WO2019050310A1

WO2019050310A1 - Needle-type electrode device for irreversible electroporation through endoscope

Info

Publication number: WO2019050310A1
Application number: PCT/KR2018/010448
Authority: WO
Inventors: 이재민; 이홍식; 전훈재; 최혁순; 김은선; 금보라; 김승한; 유인경
Original assignee: 고려대학교산학협력단
Priority date: 2017-09-06
Filing date: 2018-09-06
Publication date: 2019-03-14

Abstract

The present invention relates to a needle-type electrode for irreversible electroporation through an endoscope comprising: a hollow body; a handle which is disposed on one end of the body; a catheter which is formed from a flexible material and is connected to the other end of the body so as to be inserted according to a minimally-invasive surgical procedure connected along one direction; and a needle electrode which moves along the inside of the catheter and protrudes towards the front from the end of the catheter according to the driving of the handle. The needle electrode comprises: a needle; an anode electrode and a cathode electrode spaced apart from each other at a predetermined interval on the needle; at least one insulation part disposed along the needle so as to neighbor the anode electrode and the cathode electrode, thereby electrically separating the anode electrode and the cathode electrode; and an anode line and a cathode line connected to the anode electrode and the cathode electrode, respectively, and extending, along the catheter and the body, towards the rear.

Description

[Correction according to Rule 26, 01.11.2018] A needle-like electrode device for irreversible electric perforation through an endoscope

The present invention relates to a needle-like electrode device for irreversible electric piercing through an endoscope, and more particularly to a needle-like electrode device in which two electrodes, an anode and a cathode, are arranged on a single needle, To a needle-like electrode apparatus for irreversible electrical piercing through an electrode.

The irreversible electrosurgery (IRE) is a new treatment that induces cell necrosis with multiple holes in the cell membrane using an electrode that delivers a high voltage of up to 3 kV into the tumor. It is a therapy that induces necrosis by inserting it in vitro and then applying a high voltage electric pulse to cause fine holes in the cell wall of the tissue in the gap between the electrodes. This treatment induces cell death by passing a pulsed electric pulse through the tumor at millions of times per second to induce microscopic pores in the cell membrane.

These irreversible electrosurgical procedures were initially introduced by Davalos et al. In 2005 and were approved by the FDA in 2011 and are now being used with limited limited scope in new topical treatments for patients unable to undergo surgical treatment adjacent to major vessels and organs .

Previously, irreversible electrosurgery was performed using an elongated rod-shaped electrode consisting of an anode and a cathode, and a method of inserting an electrode rod needle into a lesion in vitro after undergoing general anesthesia or under CT guidance was used. However, general anesthesia is necessary, repetitive procedures are difficult, and there is a risk of infection, which limits clinical use widely. It is difficult to apply to the pancreas and other organs located deeply in the back of the abdominal cavity because the needle must be inserted through the abdominal organs.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a needle-like electrode device for irreversible electric piercing through an endoscope in which two electrodes, an anode and a cathode, are arranged in a single needle and can be performed by a non-invasive method through an endoscope.

The objects of the present invention are not limited to the above-mentioned objects, and other objects not mentioned can be clearly understood by those skilled in the art from the following description.

In order to achieve the above object, according to an embodiment of the present invention, there is provided a hollow body, a handle disposed at one end of the body, and a flexible material inserted into the body in accordance with a minimally invasive procedure, A needle-like electrode for irreversible electrical piercing through an endoscope including a needle electrode moving along a catheter and an interior of the catheter and protruding forward at a catheter end as the handle is driven, the needle electrode comprising: a needle; An anode electrode and a cathode electrode spaced apart from each other by a predetermined distance on a needle; At least one insulating portion disposed adjacent to the anode electrode and the cathode electrode along the needle to electrically separate the anode electrode and the cathode electrode; And cathode and cathode lines connected to the anode and cathode electrodes, respectively, extending backward along the catheter and the body.

In this embodiment, at least one of the anode electrode and the cathode electrode may be formed in a polygonal shape so as to widen the contact area along the circumferential direction.

In this embodiment, the insulating portion includes a fixed insulating portion disposed between the anode electrode and the cathode electrode; And a variable insulation portion disposed at the rear of the fixed insulation portion to variably adjust an exposed area of the anode electrode and the rear electrode of the cathode electrode.

According to another embodiment of the present invention, there is provided a catheter comprising: a flexible catheter inserted according to a minimally invasive procedure connected along one direction; a needle inserted along the inside of the catheter and projecting forward from the catheter end according to the driving of the handle, A needle electrode of a needle-like electrode which includes an electrode and induces the activity of a beta cell responsible for insulin secretion of the pancreas as a stimulus of light to promote insulin secretion in a diabetic patient; An optical fiber attached to the needle; And a protective film for protecting the optical fiber, wherein the protective film is formed with at least one incision along one direction so that a region of light provided from the optical fiber is provided to the pancreas.

In another embodiment of the present invention, the light provided through the optical fiber may be formed of a red wavelength (RED) of 600 nm or a near-infrared ray of 800 nm.

The needle-like electrode for irreversible electric perforation through the endoscope according to the present invention can be inserted into the body through the endoscopic procedure by disposing the cathode and the anode respectively on one needle so that the organ such as the pancreas, It is possible to perform necrosis by inducing fine holes in the cell wall of the tissue at intervals between the electrodes by applying an electric pulse.

The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned can be clearly understood by those skilled in the art from the following description.

1 is an operational state view of a needle-like electrode device having a needle-like electrode for irreversible electric piercing through an endoscope according to an embodiment of the present invention.

FIG. 2 is a view illustrating various embodiments of a cross-sectional shape of a needle electrode of a needle-like electrode for irreversible electric drilling through an endoscope according to an embodiment of the present invention.

3 is an operational view of an insulating portion of a needle electrode of a needle-like electrode for irreversible electric perforation through an endoscope according to an embodiment of the present invention.

FIG. 4 is a view of a needle-like electrode for promoting insulin secretion in a diabetic patient for irreversible electroporation through an endoscope according to another embodiment of the present invention. FIG.

5 to 7 are experimental examples in which irreversible electrosurgery through an endoscope according to an embodiment of the present invention is applied to a livestock.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. Note that, in the drawings, the same components are denoted by the same reference symbols as possible. Further, the detailed description of known functions and configurations that may obscure the gist of the present invention will be omitted. For the same reason, some of the components in the drawings are exaggerated, omitted, or schematically illustrated.

Also, throughout the specification, when an element is referred to as " including " an element, it is understood that the element may include other elements as well, without departing from the other elements unless specifically stated otherwise. Also, throughout the specification, the term " on " means located above or below a target portion, and does not necessarily mean that the target portion is located on the upper side with respect to the gravitational direction.

1, a needle-like electrode device 10 having a needle-like electrode for irreversible electric piercing according to an embodiment of the present invention includes a hollow body 110, The catheter 130 and the catheter 130 that are connected to the other end of the handle 120 and the body 110 and are connected along one direction to be inserted according to the minimally invasive procedure, And a needle electrode 140 protruding forward from the end of the catheter 130 according to driving of the catheter 130.

The hollow body 110, the handle 120 and the flexible material catheter 130 described above are connected to the needle electrode 140 through manipulation of the handle connected to the electrode on the inner skin of the flexible catheter 130, A detailed description of the needle electrode 140 except for the needle electrode 140 will be omitted.

Fig. 2 shows various embodiments of the cross-sectional shape of a needle electrode of a needle-like electrode for irreversible electric piercing through an endoscope according to an embodiment of the present invention. Fig. 3 is a cross- Fig. 7 is an operational view of the insulating portion of the needle electrode of the needle-like electrode for perforation.

2 and 3, the needle electrode 140 according to the embodiment of the present invention includes a needle 141, an anode electrode 142a and a cathode electrode 142b, an insulating portion 143, (144).

The needle 141 is inserted into the catheter 130 and protrudes forward according to an operation part provided on the handle 120. [

The anode electrode 142a and the cathode electrode 142b are arranged along the circumferential direction of the needle 141 and spaced apart from the needle at a predetermined interval. At this time, the anode electrode 142a and the cathode electrode 142b may be formed in a circular shape or may be formed in a polygonal shape so that the contact area increases along the circumferential direction. At this time, more preferably, the contact area may be formed in a wrinkled shape. Although the star-shaped polygonal shape is described as an example in the present embodiment, it may be formed in various shapes to increase the contact area. At this time, the cross-sectional shape of the needle 141 may be formed in a polygonal shape corresponding to the shapes of the anode electrode 142a and the cathode electrode 142b.

As described above, when the anode electrode 142a and the cathode electrode 142b attached to the needle 141 are formed in a polygonal shape, the amount of internal charge can be increased. Since the effect of irreversible electrosurgery is proportional to the electric field externally applied, this electric field can increase the effectiveness of irreversible electrosurgery in proportion to the number of free electrons that the metal possesses, that is, the amount of charge. In addition, when the pancreas is formed into a polygonal shape with a wrinkle shape rather than a smooth surface due to the development of microvessels, the contact force with the microvessels can be increased, thereby maximizing the effect of irreversible electrical punching.

The insulating portion 143 is disposed adjacent to the anode electrode 142a and the cathode electrode 142b along the needle and electrically separates the anode electrode 142a and the cathode electrode 142b from each other. The insulating portion 143 may be fixedly disposed on the neighboring anode electrode 142a and cathode electrode 142b, respectively, as shown in FIG. 3A.

Alternatively, as shown in FIG. 3B, the insulating portion 143 may be provided as a fixed insulating portion 143a and a variable insulating portion 143b. The fixed insulating portion 143a is disposed between the anode electrode 142a and the cathode electrode 142b located at the end of the needle 141. [

The variable insulation portion 142b is disposed at the rear of the cathode electrode 142b and the syllable edge portion 143 is disposed adjacent to the anode electrode 142a and the cathode electrode 142b along the needle to form the anode electrode 142a and the cathode electrode 142b, (142b), and at least one of them is provided. The insulating portion 143 may be fixedly disposed on the neighboring anode electrode 142a and cathode electrode 142b, respectively, as shown in FIG. 3A.

The variable insulation portion 142b is disposed behind the cathode electrode 142b and can be variably moved toward the cathode electrode 142b so that the exposed area of the cathode electrode 142b disposed at the rear can be variably adjusted. The variable insulation portion 142b maximizes the effect of the irreversible electric perforation by allowing the amount of the internal charge to be further accommodated by variably adjusting the exposed area of the electrode, thereby increasing the exposed area of the electrode and exposing the electric field to the tissue By increasing the frequency that can be done, the therapeutic effect can be greatly increased. In the present invention, the anode electrode 142a is positioned at the end of the needle 141, but the cathode electrode 142b may be positioned at the end of the needle 141, and the arrangement method thereof is not limited thereto .

The positive and negative electrodes 144 are coupled to the anode electrode 142a and the cathode electrode 142b respectively and extend backward along the catheter 130 and the body 110. [ At this time, the cathode line and the cathode line 144 may be connected to a generator for irreversible electric drilling to form electric pulses at the anode electrode 142a and the cathode electrode 142b.

Referring to FIG. 4, a needle-like electrode for promoting insulin secretion in a diabetic patient for irreversible electrical perforation according to another embodiment of the present invention includes a flexible material inserted according to a minimally invasive procedure connected along one direction And a needle electrode inserted along the inside of the catheter and inside the catheter to protrude forward from the end of the catheter according to the driving of the handle to provide light. Hereinafter, only the needle electrode will be described in detail.

The needle electrode 200 includes a needle 210, an optical fiber 220 and a protective film 230. The needle electrode 200 induces the activity of a beta cell responsible for the insulin secretion of the pancreas as a light stimulus, .

As described above, the needle 210 is inserted into a catheter (not shown) and protrudes forward according to an operation part provided on a handle (not shown).

The optical fiber 220 is attached to the needle 210 and provides light according to an external signal. At this time, the provided light may be formed of a red wavelength (RED) of 600 nm or a near-infrared ray of 800 nm.

The protective film 230 serves to fix the optical fiber 220 to be attached to the needle 210 and the cutout portion 231 is formed in the protective film 230 so that the light projected to the optical fiber 220 is exposed to the outside. Therefore, light can be projected toward a lesion or the like of the pancreas through the incision 231. [ At this time, the incision part 231 is formed with a front incision part 231a and a rear incision part 231b, and the front incision part 231a and the rear incision part 231b respectively irradiate the front part and the back part of the pancreas, It is possible to uniformly irradiate beta cells distributed over the entire surface area. In addition, depending on the state of the pancreas, the front incision section 231a and the rear incision section 231b may be irradiated with light having different intensities.

The method of irradiating light is CW (continuous wave) and PW (pulsed wave) type, and it is preferable to use PW having excellent efficiency and effect, but the method of irradiating light is not limited thereto.

Hereinafter, with reference to FIGS. 5 to 7, procedures and results of testing the performance of a needle-like electrode device for irreversible electric drilling through an endoscope according to an embodiment of the present invention will be described.

[Example]

- Animal condition of the subject -

35 kg ± 5 kg of Yorkshire pigs were used. The pigs were housed in the housing for 7 days at 22 to 24 ° C, 55% humidity and 12 hours (day) and 12 hours (night). Animals did not feed on the night before surgery. Surgery was performed by intravenous injection of midazolam (0.5 ml / kg) and ketamine (25 mg / kg) under general anesthesia. This procedure has been approved by Korea University's Institutional Animal Care and Use Committee (IACUC number: KOREA-2016-0062).

- Experimental (surgical) procedures -

In this example, we used two approaches for IRE ablation, the surgical approach and the EUS-guided endoscopic approach. Laparotomy was performed after induction of general anesthesia in a surgical approach. The pancreas was exposed in the abdomen and mobilized to perform the IRE. IRE resection was performed by manual endoprosthesis using an endoscopic needle electrode. In the EUS guided endoscopic approach, the linear EUS endoscope advances stomach. The endoscope needle-electrode was inserted through the working channel of the scope. The needle electrode was pierced and passed through the pancreas toward the needle or tail. The delivered energy is 10 consecutive pulse waveforms with 5 pulses, pulse duration of 100 μs, amplitude of 2000 V, repetition frequency of 1 Hz, and a pause of 2 seconds between 5 pulse sequences.

- Evaluation after surgery (surgery) procedure -

The pigs were sacrificed 24 hours after the procedure and the pancreas was excised for histopathological evaluation. After formalin fixation, the thalamus of each pancreas was sampled at a thickness of about 2-3 mm from the thickness of the puncture site. Paraffin-embedded sections were cut and stained with hematoxylin and eosin (H & E).

The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate digoxigenin nick endlabeling assay was also performed. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate digoxigenin nick endlabeling assay was performed. A digitized slide was obtained from the scanner and analyzed using the viewer software.

- result -

Resection and Clinical Course

Six female Yorkshire pigs underwent IRE resection for the pancreas (three pigs with a surgical approach and three pigs with an EUS-guided endoscopic approach). The removal of IRE for the pancreas was technically successful and effective using needle electrodes using the endoscopic approach.

In both methods, no sparks or shorts were observed in the procedure using devices with linearly arranged electrodes. In the EUS guided endoscopic approach, the device was well visualized with a high echo line with a significant band of electrodes on the EUS. IRE resection was successfully performed in all cases of 2000 V. IRE resection had short-term muscle contraction.

Immediately after the IRE was performed, there was no significant change in the resected pancreas except for local bleeding at the thoracic site. All pigs tolerated the procedure at the time of the procedure and 24 hours after the procedure, and serious complications did not occur during the study.

A needle-like electrode device for irreversible electric drilling was used as described above.

- Pathology -

No significant findings of the pancreas were found except for small hematoma at the thoracic site (Fig. 5A). Pathologic examination after sagittal incision showed well-differentiated pancreatic lesions (Fig. 5b). The ablation site was round and measured 10-15 mm in size. A small round hematoma near the ablation site was found in one pig. Pathologic examination showed good necrosis of pancreatic parenchyma. The pancreatic tissue stained with H & E showed round-shaped diffusion cell death at the center of the puncture site (FIG. 6A). A necrotic, inflammatory change was noted if there was a residual pancreatic site at the ablation site (Fig. 6b).

Pancreatic tissue away from the puncture site was less damaged and normal acinar cells were preserved (Figure 6b). A clear distinction was made between pancreas survival and non-viable tissues after IRE resection (Figure 6d). At high magnification, blood vessels such as extracellular matrix, ducts and small arteries and arterioles are preserved. Within the restricted area, their original structure was preserved. Positive results of the TUNEL assay (TUNEL assay) in the resected area indicate involvement of apoptosis (Figure 7). In the round resected area, cell thickening (pyknosis) and pancreatic parenchymal karyorrhexis were observed. There were no significant differences in resection results between the surgical approach and the EUS - guided endoscopic approach.

The present invention has revealed that EUS induced IRE elimination of the pancreas is feasible and effective. Under real-time monitoring of EUS, the entire procedure could be performed and the pancreatic lesion could be accurately targeted. Experimental procedures were performed in only 6 animals, but no serious complications such as perforation, burns and procedural bleeding occurred. On the other hand, conventional THA requires open abdominal surgery under general anesthesia, and EUS induced IRE can be performed using only EUS without surgery.

In addition, the endoscope IRE is easily performed under the EUS and can be visualized well. EUS induced IRE was effective in eliminating pancreatic lesions and inducing necrosis of pancreatic parenchyma. The electrodes were arranged linearly on the needle, but the resection was formed in a round shape. The ablation site showed positive results of TUNEL analysis and cell death. The original structure of the extracellular matrix, pancreatic duct, and blood vessels was preserved within the resected region.

It should be noted that the embodiments of the present invention disclosed in the present specification and drawings are only illustrative of the present invention in order to facilitate description of the present invention and to facilitate understanding of the present invention and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that other modifications based on the technical idea of the present invention are possible in addition to the embodiments disclosed herein.

Claims

A catheter comprising: a hollow body; a handle disposed at one end of the body; a flexible catheter inserted in accordance with a minimally invasive procedure connected to the other end of the body in one direction; A needle-like electrode device for irreversible electric piercing through an endoscope including a needle electrode protruding forward from a terminal end of the catheter according to driving,

The needle electrode

needle;

A cathode electrode and a cathode electrode spaced apart from the needle at a predetermined interval;

At least one insulating portion disposed adjacent to the anode electrode and the cathode electrode along the needle to electrically separate the anode electrode and the cathode electrode; And

And an anode and a cathode connected to the anode and the cathode and extending backward along the catheter and the body, respectively.
The method according to claim 1,

Wherein at least one of the positive electrode and the negative electrode comprises:

Wherein the electrode is formed in a polygonal shape so as to widen the contact area along the circumferential direction.
The method according to claim 1,

Wherein the insulating portion comprises:

A fixed insulating portion disposed between the positive electrode and the negative electrode; And

And a variable insulation portion disposed rearward of the fixed insulation portion and configured to variably adjust an exposed area of the anode electrode and the electrode disposed behind the cathode electrode. The endoscope according to claim 1, Electrode device.
A catheter comprising: a hollow body; a handle disposed at one end of the body; a flexible catheter inserted into the body in accordance with a minimally invasive procedure connected to the other end along one direction; And a needle electrode protruding forward from the end of the catheter to provide light, wherein the needle electrode for promoting insulin secretion in a diabetic patient by inducing the activity of a beta cell responsible for insulin secretion of the pancreas to light stimulation, In this case,

The needle electrode

needle;

An optical fiber attached to the needle; And

And a protective film for protecting the optical fiber,

The protective film may be formed,

Wherein at least one incision is formed along one direction so that a region of light provided by the optical fiber is provided to the pancreas.
5. The method of claim 4,

Wherein the light provided through the optical fiber is a red wavelength (RED) in the 600 nm band or a near infrared ray in the 800 nm band.