon electrodes  74  being used in gradient generating mode. Still further, the balloon  72 , electrodes  74 , and/or the ablation device  14  may be coated with a layer of TSA  26 , as shown and described in  FIGS. 4A and 4B . 
         [0060]    Referring now to  FIGS. 11A and 11B , a first exemplary embodiment of an ablation device  14  used in association with a second device  56  for the application of TSA to tissue  10  is shown. As shown in  FIG. 11A , the ablation device  14  may have a distal end  46  including one or more ablation elements  12 . The second device  56  may be any device capable of applying TSA  26  to the target tissue  10 . For example, the second device  56  may be a catheter-type device or swab having a distal end  58  coated with a layer of TSA  26  (as shown in  FIG. 11A ), a device having a spray nozzle (as shown in  FIGS. 7 and 11B ) or dropper apparatus in fluid communication with a TSA source (such as the TSA reservoir  40 ), or a hypodermic needle with a syringe containing a volume of TSA  26 . As shown in  FIG. 11B , both the ablation device  14  and the second device  56  may function as applicators  28 ,  28 a. The ablation device  14  may serve as an applicator  28  when, for example, an ablation balloon or distal end  46  is coated with TSA. 
         [0061]    It will be understood that any of the applicators  28  as described herein may be incorporated into either an ablation device  14  or a second device  56 . For example, an ablation device  14  may have a spray nozzle  64  at the distalmost end and a balloon ablation element  12 . Additionally, any number of second devices  56  may be used. Further, the ablation device  14  may include any number of ablation elements  12 , and may be suited for any type of ablation therapy. 
         [0062]    It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described herein above. In addition, unless mention was made above to the contrary, it should be noted that all of the accompanying drawings are not to scale. A variety of modifications and variations are possible in light of the above teachings without departing from the scope and spirit of the invention, which is limited only by the following claims.