Patent Publication Number: US-2019183563-A1

Title: Therapeutic device employing endoscope-interworking electrode

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This present application is a national stage filing under 35 U.S.C § 371 of PCT application number PCT/KR2017/006193 filed on Jun. 14, 2017 which is based upon and claims the benefit of priority to Korean Patent Application Nos. 10-2016-0074045 and 10-2017-0074861 filed on Jun. 14, 2016 and Jun. 14, 2017 respectively in the Korean Intellectual Property Office. The disclosures of the above-listed applications are hereby incorporated by reference herein in their entirety. 
    
    
     TECHNICAL FIELD 
     The present invention relates to a therapeutic device for electrically destroying a target cell in a human body in cooperation with an endoscope. 
     BACKGROUND ART 
     Generally, electroporation denotes a therapeutic technique used for injecting a target substance such as intracellular DNA or the like. Specifically, the electroporation aims to form a perforation on a cell membrane through voltage application and inject the target substance through the perforation. 
     Since the cell membrane is made of lipids, when a high voltage is applied thereto, lipids move to one side, which may result in formation of a perforation on a cell membrane. The perforation can be filled depending on the magnitude of the applied voltage. The case in which the perforation formed through the voltage application is filled as time elapses is referred to as “reversible electroporation.” 
     On the contrary, the case in which the perforation formed through the voltage application is not filled even after time elapses is referred to as “irreversible electroporation.” The irreversible electroporation is characterized in that a target cell is necrotized by forming in the target cell a perforation that is not filled even after time elapses. 
     Potassium ions (K + ), which are necessary for controlling intracellular metabolism, exist in cells. If a perforation is formed on a cell membrane, the potassium ions flow out of the cell through the perforation. The cell having an abnormal potassium concentration due to the flow out of the potassium ions receives a signal leading to apoptosis from a receptor on a cell membrane. The apoptosis caused by such irreversible electroporation can be applied to abnormal cells such as cancer cells or malignant tumors. 
     A conventional electroporation was mostly the reversible electroporation for transmitting a desired substance to a target cell, rather than the irreversible electroporation for necrotizing a target cell. The irreversible electroporation was hardly performed in a human body. This is because, in the irreversible electroporation for necrotizing a target cell in a human body, it is important to accurately set a target cell, but it is considerably difficult to accurately recognize a target cell. 
     DETAILED DESCRIPTION ON THE INVENTION 
     Technical Problem 
     The present invention provides a therapeutic device capable of performing irreversible electroporation in a human body. 
     Technical Solution 
     In accordance with one embodiment of the present invention for achieving the above object, there is provided a therapeutic device including: an endoscope channel; and an electrode inserted into a human body through the endoscope channel, wherein the electrode destroys a target cell in the human body through voltage application, and the electrode includes a first optical fiber and a second optical fiber for detecting the degree of destruction of the target cell through impedance measurement. 
     In accordance with another embodiment of the present invention for achieving the above object, there is provided a therapeutic device including: an endoscope channel; and a catheter inserted into a human body through the endoscope channel, wherein catheter includes a perforated portion provided on an end thereof, which is inserted into the human body, and a plurality of electrodes that protrudes from the end of the catheter through the perforated portion to penetrate a target cell. 
     Advantageous Effect 
     In accordance with the present invention, the electrode capable of performing irreversible electroporation can accurately recognize a target cell in a human body in cooperation with an endoscope. 
     The irreversible electroporation in accordance with the present invention is advantageous in that side effects of the treatment are reduced because only the target cell is necrotized without affecting tissues. 
     The therapeutic device in accordance with the present invention can accurately recognize the degree of necrosis of the target cell by using a pair of optical fibers provided in the electrode. 
     The therapeutic device in accordance with the present invention has therein the configuration capable of recognizing the degree of necrosis of the target cell. Therefore, there is no need to provide an additional inspection device for detecting the degree of necrosis of the target cell. Accordingly, it is not required to remove the therapeutic device and then, insert an additional inspection device in order to monitor the status of the treatment during the treatment. As a result, the treatment efficiency is improved. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  schematically shows an enlarged view of an end of a therapeutic device in accordance with an embodiment of the present invention. 
         FIG. 2  schematically shows an enlarged view of an end of a therapeutic device in accordance with another embodiment of the present invention. 
         FIG. 3  schematically shows an electrode of the therapeutic device in accordance with another embodiment of the present invention. 
         FIG. 4  shows optical fibers provided in the electrode in accordance with an embodiment of the present invention. 
         FIG. 5  shows specific examples of electrodes shown in  FIG. 2 . 
         FIG. 6A  shows other specific examples of the electrodes shown in  FIG. 2 . 
         FIG. 6B  shows another specific example of the electrodes shown in  FIG. 2 . 
     
    
    
     BEST MODE FOR THE INVENTION 
     The advantages and features of embodiments and methods of accomplishing these will be clearly understood from the following description taken in conjunction with the accompanying drawings. However, embodiments are not limited to those embodiments described, as embodiments may be implemented in various forms. It should be noted that the present embodiments are provided to make a full disclosure and also to allow those skilled in the art to know the full range of the embodiments. Therefore, the embodiments are to be defined only by the scope of the appended claims. Like reference numerals will designate like parts throughout the specification. 
     Therapeutic Device According to First Embodiment 
       FIG. 1  schematically shows an enlarged view of an end of a therapeutic device in accordance with an embodiment of the present invention.  FIG. 2  schematically shows an enlarged view of an end of a therapeutic device in accordance with another embodiment of the present invention. 
     Referring to  FIG. 1 , a therapeutic device  10  according to a first embodiment of the present invention includes an endoscope channel  100 , and a first electrode  200  that can be inserted into a human body through the endoscope channel  100 . The first electrode  200  destroys a target cell  900  in the human body through voltage application. The first electrode  200  includes a first optical fiber  210  and a second optical fiber  220  for detecting the degree of destruction of the target cell through impedance measurement. 
     Hereinafter, the components of the therapeutic device  10  according to the first embodiment will be described in detail. 
     Endoscope Channel  100   
     The endoscope channel  100  is inserted into a human body so that an operator can see an inside of a patient&#39;s body with naked eyes. The endoscope channel  100  includes a body that can be gripped by a user, an image acquisition unit (not shown) for capturing an image of the inside of the patient&#39;s body, a housing (not shown) into which the first electrode  200  can be inserted, and an image output unit for visually outputting the captured image of the inside of the patient&#39;s body to the user. 
     The body of the endoscope channel  100  is formed in a shape that can be easily gripped and manipulated by the user, and has an inner space. The housing into which the first electrode  200  can be inserted, and a wiring that connects the image acquisition unit and the image output unit are provided in the inner space of the body. 
     When the endoscope channel  100  is inserted into the body of the patient, the body performs a function of protecting the wiring, the first electrode  200  and the like from body fluids of the patient. Therefore, the body needs to be able to withstand acidic body fluids such as gastric acid and the like. Further, the body is brought into direct contact with the inside of the patient&#39;s body, and thus should not release chemicals that are harmful to the human body. In order to satisfy the above two conditions, the body can be made of a medical polymer material such as fluorocarbons, polyamide, polyester, polyester elastomer, or the like. 
     The image acquisition unit is provided at an end of the body which is inserted into the human body. As for the image acquisition unit, it is possible to use various optical devices capable of obtaining an image by receiving light, such as a lens, an optical cable, and the like. The image acquisition unit may further include a light emitting device capable of emitting light to the front side of the body. 
     The housing is a space for accommodating the first electrode  200 . The housing has a diameter that allows the first electrode  200  to pass therethrough. Preferably, the housing has a diameter of 100 to 1000 μM. 
     When the housing has a diameter greater than 1000 μm, the body that accommodates the housing becomes excessively large, which makes it difficult to insert the endoscope channel  100  into the patient&#39;s body through an esophagus. When the housing has a diameter smaller than 100 μM, the intensity that is enough to protect the electrode may not be ensured. The housing as well as the body need to be able to withstand the acid body fluids such as gastric acid and the like, and should not release chemicals that are harmful to the human body. Therefore, the housing can also be made of a medical polymer material such as fluorocarbons, polyamide, polyester, polyester elastomer, or the like. 
     The image output unit outputs the image of the inside of the patient&#39;s body which has been captured by the image acquisition unit (not shown) so that the user can visually monitor the inside of the patient&#39;s body. The image output unit includes a display unit for visual output. The image output unit may be a portable unit that can be carried by a user, or may be a fixed unit such as a computer. 
     First Electrode  200   
       FIG. 3  schematically shows an electrode of the therapeutic device in accordance with another embodiment of the present invention. 
     Referring to  FIG. 3 , the first electrode  200  is a device for destroying a target cell through voltage application. Specifically, the first electrode  200  forms a perforation in a cell membrane made of lipids by applying a high voltage to the target cell. 
     If a sufficiently high voltage is applied to the target cell, the perforation in the cell membrane is not filled even after time elapses. If the perforation permanently exists in the cell membrane, potassium ions (K+) in the cell constantly flow out into the blood. Since the potassium ions control cellular metabolism, cells deficient in the potassium ions cannot perform a function such as cell replication or the like. Such abnormal cells receive a signal leading to apoptosis from a receptor on a cell membrane and result in necrosis. 
     The above-described series of processes from the voltage application to the target cell is referred to as “irreversible electroporation.” The apoptosis caused by the irreversible electroporation can be applied to abnormal cells such as cancer cells or malignant tumors. 
     In the case of physically excising the abnormal cells such as cancer cells and the like, normal cells or blood vessels in the vicinity thereof may be affected. However, in the case of using the irreversible electroporation, only the target cell is necrotized and, thus, adverse effects on surrounding tissues can be minimized. 
     The first electrode  200  according to the first embodiment may preferably have a pad shape. The pad-shaped first electrode  200  is brought into close contact with the target cell  900  such as a stomach wall or the like. Since the pad-shaped first electrode  200  is not inserted into the target cell  900 , the cell damage caused by the insertion does not occur. For example, in the case of using a therapeutic device on a stomach wall, if the first electrode  200  is inserted into the stomach wall, a scar, i.e., a perforation, from the insertion of the first electrode  200  into the stomach wall is left after the treatment. The perforation can be expanded by gastric acid, which may cause other side effects such as gastric ulcer and the like to the patient. 
     The first electrode  200  needs to apply a voltage to the stomach wall, and thus should be made of a material having a high electrical conductivity. The first electrode  200  as well as the housing or the body need to be able to withstand acidic body fluids such as gastric acid and the like, and should not release chemicals that are harmful to the human body. Therefore, the first electrode  200  can be preferably made of a metallic material such as 316 stainless steel, Co—Cr alloy, or Ti alloy. 
     First Optical Fiber  210  and Second Optical Fiber  220   
       FIG. 4  shows optical fibers provided in the electrode in accordance with an embodiment of the present invention. 
     Referring to  FIG. 4 , the first electrode  200  includes a first optical fiber  210  and a second optical fiber  220  for detecting the degree of destruction of the target cell through impedance measurement. In other words, the first optical fiber  210  and the second optical fiber  220  may be provided on one or more surfaces of the first electrode  200 . 
     The first optical fiber  210  and the second optical fiber  220  measure the degree of destruction of the target cell through voltage application by a near-infrared spectroscopy system. The near-infrared rays are emitted from the first optical fiber  210  toward the target cell. The target cell absorbs the near-infrared rays. The degree of absorption of the near-infrared rays may vary depending on the structure of the cell. The near-infrared rays that have passed through the target cell are detected by the second optical fiber  220 . Therefore, the user can recognize the degree of cell destruction by comparing the intensity of the near-infrared rays emitted from the first optical fiber  210  and the intensity of the near-infrared rays that have passed through the target cell and detected by the second optical fiber  220 . At this time, the impedance is an index for evaluating the degree of absorption of the near-infrared rays. 
     The near-infrared rays are not easily absorbed by water molecules and blood molecules, and thus can penetrate deep into tissues. Therefore, the near-infrared rays are advantageous in detecting the cell destruction compared to waves in other wavelength ranges. The wavelength range of the waves that can be used as the near-infrared rays is preferably 0.75 to 3 μM. When the wavelength of the waves is less than 0.75 μM, the cell may mutate due to the waves. When the wavelength of the waves is greater than 3 μM, the waves are hardly absorbed by the cell, which makes it difficult to detect the absorption of the waves by the cell depending on the structure of the cell. 
     The degree of destruction of the target cell is measured by using the near-infrared rays based on the following Beer Lambert law. 
     [Beer Lambert Law] 
     
       
         
           
             
               
                 
                   
                     
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     (I in : incident light, I out : emitted light, optical density, A A : absorbed light, S A : scattered light) 
     Others 
     The voltage that is applied to the target cell by the first electrode  200  to perform the irreversible electroporation may be 1 KV or more. If a voltage less than 1 KV is applied to the target cell, the reversible electroporation occurs and a perforation on a target cell membrane may be filled. The therapeutic method of the present invention in which the target cell is necrotized by forming a permanent perforation on the cell membrane of the target cell cannot be performed by the reversible electroporation. 
     The first electrode  200  can have a fixed axis  230  connected to the endoscope channel  100  and rotate about the fixed axis  230 . For example, when the first electrode  200  is located in the housing  130  of the endoscope channel  100 , the first electrode  200  may be oriented in parallel to the housing  130 . Accordingly, the diameter of the housing  130  which is required for the first electrode  200  to pass therethrough can be reduced. When the first electrode  200  reaches the target cell, the first electrode  200  can rotate along the outer contour of the target cell. Since the target cell in the human body is mostly curved, the electrode that rotates along the outer curve of the target cell can be brought into closer contact with the curved target cell. Accordingly, the voltage application efficiency is improved. 
     Referring to  FIG. 4 , the first optical fiber  210  and the second optical fiber  220  may have optical fiber holes to improve the accuracy of impedance measurement. The optical fiber holes allow the near-infrared rays emitted from the first optical fiber  210  to be directly transmitted to the second optical fiber  220 . Accordingly, the errors that may occur in the measurement of the degree of destruction of the target cell due to indirect transmission of the near-infrared rays are decreased. 
     Therapeutic Device According to Second Embodiment 
       FIG. 5  shows specific examples of the electrode shown in  FIG. 2 . 
     Referring to  FIGS. 2 and 5 , a therapeutic device according to a second embodiment includes an endoscope channel, and a catheter that can be inserted into a human body through the endoscope channel. The catheter includes a perforated portion formed on an end thereof, which is inserted into the human body, and a plurality of electrodes that can protrude from the end of the catheter through the perforated portion to penetrate a target cell. 
     The configuration of the endoscope channel  100  of the device according to the second embodiment of the present invention is substantially the same as that of the endoscope channel  100  of the device according to the first embodiment. Therefore, hereinafter, a catheter  300  according to the second embodiment and a second electrode  320  different from the first electrode will be described in detail. 
     Catheter  300   
     The therapeutic device according to the second embodiment of the present invention includes the catheter  300 . The catheter  300  includes a perforated portion  310  formed on an end thereof, which is inserted into the human body, and a plurality of electrodes  320  that can protrude from the end of the catheter through the perforated portion  310  to penetrate a target cell. 
     The catheter  300  needs to be able to withstand acidic body fluids such as gastric acid and the like, and should not release chemicals that are harmful to the human body. 
     Accordingly, the catheter  300  can be made of a medical polymer material such as fluorocarbons, polyamide, polyester, polyester elastomer, or the like. 
     The perforated portion  310  is provided on an end of the catheter  300 . The perforated portion  310  serves as a passage where the second electrodes  320  protrude from the catheter  300 . The number of the perforated portions  310  is not limited and can be adjusted, if necessary, by those skilled in the art. 
     The second electrode  320  according to the second embodiment of the present invention is inserted into the target cell and applies a voltage to the target cell. Therefore, the second electrode  320  can be formed in a shape suitable for insertion, preferably in a probe shape. The second electrode  320  needs to be made of a material having a high electrical conductivity in order to apply a voltage to a stomach wall. Further, the second electrode  320  as well as the catheter  300  need to be able to withstand acidic body fluids such as gastric acid and the like, and should not release chemicals that are harmful to the human body. Therefore, the second electrode  320  can be preferably made of a metallic material such as 316 stainless steel, Co—Cr alloy, or Ti alloy. 
     The voltage that is applied to the target cell by the second electrode  320  according to the second embodiment of the present invention to perform the irreversible electroporation may be  1  KV or more. If a voltage less than KV is applied to the target cell, the reversible electroporation occurs and a perforation on a target cell membrane may be filled. The therapeutic method of the present invention in which the target cell is necrotized by forming a permanent perforation on the cell membrane of the target cell cannot be performed by the reversible electroporation. 
     In accordance with the second embodiment of the present invention, there may be provided a plurality of second electrodes  320 . Preferably, the number of the second electrodes  320  may be the same as the number of perforated portions  310 . 
     Each of the second electrodes  320  has both of an anode and a cathode. When a current flows through the second electrode  320  in a state where the second electrode  320  is inserted into the target cell, an electric field is generated between the anode and the cathode in the second electrode  320 . A voltage is applied to the target cell due to the electric field thus generated. Since each of the second electrodes  320  of the present invention has both of the anode and the cathode, even if some of the second electrodes  320  are damaged, the treatment can be performed by other second electrodes  320 . 
     The second electrode  320  according to the second embodiment of the present invention may include a first optical fiber and a second optical fiber for detecting the degree of destruction of the target cell through impedance measurement. The description on the first optical fiber and the second optical fiber are the same as that on the first optical fiber  210  and the second optical fiber  220  according to the first embodiment. 
     Referring to  FIG. 5 , one or more protrusions having a curved surface may be formed at the second electrode  320 . One or more protrusions have a circular or an elliptical surface. In addition, one or more holes penetrating through the second electrode in one or more directions are formed at the second electrode. One or more holes may be formed to correspond to the positions of one or more protrusions. One or more holes may have a circular or an elliptical shape. 
     Even when the endoscope channel  100  is inserted into a patient&#39;s body, especially into a tissue, a target cell, a stomach or the like, the tissue, the target cell, the stomach, or the like keeps working. Thus, the insertion of the second electrode  320  into the tissue, the target cell, the stomach or the like is disturbed, or the second electrode  320  inserted into the tissue, the target cell, the stomach or the like is released therefrom. 
     However, a surface adhesive strength of the second electrode  320  can be improved by increasing a surface contact area of the second electrode  320  by forming one or more protrusions on the surface of the second electrode  320  or by forming one or more holes at the second electrode  320 . If the second electrode  320  is inserted into the tissue, the target cell, the stomach or the like in a state where the surface contact area of the second electrode  320  is increased, an insertion coupling force increases and the efficiency of the treatment can be improved. 
       FIG. 6A  shows other specific examples of the electrode shown in  FIG. 2 . And  FIG. 6B  shows another specific example of the electrodes shown in  FIG. 2 . 
     Referring to  FIGS. 2, 6A and 6  B, there are provided a plurality of third electrodes  330  of the present invention. Preferably, the number of the third electrodes  330  may be the same as the number of perforated portions  310 . 
     Each of the third electrodes  330  is separated into one or more anodes (+) and one or more cathodes (−) separately. In other words, each of the third electrodes  330  may be configured such that one or more anodes and one or more cathodes are arranged in parallel to each other. When a plurality of anodes (+) and a plurality of cathodes (−) are arranged in parallel to each other, the voltage application efficiency can be improved. 
     When the third electrode  330  in which a plurality of anodes (+) and a plurality of cathodes (−) are arranged in parallel to each other is inserted into a tissue, a target cells, a stomach or the like and, then, a current flows through the third electrode  330 , an electric field is generated between the anodes (+) and the cathodes (−). A voltage is applied to the target cell due to the electric field thus generated. In the case of inserting the third electrode  330  into a tissue, a target cell, a stomach or the like in a state where the anodes (+) and the cathodes (−) are arranged in parallel to each other, an insertion coupling area is increased and, thus, the treatment efficiency can be improved. 
     One or more protrusions having a curved surface may be formed at the anodes (+) and the cathodes (−) arranged in parallel to each other. One or more protrusions have a circular or an elliptical surface. In addition, one or more holes penetrating through the anodes (+) and the cathodes (−) in one or more directions are formed at the anodes (+) and the cathodes (−). One or more holes may be formed to correspond to the positions of one or more protrusions. One or more holes may have a circular shape or an elliptical shape. 
     When the surface contact areas of the anodes (+) and the cathodes (−) are increased by forming one or more protrusion or one or more holes on the surfaces of the anodes (+) and the cathodes (−), the surface adhesive strength of the anodes (+) and the cathodes (−) can be improved. If the third electrode  330  is inserted into a tissue, a target cell, a stomach or the like in a state where the surface contact areas of the anodes (+) and the cathodes (−) are increased, the insertion coupling force increases and the efficiency of the treatment can be improved. 
     While the present invention has been shown and described with respect to the embodiments, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the scope of the present invention as defined in the following claims.