Abstract:
A method of cryoablating diseased tissue is provided. The method includes providing an embolization agent. The embolization agent includes an inner core made of a first material. The inner core has a diameter less than a diameter of an opening of a target vessel. The embolization agent further includes an erodible outer shell made of a second embolization material encompassing the inner core. The erodible outer shell has an initial diameter greater than the diameter of the opening to occlude the target vessel. The method further includes occluding the opening of the target vessel with the embolization agent to reduce blood flow in the diseased tissue. The method further includes cryoablating the diseased tissue with a cryoablation probe while the target vessel is occluded by the embolization agent.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    1. Field of the Invention 
         [0002]    The present disclosure generally relates to cryoablation procedures. More specifically, the present disclosure relates to the use of an embolization agent in a cryoablation procedure. 
         [0003]    2. Background 
         [0004]    Cryoablation is an effective treatment method for localized cancerous tumors. Cryoablation probes (cryoprobes) are cooled, thermally conductive needles with chilled tips which remove heat from tissue in contact with the cryoablation probe. 
         [0005]    Cryoablation is especially effective for tumors in kidneys, where healthy tissue surrounding a tumor has a higher blood flow rate than that of the tumor tissue. The healthy tissue&#39;s increased blood flow allows it to survive cryoablation tissue more easily than the tumor tissue. Successful treatment and thawing converts the tumor tissue into an inert necrotic abscess which eventually assimilates into the body. 
         [0006]    However, cryoablation is less effective in treating cancerous tumors in most other organs other than kidneys, because tumor tissue in these organs generally has higher blood flow than in surrounding tissue. As a result, there is risk of significant damage to healthy tissue, and increased blood flow at the edges of the tumor can protect the remaining cancerous tissue from cryoablation. 
       SUMMARY 
       [0007]    In overcoming the drawbacks and other limitations of the related art, the present disclosure provides an erodible embolization agent which decreases blood flow in tumor tissue relative to blood flow in surrounding healthy tissue just prior to or during cryoablation. As a result, cryoablation is more effective for a broader range of tumor tissues, including those in which blood flow is otherwise greater than in surrounding healthy tissue. Additionally, the survival rate of surrounding healthy tissue after cryoablation is improved. 
         [0008]    In some embodiments, the present disclosure relates to a method of cryoablating diseased tissue. The method includes providing an embolization agent. The embolization agent includes an inner core made of a first material. The inner core has a diameter less than a diameter of an opening of a target vessel. The embolization agent further includes an erodible outer shell made of a second embolization material encompassing the inner core. The erodible outer shell has an initial diameter greater than the diameter of the opening to occlude the target vessel. The method further includes occluding the opening of the target vessel with the embolization agent to reduce blood flow in the diseased tissue. The method further includes cryoablating the diseased tissue with a cryoablation probe while the target vessel is occluded by the embolization agent. 
         [0009]    In some embodiments, the present disclosure relates to a method of cryoablating diseased tissue. The method includes providing an embolization agent. The embolization agent includes an inner core made of a first material. The inner core has a diameter less than a diameter of an opening of a healthy vessel adjacent to a diseased vessel located in the diseased tissue. The embolization agent further includes an erodible outer shell made of a second embolization material encompassing the inner core. The erodible outer shell has an initial diameter less than a diameter of an opening of the diseased vessel and greater than the diameter of the opening of the healthy vessel to occlude the healthy vessel. The method further includes occluding the opening of the healthy vessel with the embolization agent to reduce blood flow in the diseased tissue. The method further includes cryoablating the diseased tissue with a cryoablation probe while the healthy vessel is occluded by the embolization agent. The method further includes allowing the erodible outer shell to erode at a predetermined rate. 
         [0010]    In some embodiments, the present disclosure relates to a method of cryoablating diseased tissue. The method includes providing an introducer apparatus. The method further includes providing an embolization agent. The embolization agent includes an inner core made of a first material. The inner core has a diameter less than a diameter of an opening of a target vessel. The embolization agent further includes an erodible outer shell made of a second embolization material encompassing the inner core. The erodible outer shell has an initial diameter greater than the diameter of the opening to occlude the target vessel. The method further includes occluding the opening of the target vessel with the embolization agent to reduce blood flow in the diseased tissue. The method further includes introducing with the introducer apparatus the embolization agent to the opening of the target vessel. The method further includes occluding the opening of the target vessel with the embolization agent to reduce blood flow in the diseased tissue. The method further includes cryoablating the diseased tissue with a cryoablation probe while the target vessel is occluded by the embolization agent. 
         [0011]    Further features and advantages of the present disclosure will become apparent from consideration of the following description and the appended claims when taken in connection with the accompanying drawings. It should be understood that the description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  is a cross-sectional view of an erodible embolization agent; 
           [0013]      FIG. 2A  is a side view of an introducer apparatus including a wire guide, catheter, needle, and introducer sheath for use with an embolization agent; 
           [0014]      FIG. 2B  is a side view of a cryoablation probe for use in a cryoablation procedure; 
           [0015]      FIG. 3A  is an environmental view of body tissue before embolization and cryoablation treatments begin; 
           [0016]      FIG. 3B  is an environmental view of body tissue as the embolization agents are introduced in the body tissue; 
           [0017]      FIG. 3C  is an environmental view of body tissue as the embolization agents become lodged at the boundary between the diseased and healthy vessels and the diseased tissue is cryoablated; 
           [0018]      FIG. 3D  is an environmental view of body tissue after cryoablation and thawing of the diseased tissue are complete and as the embolization agents are eroding; and 
           [0019]      FIG. 3E  is an environmental view of body tissue after the outer shells have eroded and as the inner cores are dispersing. 
       
    
    
       [0020]    The drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure in any way. 
       DETAILED DESCRIPTION 
       [0021]    The following description is merely exemplary in nature and is in no way intended to limit the present disclosure or its application or uses. It should be understood that throughout the description and drawings, corresponding reference numerals indicate like or corresponding parts and features. 
         [0022]      FIG. 1  illustrates an embolization agent  10  (i.e. embolization material) comprising an inner core  12  made of a fast dispersing material that has a diameter less than a predetermined size for an initial opening in a target vessel and an outer shell  14  made of an embolization material that encompasses the inner core  12  and has an initial diameter that will occlude the initial opening in the target vessel. In some embodiments, the outer shell  14  erodes at a predetermined rate to enhance penetration of the embolization agent  10  into the opening of the target vessel. Upon becoming exposed by the erosion of the outer shell  14 , the inner core  12  preferably disperses rapidly into the target vessel within a matter of seconds to hours without obstructing subsequent blood flow. Target vessels may be fluid-transfer vessels, including but not limited to vascular or lymphatic vessels. 
         [0023]    In this embodiment, the outer shell  14  of embolization material erodes at a predetermined rate that is predictable and controllable. By erosion, the embolization material may become disassembled, digested, or metabolized into smaller or dispersed molecules through the action of the surrounding environment present in the targeted tissues vessels. Eroded embolization material may form fragments that will continue to erode. These erodible fragments of embolization material are smaller than the size expected to cause a stroke or any other type of complication in the patient. 
         [0024]    This predetermined rate of erosion results in substantial erosion of the outer shell  14  in a timeframe of about 30 seconds to 24 hours, or about 5 minutes to an hour, or about 5 minutes to 30 minutes, or about 10 minutes to 20 minutes, or about 15 minutes. Upon substantial erosion of the outer shell  14 , the inner core  12  is able to disperse into the target vessel. The properties of the embolization material may be adjusted to be suitable for use with vascular, lymphatic, or other fluid-transfer vessels. In addition, the outer shell  14  of embolization material may erode at a similar rate when in contact with the vessel walls or when in contact with a fluid located in the vessels. Maintaining a similar rate of erosion during treatment assists in keeping the embolization effect substantially constant as the embolization agent  10  progresses through smaller and smaller vessels. 
         [0025]    The outer shell  14  may be comprised of a single layer or multiple layers that are different or similar in composition. The single layer or each of the multiple layers may be selected from any suitable embolization material known in the art, for example a bioerodible material. In some examples, the material can be polylactic acid, polyvinyl alcohol, tris-acryl gelatin microshells, gelatin sponge microfibrillar collagen, ethoiodized oil, autologous materials, celluloses, polyacrylic acids, polyacylamides, and alginates or mixtures thereof. The embolization material may be multi-component, for example it may include a polymer solution and a gelling precursor. The outer shell  14  of embolization material  10  may further comprise anti-thrombogenic agents to prevent eroded fragments from clotting as the fragments disperse. 
         [0026]    The material of the inner core  12  may be any fast dissolving or dispersing solid or liquid material that does not adversely affect the body known to one skilled in the art including but not limited to sugar, sucrose, lactose, fructose, salt, or any fast dissolving or dispersing polymer known in the art. The inner core may be ionically or covalently bonded to the embolization material of the outer shell  14  or held in place by entanglement, van der Waal forces, hydrogen bonding, or any other means known to one skilled in the art of particle encapsulation. Optionally, the inner core  12  may expand upon freezing. In some examples, the materials of the inner core  12  are obtained from compression or suspension/emulsion polymerization. The outer shell  14  may be applied through a fluid bed coating process like Wurster coating. 
         [0027]    In some examples, after the outer shell  14  has eroded, the material of the inner core  12  may immediately dissolve and disperse into the target vessel. The material of the inner core  12  may be two-phase system to facilitate dissolving and dispersal. In some examples, upon the material of the inner core  12  may expand upon freezing, causing the outer shell  14  to contact a vessel wall and shatter, after which the material of the inner core  12  dissolves and disperses. 
         [0028]    In some embodiments, the embolization agent  10  may have a spherical, ellipsoidal, non-spherical, or non-ellipsoidal shape. However, some sort of symmetry is preferred to obtain a uniform and predictable erosion rate. Since the embolization agent  10  will be disposed within blood vessels having a circular cross-section, the symmetry is preferably at least radial to obtain consistent embolization time intervals. For example, the embolization agent  10  may take the shape of a shell or ellipsoid with two axes having a length approximately equal to one another and a third axis greater than the other two, i.e., football-shaped without the pointed ends. Shaping of the embolization agent  10  may occur during or after formation of the embolization agent  10  using any process known to one skilled in the art, such as molding, compression, or agglomeration, among others. 
         [0029]    In some embodiments, one or both of the inner core  12  and outer shell  14  may further comprise a radiopaque material. The radiopaque material may be discrete particles or a coating. The radiopaque material may be a polymer, ceramic, or a noble metal. Examples of noble metals include gold, platinum, iridium, palladium, or rhodium, or a mixture thereof. The radiopaque material provides enhanced fluoroscopy to more easily identify the location of the embolization agent  10  during delivery. 
         [0030]      FIG. 2A  depicts an introducer apparatus  16  for introducing one or more embolization agents  10  into body tissue. The introducer apparatus  16  includes a hollow needle  18  to pierce the patient&#39;s skin and enter the body tissue at an angle with respect thereto. A wire guide  20  is then inserted into the hollow needle  18  and is advanced percutaneously into the body tissue to the desired position for delivery of the embolization agent  10  to the target vessels. The hollow needle  18  is then pulled in a backward direction so as to be removed from the body tissue and from contact with the wire guide. Next, a catheter  22  is advanced along the wire guide  20  to the desired position. 
         [0031]    The catheter  22  has a distal end  24  through which the embolization agent  10  is delivered into the target vessels. The catheter is preferably made of a soft, flexible material such as silicon or any other suitable material. Generally, the catheter also has a proximal end  26  and a plastic adaptor  28  to receive the embolization agent  10 . The diameter of the catheter is based upon the size of the body tissue into which the catheter is inserted and the amount of embolization agent  10  to be delivered. The inner diameter of the catheter  22  is greater than the diameter of the outer shell  14  of the embolization agent  10  to allow delivery of the agent to the target vessel. 
         [0032]    The introducer apparatus  16  may further include a polytetrafluoroethylene (PTFE) introducer sheath  30  to assist the percutaneous introduction of the wire guide  20  and the catheter  22  in the body tissue. Of course, any other suitable material may be used for the sheath  30 . The introducer sheath  30  facilitates inserting the catheter  22  percutaneously to a desired location in the body tissue, and provides stability to the catheter  22 . 
         [0033]      FIG. 2B  depicts a cryoablation probe  32  for cryoablating diseased tissue. However, any cryoablation probe or cryoablation technique may be used without falling outside the scope of the present disclosure. The cryoablation probe  32  has a chilled tip  33  configured to freeze tissue on contact. 
         [0034]      FIGS. 3A-3F  illustrate steps in a cryoablation procedure using the embolization agent  10 .  FIG. 3A  illustrates an environmental view of body tissue  34  before embolization and cryoablation treatments begin. The body tissue  34  may be any tissue or organ in the body, for example a liver. The body tissue  34  has diseased tissue  36  and healthy, non-diseased tissue  38  surrounding or adjacent to the diseased tissue  36 . The diseased tissue  36  may be a cancerous tumor, for example. The healthy tissue  20  and the diseased tissue  36  meet at a boundary  40 . As shown in the magnified portion of the body tissue  34  at the boundary  40 , the diseased tissue  36  contains diseased vessels  42  and the healthy tissue  38  contains healthy vessels  44 . The vessels  42 ,  44  may be fluid-transfer vessels, including but not limited to vascular or lymphatic vessels. The direction of downstream blood flow is indicated by arrow  46 . 
         [0035]    In some examples, the diameter of the outer shell  14  of embolization material is typically less than about 100 micrometers but greater than about 80 micrometers or 85 micrometers, while the diameter of the inner core  12  of fast dispersing material is preferably less than about 40 micrometers or 35 micrometers. By comparison, liver tumor vasculature vessels have an opening on the order of about 40 to 80 micrometers, while normal healthy liver tissue has vascular vessels with openings between about 7 to 40 micrometers. Thus, the outer shell  14  has a diameter that is slightly greater than the initial opening in the targeted vessels, while the inner core  12  has a diameter either the same or slightly smaller than the expected size of the opening in the targeted vessels. The exact size of the openings associated with other vascular or lymphatic tissue vessels may vary from the above description. Such variation is contemplated to be within the scope of the present invention. 
         [0036]    In this example, the diseased vessels  42  have greater diameters than the surrounding healthy vessels  44 , as is common for many types of diseased tissue  36  surrounded by healthy tissue  38 . In some examples, large vessels  48  may allow blood to flow into the diseased tissue  36  from the healthy tissue  38  in a downstream direction as indicated by arrow  50 . However, because of blockages caused by the diseased tissue  36 , there may be no corresponding large vessel allowing outflow of the blood that flowed into the diseased tissue  36  through large vessels  48 . 
         [0037]      FIG. 3B  illustrates an environmental view of body tissue  16  as the embolization agents  10  are introduced in the body tissue  34 . The embolization agents  10  may be placed in the catheter  22  prior to or after insertion of the catheter  22  into the body tissue  34 . When the distal end  24  of the catheter  22  is at a location near the target vessel, the embolization agents  10  is advanced through the catheter  22  preferably from the proximal end  26  and distally beyond the distal end  24  of the catheter  22  to a location within the body tissue  34  near or at the target vessel. A shaft or pusher member advances the embolization agents  10  through the catheter  22 . Alternatively or additionally, the embolization agents  10  can be suspended in and premixed in a solution which may include saline and which is advanced through the catheter  22  and into the body tissue  34  by a fluid delivery apparatus, optionally in combination with the shaft or pusher member. 
         [0038]    In some examples, the target vessels in which the embolization agents  10  are introduced may one or more diseased vessels  44  throughout the diseased tissue  36 , including the interior of the diseased tissue  36  and near the boundary  40 . In other examples, the target vessels in which the embolization agents  10  are introduced are large vessels  48  located in healthy tissue  38 . In some examples, embolization agents  10  can be introduced in all of the above locations in a single procedure. Regardless of where the embolization agents  10  are introduced, the embolization agents  10  flow downstream in the direction of arrow  48  until they reach the boundary  40 . 
         [0039]      FIG. 3C  illustrates an environmental view of body tissue  16  as the embolization agents  10  become lodged at the boundary  40  between the diseased vessels  42  and healthy vessels  44 , during which time the diseased tissue  36  is cryoablated. The embolization agents  10  occlude the boundary  40  and are prevented from passing into the healthy vessels  44  because the diameter of the outer shells  14  is greater than the diameter of the healthy vessels  44 . Additionally, because large outflow vessels corresponding to the large inflow vessels  48  may be blocked, embolization agents  10  introduced into the large inflow vessels  48  may not have a large diameter vessel through which to escape the diseased tissue  36 , and will instead become lodged at the boundary  40  of the smaller vessels  42 ,  44 . 
         [0040]    Because of the lodged embolization agents  10 , the diseased tissue  36  experiences reduced or stopped blood flow in the entire diseased tissue  36  or around the boundary  40 . In body tissue  34  where diseased tissue  36  normally experiences greater blood flow than the surrounding healthy tissue  38 , the blood flow in the diseased tissue  36  is preferably reduced sufficiently to be lesser than the blood flow in the surrounding healthy tissue  38 . 
         [0041]    In embodiments where the embolization agents  10  include radiopaque material, fluoroscopy helps determine when blood flow has been reduced. Specifically, agglomeration of embolization agents  10  around the boundary  40 , as viewed by the practitioner using a fluoroscope, indicates reduction in blood flow. 
         [0042]    Once the embolization agents  10  are lodged at the boundary  40 , the cryoablation probe  32  is inserted into the diseased tissue  36 . The cryoablation probe  32  can be used to ablate the diseased tissue  36  at its in interior, and the diseased tissue  36  near and/or at the boundary  40 . In some examples, the cryoablation probe  32  can be used to create an ice ball  52  that expands throughout the diseased tissue  36  until it reaches the boundary  40 . Since, due to embolization, the healthy tissue  38  has a greater blood flow than the diseased tissue  36 , the healthy tissue  36  is more resistant to the cryoablation procedure, and there is less risk of destroying the healthy tissue  36 . In the optional embodiment where the inner core  12  expands upon freezing (not shown), the embolization agent  10  may embolize the boundary  40  during cryoablation but immediately cease to embolize the boundary  40  after thawing. Thus the healthy tissue  36  adjacent the boundary  40  is further protected. 
         [0043]    Once cryoablation is complete, the diseased tissue  36  is destroyed and becomes a necrotic abscess, the cryoablation probe  32  is removed, and the necrotic abscess thaws. The cryoablation procedure may be timed to ensure completion before the embolization agents  10  erode sufficiently to disperse in the healthy vessels  44 . 
         [0044]      FIG. 3D  illustrates an environmental view of body tissue  16  after cryoablation and thawing of the diseased tissue  36  are complete and as the embolization agents  10  are allowed to erode at a predetermined rate to expose the inner cores  12 . 
         [0045]      FIG. 3E  illustrates an environmental view of body tissue  16  after the outer shells  14  have substantially or fully eroded, and thus the inner cores  12  are dispersing along the blood flow gradient  46  into the healthy vessels  44 . Once the inner cores  12  disperse, the surrounding healthy tissue  38  assimilates the necrotic abscess. 
         [0046]    The effective concentration or dosage of the embolization agent  10  can be determined and varied by the physician treating the patient. Such a decision should be based on the nature, severity, and location of the condition to be treated, the extent of desired reduction in blood flow or reduction in blood flow necessary for successful cryoablation, and the method selected to administer the embolization agent  10 . Any means known to one skilled in the art may be used to introduce an acceptable dosage of the embolization agent  10  to the target vessel. 
         [0047]    A person skilled in the art will recognize from the previous description that modifications and changes can be made to the present disclosure without departing from the scope of the disclosure as defined in the following claims.