Patent Document

BACKGROUND 
       [0001]    Breast cancer will be diagnosed in approximately one in eight women in their lifetime and one in 30 will die of the disease. It is the leading cause of cancer deaths in women 40-55 years of age and the second leading cause of cancer deaths in women overall. 
         [0002]    In order to treat and prevent breast cancer, it is often desirable and necessary to detect and test tissue abnormalities for pre-malignant conditions. This is particularly important in the diagnosis and treatment of patients with cancerous tumors, or lesions. Typically, a medical professional will diagnose the existence of suspicious circumstances by palpation, mammography, x-ray, MRI, or ultrasound imaging. The medical professional will then collect a biopsy to determine whether the tissue is cancerous. 
         [0003]    If removal is recommended as a viable treatment, then the tumor or lesion will be marked to facilitate its removal during surgery. Marking prior to surgery is required because some tumors, such as Ductal Carcinoma in Situ (DCIS), are not palpable which makes locating the lesion during surgery problematic because the physician cannot feel the tumor. A number of procedures and devices for marking and locating particular tissue locations are known. For example, wire guides may be used for locating lesions. The wire guides have a tubular introducer needle and an attached wire guide with a helical coil configuration for locking into position once inside or near the targeted lesion. 
         [0004]    The medical professional locates the lesion site using an imaging system, for example, x-ray, ultrasound or magnetic resonance imaging (MRI), in order to deploy the wire guides in or around the lesion. The needle may then be removed from the wire guide which remains locked in the lesion for guiding a surgeon down the wire to the lesion site during subsequent surgery. Wire guides have some disadvantages including inability to mark the entire lesion, and inability to mark the lesion in three dimensions. 
         [0005]    Using the existing techniques for locating the lesions to be removed physicians can locate and remove cancerous tissue. However, for some types of cancer such as DCIS the national reexision rate, the cases in which the surgeon must do another surgery to completely remove the lesion, is around 40-50%. This is because the surgeon may fail to remove enough tissue around the lesion, the “margin,” and as a result leave cancerous cells within the patient. Inadequate excision of cancer-free margin of tissue is known to increase the risk of local recurrence of breast cancer. Alternatively, the physician may remove more tissue than is necessary. There is a need for improved techniques to ensure that the entire lesion can be marked, ensure that sufficient margin is removed, and thus decrease the need for reexcision. 
       SUMMARY 
       [0006]    A poloxamer, or hydrogel such as poly(N-isopropylacrylamide) can be used to effectively mark a lesion in preparation for surgery. When Poly(N-isopropylacrylamide) increases in temperature above a transition temperature it undergoes a reversible phase change from liquid phase to solid phase. 
         [0007]    During visualization of the lesion using a technique such as mammography, the polymer may be injected directly into the lesion. Alternatively, the polymer may be injected around the tumor. The polymer permeates the tissue, leaving it unchanged except for the presence of the polymer and hardens as it approaches a transition temperature of 37 degrees Celsius. Following polymerization the lesion will be palpable and will increase the chances of a complete excision. 
         [0008]    The necessary items for performing the methods of the invention can be included in a kit. The kit may include the temperature responsive hydrogel, a syringe that is at least partially insulated and an insulated needle. The hydrogel comprises a poloaxomer such as poly(N-isopropylacrylamide) and will undergo a reversible phase change at a transition temperature. The kit can also include a temperature controlling device to keep the polymer below the transition temperature and in a liquid state. The polymer may be contained in a carpule to be loaded into the syringe, or may be stored in the syringe. 
         [0009]    This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0010]    The Detailed Description is set forth with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The use of the same reference numbers in different figures indicates similar or identical items. 
           [0011]      FIG. 1  is a view of an injection of a temperature responsive polymer into a lesion within a tissue. 
           [0012]      FIG. 2  is a view of an injection of a temperature responsive polymer into tissue surrounding a lesion. 
           [0013]      FIG. 3  is a view of an excision of a marked lesion. 
           [0014]      FIG. 4  is a view of a temperature responsive polymer draining from an excised lesion. 
           [0015]      FIG. 5  is a view of a lesion marked with a temperature responsive polymer containing beads. 
           [0016]      FIG. 6  is a view of a medical professional injecting a temperature responsive polymer into a patient. 
           [0017]      FIG. 7  is a view of a medical professional removing a lesion marked with a temperature responsive polymer from a patient. 
           [0018]      FIG. 8  is a photograph of a chicken breast being injected with a temperature responsive polymer. 
           [0019]      FIG. 9  is a photograph of a dissected chicken breast following injection with a temperature responsive polymer. 
       
    
    
     DETAILED DESCRIPTION 
       [0020]    This application describes tissue marking for lesion removal. The lesion removal includes identifying a region containing an area of interest and then marking the area with a temperature responsive hydrogel/polymer. The polymer undergoes a reversible phase change from liquid to solid when a transition temperature is reached. The polymer may make the tissue easier to detect by changing density of the tissue, marking the tissue with a color, making the tissue radio-opaque, and the like. However, the polymer does not change any aspect of the tissue related to diagnosis or analysis of the tissue. 
         [0021]    By making the area of interest palpable to a medical professional the area can then be removed for further study and to prevent spread of potentially cancerous cells. This will benefit individuals that require a surgery to remove tissue as part of the treatment by helping a medical professional remove all affected tissue thus decreasing the chance that another surgery will be necessary. 
         [0022]      FIG. 1  is an illustration  100  of marking tissue  102  containing a lesion  104  in situ. The tissue  102  may include any form of tissue found in the body such as kidney, lung, stomach, liver, but, in one implementation the tissue  102  is breast tissue. The lesion  104  could include any type of atypical or cancerous lesion which may be palpable or unpalpable. In one implementation the lesion  104  is ductal carcinoma in situ (DCIS). 
         [0023]    The lesion  104  is identified and visualized using a technique such as mammography, sonography, magnetic resonance imaging, breast specific gamma imaging, thermography, or the like. The polymer  108  is then delivered to the site of the lesion  104 . A syringe  106  may be used to deliver the polymer  108  through the epidermis of a patient into the lesion  104  by placing a tip of a needle  110  at the location of the lesion  104 . 
         [0024]    The polymer  108  may be selected from the family of hydrogels which include poloaxomers and poly(N-isopropylacrylamide), and undergoes a reversible phase change, from liquid to solid, when the polymer  108  is heated up to the in situ temperature of the breast tissue  102  containing the lesion  104 . 
         [0025]    The properties of the breast tissue  102  and the lesion  104  remain unchanged after injection of the polymer  108  and the polymer  108  will permeate the lesion  104  making the lesion palpable once the polymer  108  reaches a transition temperature. Making the lesion  104  palpable will facilitate its excision by a medical professional. To protect the polymer  108  from reaching the transition temperature prematurely the syringe  106  may be at least partially insulated and the needle  110  may also be insulated. 
         [0026]      FIG. 2  is an illustration  200  of a different technique to mark tissue  102  containing an unpalpable lesion  104  in situ. In one implementation, the tissue  102  may be breast tissue but is not limited to one particular type of tissue. The lesion  104  in one implementation may be a cancerous tumor, such as DCIS, which is not palpable but may be identified and visualized using an imaging technique such as mammography, sonography, magnetic resonance imaging, or thermography. 
         [0027]    The polymer  108  is then delivered to the area of interest. A syringe  106  may be used to deliver the temperature responsive polymer  108  into the tissue  102  surrounding the lesion  104  forming a coating around the lesion  104  that may encompass sufficient margins to aid in the removal of all potentially atypical and/or cancerous cells. 
         [0028]    The polymer  108  may be a one or more hydrogels including poloaxomers and poly(N-isopropylacrylamide) the undergoe a reversible phase change, from liquid to solid, when the polymer  108  is heated up above the transition temperature to the in situ temperature of the breast tissue  102 . 
         [0029]    The properties of the breast tissue  102  and lesion  104  remain unchanged after injection of the polymer  108  and the polymer  108  will permeate the tissue  102  surrounding the lesion  104  making the lesion  104  palpable and facilitating its excision by a medical professional. 
         [0030]    Similar to the technique illustrated in  FIG. 1 , it may be desirable to prevent the polymer  108  from reaching the transition temperature before being injected. To protect the polymer  108  from reaching the transition temperature prematurely, the syringe  106  may be at least partially insulated and the needle  110  may also be insulated. 
         [0031]    The polymer  108  may also be precooled so that during transportation or distribution the polymer  108  will remain in its liquid state. This can be accomplished by the use of traditional coolants, which may include wet ice, dry ice, insulation, or the like. 
         [0032]      FIG. 3  is an illustration  300  of excising the lesion  104  from the tissue  102 . The location of the lesion  104  within the breast tissue  102  may be marked by either of the techniques illustrated in  FIG. 1  or  2  and it then excised by a medical professional. In one non-limiting implementation the medical professional uses a scalpel  302  to free the lesion  104  from the surrounding tissue; however, other techniques could be conceivably used to excise the lesion  104  from the tissue  102 . For example, other sharp or cautery dissections techniques including knives, scissors, and cautery/heat. 
         [0033]      FIG. 4  is an illustration  400  of the temperature responsive polymer  108  draining from the lesion  104  once the lesion  104 , and the included polymer  108 , cools below the transition temperature. The tissue of interest may be breast tissue in one implementation, and the lesion  104  may be a cancerous tumor; however, the tissue  102  of interest and the lesion type could be any conceivable tissue or lesion type. 
         [0034]    As the lesion  104  cools below the transition temperature the temperature responsive polymer  108  undergoes another phase transition from solid back to liquid. Liquid polymer  402  may drain from the tissue  102 . Once in a liquid state the liquid polymer  402  can be easily separated from the excised lesion  104 . After the liquid polymer  402  has completely drained, the lesion  104  retains all of its original properties. 
         [0035]      FIG. 5  shows an illustrative example  500  of an implementation of the technique illustrated in  FIG. 1  in which the temperature responsive polymer  108  contains beads  502 . The addition of beads  502  may also be used with the technique illustrated in  FIG. 2 . In the implementation shown in  FIG. 1  the beads  502  in the polymer  108  can be colored to make the lesion  104  visibly distinct and in the implementation shown in  FIG. 2  a boundary of the lesion  104  can be visibly distinguishable from the surrounding tissue by the presence of colored polymer  108  around the lesion  104 . Additionally or alternatively, the polymer itself may be colored with a dye such as methylene blue to increase intraoperative visibility. The addition of the beads  502  may also increase the palpability of the solidified polymer  108 . 
         [0036]    In another implementation the beads  502  are made of radio opaque material so that they are visible using a technique such as radiography. In another implementation the beads  502  may improve the palpability of the polymer  108  by making the polymer  108  more rigid when the polymer  108  has reached the transition temperature and has undergone the phase change from liquid to solid. 
         [0037]      FIG. 6  is an illustrative example  600  of the techniques from  FIG. 1  or  FIG. 2  wherein a medical professional  602  injects a temperature responsive polymer into a patient  604 . The medical professional  602  takes a syringe containing polymer  606  and injects the polymer  606  into or around a lesion  104  found in the breast (or other) tissue of the patient  604  to mark a location of the lesion  104  for excision. 
         [0038]      FIG. 7  is an illustrative example  700  of the techniques shown in  FIG. 1  or  FIG. 2  wherein a medical professional  602  removes a lesion  104  marked with a temperature responsive polymer  108  from the patient  604 . The lesion  104  may be removed with a sharp or cautery dissection (e.g., the scalpel  302  as shown above in  FIG. 3 ). The medical professional  602  uses the polymer  108  as a way to increase the palpability of the lesion  104  so to increase the chance of removing the entire lesion  104  including the margin and by so doing decreasing the likelihood that re-excision will be needed. Once removed, the excised lesion  702  can be placed in tray  704  or other container and allowed to cool to room temperature or refrigerated. The polymer  108  can be removed or drained from the excised lesion  702  after the polymer  108  returns to a liquid state. After the polymer  108  drains away from the excised lesion  702  the tissue of the lesion is unchanged from its state in situ so the excised tissue is suitable for examination because the polymer  108  does not leave artifacts. 
       EXAMPLES 
     Testing Polymer Reaction to Addition of Titanium Oxide Beads 
       [0039]    The purpose of the experiment was to determine how the addition of a radiopaque material to the hydrogel would affect the rate at which the hydrogel polymer  108  hardens in vivo. The hydrogel polymer  108  was colored with methylene blue to enhance in vivo visualization In  FIGS. 8 and 9  a radiopaque material was used to examine if a polymer  108  including radiopaque beads exhibits increased palpability upon set-up. A radiopaque material in bead form may also act as a visible dye which would additionally aid in making the polymer easily detectable during surgery. 
         [0040]    Uncooked chicken breasts  802  were used and heated to approximately 37 degrees Celsius, in a water bath  804  to simulate human breast tissue. A 16 gauge needle  806  was inserted in the breasts to inject the solutions comprising distilled water, 28% poly(N-isopropylacrylamide) and titanium oxide beads. Three different weight percentages to titanium oxide beads were tested: the first was no titanium oxide; the second was 10% titanium oxide; and, the third was 25% titanium oxide by weight. Following injection the solutions were allowed to sit for 30 minutes at 37 degrees Celsius before dissection to evaluate the effectiveness of the titanium oxide bead addition. 
         [0041]      FIG. 9  illustrates the solution, comprising the distilled water, colored polymer, and radiopaque beads, following injection of the solution, a 30 minute wait to allow the solution to harden, and incision into the chicken breast tissue  802 . Incision into the chicken breast tissue  802  exposes the hardened polymer  902  for inspection of the injected solution. The methylene blue coloration of the hardened polymer  902  provided good contrast relative to the chicken breast tissue  802 . 
         [0042]    None of the injected solutions were palpable from the outside of the chicken breast tissue  802 , but owning to the thickness and density of chicken breast tissue  802  this was not entirely unexpected. Human breast tissue is less dense than chicken breast so it is possible that the hardened polymer  902  may be externally palpable in a human breast. After the 30 minute wait the chicken breast tissue  802  was cut open to examine the injected polymer  902 . The first two solutions (i.e., 0% titanium oxide and 10% titanium oxide) polymerized  902  and were palpable, but the third solution (i.e., 25% titanium oxide) failed to completely solidify and ultimately returned to its liquid state before it could be examined. 
         [0043]    The hardened polymer  902  resulting from the first solution permeated the tissue within the breast to the size of a 1×0.5−0.25 inch (2.54×1.25−0.64 centimeter) rectangle. It is also possible to leave a trail of polymer leading to the injection site by continuing to inject the polymer as the needle is withdrawn. The second and third solutions returned to their liquid state before it was possible to take any size or permeability measurements. 
         [0044]    This experiment shows that addition of titanium oxide beads at higher concentrations may have a negative effect on polymerization at body temperature. It follows then that if titanium oxide beads are to be used with poly(N-isopropylacrylamide) in distilled water, a weight percent of 10% or less should be used. 
       CONCLUSION 
       [0045]    Although the subject matter has been described in language specific to structural features and/or methodological acts, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features or acts described. It will be appreciated that, based on the teachings of the present disclosure, a variety of alternate implementations may be conceived, and that the present disclosure is not limited to the particular implementations described herein and shown in the accompanying figures. Rather, the specific features and the acts are disclosed as exemplary forms of implementing the claims.

Technology Category: a