tissue separator

Abstract

A biopsy apparatus comprising: a hollow sampling section including an elongated body having a long axis, a proximal end, a distal end, and an internal lumen located along the long axis, wherein the distal end of the sampling section has a distal opening set in shape and size to allow tissue to enter the internal lumen when the hollow sampling section advances axially into biological tissue; and at least one movable tissue manipulator extending from the wall of the body of the sampling section into the internal lumen and toward the proximal end of the sampling section, configured to move outward toward the wall and inward toward the internal lumen.

Description

[Technical Field]

[0001] Related Application This application claims the benefit of U.S. Provisional Patent Application No. 63 / 532,930, filed on August 16, 2023, the content of which is incorporated herein by reference. [Background Art]

[0002] In some embodiments, the present invention relates to tissue sampling, and more particularly, but not by way of limitation, to soft tissue sampling for biopsy. [Summary of the Invention]

[0003] Some examples of several embodiments of the present invention are set forth below (an embodiment may comprise fewer features than the features of one or more examples and / or all features of the examples).

[0004] Example 1 a. A hollow sampling portion comprising an elongated body having a longitudinal axis, a proximal end, a distal end, and an inner lumen therein, the elongated body positioned along the longitudinal axis, wherein the distal end of the sampling portion is provided with a distal opening shaped and sized to allow tissue to enter the inner lumen when the hollow sampling portion is advanced axially into biological tissue, the sampling portion; b. At least one movable tissue manipulator extending from a wall of the body of the sampling portion into the inner lumen and toward the proximal end of the sampling portion, wherein the at least one tissue manipulator is configured to move outward toward the wall and inward toward the inner lumen, the at least one tissue manipulator; A biopsy device comprising:

[0005] Example 2 The apparatus according to Example 1, wherein the at least one movable tissue manipulator is shaped and sized such that it is pushed toward the inner surface of the wall of the sampling section by the tissue entering the inner lumen, and returns toward the inner lumen to apply force to the tissue within the inner lumen.

[0006] Example 3 The apparatus according to Example 1 or 2, wherein the at least one tissue manipulator is configured to return to the inner lumen when the axial advance of the hollow sampling section stops.

[0007] Example 4 The apparatus according to any one of Examples 1 to 3, wherein the at least one tissue manipulator is an elastically flexible tissue manipulator configured to elastically bend toward the inner surface of the wall as the tissue enters the inner lumen through the distal opening, and to recover from the bending when the axial advance of the hollow sampling section into the biological tissue stops.

[0008] Example 5 The apparatus according to any one of Examples 1 to 4, wherein the at least one tissue manipulator is a partial cutout of the wall of the sampling section.

[0009] Example 6 The apparatus according to any one of Examples 1 to 5, wherein the at least one tissue manipulator is formed from the wall material.

[0010] Example 7 The apparatus according to any one of Examples 1 to 6, wherein the at least one tissue manipulator is formed by forming an arc-shaped notch in the wall, the width of the notch being 0.005 mm to 0.05 mm.

[0011] Example 8 The apparatus according to any one of Examples 1 to 7, wherein the at least one tissue manipulator comprises a distal end adjacent to the distal end of the sampling section and connected to or integrated with the wall, and a proximal end configured to be located within the inner lumen, wherein the distal end of the at least one tissue manipulator is located at a distance of 0.1 mm to 20 mm from the distal end of the sampling section, or at a distance of up to four times the inner width of the sampling section from the distal end of the sampling section.

[0012] Example 9 The apparatus according to any one of Examples 1 to 8, wherein the distal end of at least one tissue manipulator is located at the level of the wall of the hollow sampling section and / or is aligned with the wall of the hollow sampling section.

[0013] Example 10 The apparatus according to any one of Examples 1 to 9, wherein the radius of curvature of the at least one tissue manipulator between the distal end and the proximal end is the same as the radius of curvature of the wall of the hollow sampling section.

[0014] Example 11: The apparatus according to any one of Examples 1 to 10, wherein the radius of curvature of the at least one tissue manipulator between the distal end and the proximal end is up to 30% smaller or larger than the radius of curvature of the wall of the hollow sampling section.

[0015] Example 12: The apparatus according to any one of Examples 1 to 11, wherein the at least one tissue manipulator between the distal end and the proximal end is linear.

[0016] Example 13 The apparatus according to any one of Examples 1 to 12, wherein the pitch angle between the at least one tissue manipulator and the plane perpendicular to the long axis of the sampling unit is 5 to 30 degrees.

[0017] Example 14 The apparatus according to any one of Examples 1 to 13, wherein the at least one tissue manipulator is formed from a superelastic material and / or a shape memory alloy.

[0018] Example 15 The apparatus according to any one of Examples 1 to 14, wherein the at least one tissue manipulator is configured to return toward the inner lumen and apply force to the tissue within the inner lumen, thereby forming a tissue separation region in the tissue, the tissue separation region being a region more prone to tissue separation than other regions of the biological tissue.

[0019] Example 16 The apparatus according to any one of Examples 1 to 15, wherein the at least one tissue manipulator is configured to return toward the inner lumen and penetrate the tissue within the inner lumen, thereby forming a tissue separation region in the tissue, the tissue separation region being a region more prone to tissue separation than other regions of the biological tissue.

[0020] Example 17 The apparatus according to any one of Examples 1 to 16, wherein when the hollow sampling section rotates and / or retracts, the hollow sampling section applies sufficient force to the tissue in the inner lumen to separate the tissue sample from the tissue in the tissue separation region.

[0021] Example 18 The apparatus according to any one of Examples 15 to 17, wherein the hollow sampling section advances axially into the biological tissue while rotating in a first direction, and when the axial advance stops and the hollow sampling section rotates in a second opposite direction, the at least one movable tissue manipulator is configured to form the tissue separation region.

[0022] Example 19 The apparatus according to any one of Examples 1 to 18, wherein the at least one tissue manipulator includes a tissue penetration edge configured to form the separation region by contacting the tissue in the inner lumen and forming at least a partial circumferential groove or at least a partial circumferential slit in the tissue when the hollow sampling portion rotates.

[0023] Example 20 The apparatus according to any one of Examples 1 to 19, wherein the at least one tissue manipulator comprises at least two tissue manipulators each having a tissue contact end configured to contact the tissue within the inner lumen, and the tissue contact ends of the at least two tissue manipulators are located on a single plane substantially perpendicular to the long axis when each of the at least two tissue manipulators is fully extended into the inner lumen.

[0024] Example 21 The apparatus according to any one of Examples 1 to 20, further comprising at least one actuator and a shaft having a distal end and a proximal end, wherein the at least one actuator is connected to the proximal end of the shaft, the hollow sampling portion is connected to the distal end of the shaft, and the shaft is configured to rotate and / or axially advance the hollow sampling portion within the biological tissue.

[0025] Example 22 The apparatus according to any one of Examples 1 to 21, wherein the shaft rotates the sampling portion in a first direction while the sampling portion axially advances into the biological tissue, and rotation of the sampling portion by the shaft in a second, opposite direction causes the at least one tissue manipulator to form a tissue separation region and / or separates a tissue sample from tissue within the inner lumen.

[0026] Example 23 The apparatus according to any one of Examples 1 to 22, wherein the at least one actuator is configured to rotate the sampling portion at a tangential velocity of 2.5 to 1000 mm / sec.

[0027] Example 24 The apparatus according to any one of Examples 1 to 23, wherein the at least one actuator is configured to axially advance the sampling portion at an axial velocity of 1 to 100 mm / sec.

[0028] Example 25 The apparatus according to any one of Examples 1 to 24, wherein a ratio of an axial velocity to a tangential velocity of the sampling portion is 1 to 10.

[0029] Example 26: The apparatus according to any one of Examples 1 to 25, wherein the ratio of the axial speed to the tangential speed of the sampling unit is 2 to 5.

[0030] Example 27: The apparatus according to any one of Examples 1 to 26, wherein the shaft is a flexible shaft.

[0031] Example 28: The apparatus according to any one of Examples 1 to 27, wherein the sampling unit is shaped and sized to advance toward the biological tissue within the working channel of the endoscope. Example 29: The apparatus according to any one of Examples 1 to 28, wherein the hollow sampling section is equipped with a sampling needle.

[0032] Example 30: The apparatus according to any one of Examples 1 to 29, wherein the distal end of the sampling unit is substantially perpendicular to the long axis of the sampling unit.

[0033] Example 31 The apparatus according to any one of Examples 1 to 30, wherein the distal end of the sampling portion has an inner and / or outer sharp edge configured to form a circular notch that penetrates the biological tissue during the axial advance and / or rotation of the sampling portion into the biological tissue, and the edge surrounds the distal opening.

[0034] Example 32 a. The sampling unit of the biopsy device is advanced axially into the living tissue, wherein, during the axial advancement, a portion of the living tissue enters the inner lumen of the sampling unit, pushing at least one tissue manipulator extending from the wall of the sampling unit into the inner lumen outward toward the wall, thereby advancing the device. b. When the at least one tissue manipulator returns to the inner lumen, force is applied to the biological tissue portion by the at least one tissue manipulator, c. To form a tissue separation region in the biological tissue portion, wherein the tissue separation region is a region in which tissue separation is more likely to occur compared to other regions of the biological tissue portion within the inner lumen, in response to the application of separation force to the biological tissue portion. d. By applying the separation force to the biological tissue portion, the tissue sample is separated from the biological tissue portion in the tissue separation region. A method for sampling tissue, including the following.

[0035] Example 33 The method of Example 32, wherein the at least one tissue manipulator comprises two or more tissue manipulators, and the granting includes the two or more tissue manipulators grasping the biological tissue portion in the inner lumen when the two or more tissue manipulators return to the inner lumen.

[0036] Example 34 The method according to Example 32 or 33, wherein forming the tissue separation region with the at least one tissue manipulator includes forming at least a partial circumferential groove or slit in the biological tissue by rotating the at least one tissue manipulator while applying the force.

[0037] Example 35 The method according to any one of Examples 32 to 34, further comprising rotating the sampling unit and the at least one tissue manipulator while the at least one tissue manipulator applies the force to the biological tissue unit and forms at least a partial circumferential groove or slit in the biological tissue unit.

[0038] Example 36 The method according to any one of Examples 32 to 35, wherein advancing in the axial direction includes advancing in the axial direction while rotating the sampling unit in a first direction relative to the biological tissue, and forming includes forming the tissue separation region by rotating the sampling unit and the at least one tissue manipulator in a second opposite direction while applying the force to the biological tissue by the at least one tissue manipulator.

[0039] Example 37 The method according to any one of Examples 32 to 36, comprising stopping the axial advancement before forming the tissue separation region.

[0040] Example 38 The method according to any one of Examples 32 to 37, wherein the separation includes separating the tissue sample by applying a shear force to the biological tissue by rotating the sampling unit with respect to the biological tissue located outside the sampling unit.

[0041] Example 39 The method according to any one of Examples 32 to 38, wherein the separation comprises separating the tissue sample by retracting the sampling portion from the biological tissue and applying a tearing force to the biological tissue portion.

[0042] Example 40 The method according to any one of Examples 32 to 39, comprising advancing in the axial direction, granting, forming, and separating to obtain at least one additional tissue sample from the biological tissue.

[0043] Example 41 The method according to any one of Examples 32 to 40, wherein advancing in the axial direction includes advancing the sampling unit in the axial direction into the biological tissue at an axial speed of 1 to 100 mm / second.

[0044] Example 42 The method according to any one of Examples 32 to 41, wherein advancing in the axial direction includes rotating the sampling unit while advancing the sampling unit in the axial direction at a tangential speed of 2.5 to 1000 mm / second.

[0045] Example 43: The method according to Example 42, wherein the ratio of the axial speed to the tangential speed is in the range of 3 to 5. Example 44 a. A long, slender handle equipped with a gripping member, b. A slender, flexible shaft mechanically equipped with a hollow distal sampling section having an internal lumen and a distal opening facing soft tissue, c. A soft tissue biopsy apparatus comprising at least one drive unit configured to rotate the sampling unit while advancing the sampling unit axially into the soft tissue, A soft tissue biopsy device in which the ratio of the tangential rotation speed to the axial forward speed of the sampling unit is between 1 and 10.

[0046] Example 45: The apparatus according to Example 44, wherein at least one drive unit rotates the elongated flexible shaft at a tangential speed in the range of 2.5 to 1000 mm / second.

[0047] Example 46 The apparatus according to either Example 44 or 45, wherein the at least one drive unit advances the sampling unit in the axial direction at an axial speed in the range of 1 to 100 mm / second.

[0048] Example 47: The apparatus according to any one of Examples 44 to 46, wherein the distal opening is located at the distal end of the sampling section, and the distal end of the sampling section is either a flat, straight end or substantially perpendicular to the long axis of the sampling section.

[0049] Example 48: The apparatus according to any one of Examples 44 to 47, wherein the ratio is between 2 and 5.

[0050] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the invention pertains. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of embodiments of the invention, but exemplary methods and / or materials are described below. In case of any conflict, the patent specification, including definitions, shall prevail. In addition, materials, methods, and examples are illustrative and not necessarily intended to be limiting. [Brief explanation of the drawing]

[0051] Several embodiments of the present invention are described herein with reference to the accompanying drawings for illustrative purposes only. Details shown here with particular detail in reference to the drawings are for illustrative purposes only and are intended to provide a detailed description of embodiments of the present invention. Similarly, by examining the description together with the drawings, it will be clear to those skilled in the art how embodiments of the present invention can be put into practice. [Figure 1a] This is a flowchart of a general process for generating isolated regions in tissue according to several embodiments of the present invention. [Figure 1b] This is a schematic diagram of a process for generating isolated regions in tissue according to several embodiments of the present invention. [Figure 1c] This is a schematic diagram of a process for generating isolated regions in tissue according to several embodiments of the present invention. [Figure 1d] This is a schematic diagram of a process for generating isolated regions in tissue according to several embodiments of the present invention. [Figure 1e] This is a schematic diagram of a process for generating isolated regions in tissue according to several embodiments of the present invention. [Figure 1f] This is a flowchart of a process for tissue sampling according to several embodiments of the present invention. [Figure 2] This is a schematic diagram showing the change in the position of a flexible cutter during a tissue sampling process according to some embodiments of the present invention. [Figure 3a] This is a schematic diagram of the sampling section of a biopsy apparatus according to some embodiments of the present invention, where at least one cutter is aligned with the wall of the sampling section. [Figure 3b] This is a schematic diagram of the sampling section of a biopsy apparatus according to some embodiments of the present invention, in which at least one cutter extends inward into the inner lumen of the sampling section. [Figure 3c] This is a schematic diagram showing the orientation of two cutters extending into the inner lumen of the sampling section according to some embodiments of the present invention. [Figure 3d] This is a schematic diagram showing the orientation of two cutters extending into the inner lumen of the sampling section according to some embodiments of the present invention. [Figure 3e] This is a schematic diagram showing the orientation of two cutters extending into the inner lumen of the sampling section according to some embodiments of the present invention. [Figure 3f] This is a block diagram of a tissue sampling apparatus according to some exemplary embodiments of the present invention. [Figure 4] This is a flowchart of the detailed process for tissue sampling according to several embodiments of the present invention. [Figure 5a] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5b] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5c] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5d] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5e] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5f] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5g]This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 5h] This is a schematic diagram illustrating a tissue sampling process according to several embodiments of the present invention. [Figure 6a] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 6b] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 6c] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 6d] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 6e] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 6f] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 6g] This is a schematic diagram illustrating the extraction of a tissue sample from the inner lumen of the sampling section of a biopsy device according to several embodiments of the present invention. [Figure 7a] This is a schematic diagram of a sampling section according to some embodiments of the present invention, which has a cutter extending inward from the wall of the sampling section into the lumen of the sampling section. [Figure 7b] This is a schematic diagram of a sampling section according to some embodiments of the present invention, which has a cutter extending inward from the wall of the sampling section into the lumen of the sampling section. [Figure 7c] This is a schematic diagram of a sampling section according to some embodiments of the present invention, which has a cutter extending inward from the wall of the sampling section into the lumen of the sampling section. [Figure 7d]This is a schematic diagram of a sampling section according to some embodiments of the present invention, which has a cutter extending inward from the wall of the sampling section into the lumen of the sampling section. [Figure 7e] This is a schematic diagram of a sampling section according to some embodiments of the present invention, which has a cutter extending inward from the wall of the sampling section into the lumen of the sampling section. [Figure 8a] This is a schematic diagram of a tissue manipulator, such as a cutter, according to some exemplary embodiments of the present invention. [Figure 8b] This is a schematic diagram of a tissue manipulator, such as a cutter, according to some exemplary embodiments of the present invention. [Modes for carrying out the invention]

[0052] The present invention relates, in some embodiments, to tissue sampling, and more particularly, to soft tissue sampling for biopsy, but not limited to these embodiments.

[0053] overview One aspect of several embodiments of the present invention relates to separating a tissue sample from tissue within the lumen of a biopsy device using at least one tissue manipulator extending into the lumen from the wall of the biopsy device. In some embodiments, at least one tissue manipulator is positioned in the inner lumen in an orientation suitable for forming a separation region (e.g., a separation surface within the tissue), which is achieved, for example, by reducing the width, e.g., diameter, or volume of tissue in the separation region. In some embodiments, the separation region is a region within the tissue that connects two portions of tissue on either side of the separation region with a weak force. In some embodiments, when a shear force is applied to the tissue, a separation or gap is formed between the two portions of tissue on either side of the separation region in the separation region or separation surface.

[0054] According to some exemplary embodiments, the tissue manipulator manipulates tissue within the lumen of the biopsy device by at least one manipulator, making incisions in the tissue, forming grooves in the tissue, and / or penetrating the tissue, for example, screwing into the tissue, to grasp the tissue. In some embodiments, the tissue manipulator forms a circumferential or arc-shaped incision in the tissue so as to at least partially surround the tissue. Alternatively, the tissue manipulator forms a circumferential or arc-shaped groove in the tissue so as to at least partially surround the tissue.

[0055] According to some embodiments, the tissue manipulator includes at least one movable extension extending into the lumen of the biopsy apparatus, for example, from the walls of the biopsy apparatus surrounding the lumen. In some embodiments, the movable extension includes an optionally flexible cutter extending into the lumen from the walls of the biopsy apparatus, for example, a cutting tooth. In some embodiments, at least one flexible cutter is a part of the biopsy apparatus wall configured to bend inward into the lumen of the biopsy apparatus when relaxed. In some embodiments, at least one flexible cutter is configured to move between a first state and a second state, with the distal end of the flexible cutter optionally remaining connected to or integrated with the wall, the first state being a state in which the proximal end of the flexible cutter is substantially aligned with or substantially adjacent to the wall of the biopsy apparatus, and the second state being a state in which the proximal end of the flexible cutter moves inward into the lumen of the biopsy apparatus. In some embodiments, the distal end of the tissue manipulator, for example, the cutter, is positioned at the level of the wall of the sampling section and / or aligned with the wall of the hollow section.

[0056] According to some exemplary embodiments, when tissue penetrates the lumen of the biopsy device, for example, when the biopsy device moves axially into the tissue, the penetrating tissue pushes at least one movable extension, for example, the proximal end of the movable extension toward the wall, and optionally, acquires a first state. In some embodiments, when the axial advance into the tissue (axial advance) is stopped, at least one movable extension, for example, the proximal end of the movable extension moves inward into the lumen or bends, and optionally penetrates the tissue within the lumen.

[0057] According to some embodiments, at least a portion of the movable extension, for example, a flexible cutter, is connected to or integrated with the wall of the biopsy apparatus. In some embodiments, the flexible cutter is a partial cutout of the wall of the biopsy apparatus, for example, the wall of the sampling section (e.g., sampling needle) of the biopsy apparatus.

[0058] According to some embodiments, the angle between the movable extension, for example, the flexible cutter, and a plane perpendicular to the long axis of the biopsy device, for example, the pitch angle, is in the range of 5 to 30 degrees, for example, 10 to 20 degrees, 10 to 15 degrees, 12 to 15 degrees, 12 to 17 degrees, 13 to 18 degrees, 12 to 30 degrees, or any intermediate smaller or larger pitch angle or range of pitch angles toward the proximal end of the biopsy tube.

[0059] According to some embodiments, the distal end of the flexible cutter, away from its base, is provided with a cutting edge. In some embodiments, rotation of the distal end cutting edge of the flexible cutter cuts tissue in contact with the flexible cutter. In some embodiments, at least one flexible cutter comprises at least two flexible cutters extending into the lumen of the biopsy device from at least two positions on the circumference of the wall. Optionally, the two positions are in similar axial positions along the length of the biopsy device. Optionally, the two positions are in opposite positions on the circumference of the biopsy device wall. In some embodiments, the orientation between the base and distal end of each flexible cutter is similar, for example, along the rotational path of the biopsy tube.

[0060] Some embodiments of the present invention relate to forming a circumferential groove, or circumferential notch, in the tissue within the lumen by introducing tissue into the lumen of a biopsy device needle while rotating it in a first direction, and then rotating the needle in a second direction opposite to the first direction. In some embodiments, the tissue is shaped by a tissue manipulator extending into the lumen. In some embodiments, the tissue manipulator is a cutter extending into the lumen from the wall of the biopsy device needle and configured to cut the tissue when the biopsy tube rotates in the second direction. In some embodiments, the circumferential notch or groove is formed in a single cut surface, for example, to reduce the diameter of the tissue at the cut surface.

[0061] Although a tissue manipulator is described herein as a cutter that forms an incision in tissue, it should be noted that a tissue manipulator can grip or create a partial or complete groove in the tissue, such as a circumferential groove or an arcuate groove, and a tissue incision is an example of a groove. In some embodiments, the groove forms a separation region, which is an area of ​​tissue that is easily detached or separated. In some embodiments, the tissue sample is torn from the tissue within the inner lumen of the biopsy tube by rotation and / or retraction of the biopsy tube, but forming an incision in the tissue is optional.

[0062] Alternatively, or in addition to the above, a tissue manipulator is used to grasp tissue and therefore acts as a tissue grasper. In some embodiments, grasping tissue can, for example, apply force to the tissue by the rotation and / or axial retraction of the sampling section when the biopsy device retracts, thereby separating the grasped tissue from the tissue in the biopsy device lumen located distal to the tissue manipulator.

[0063] A potential advantage of having a separation region on a single surface is that it allows for the separation of the proximal tissue sample, which continues to flow within the inner lumen of the sampling section, from the distal tissue, which continues to be attached to the organ tissue. If the tissue manipulators in the sampling section are not positioned in similar axial positions relative to each other, after the separation of the tissue sample, the tissue may be captured by the tissue manipulators, preventing the tissue from penetrating the sampling section.

[0064] A further potential advantage of having one or more tissue manipulators extending into the inner lumen of the sampling section is that it reduces the cross-sectional area of ​​the sampling section, and in particular when optionally using a sampling needle with an inner diameter greater than 0.4 mm, it prevents penetration of body fluids, such as blood, into the sampling section and prevents contamination of the tissue sample by body fluids.

[0065] One aspect of several embodiments relates to a biopsy apparatus having a hollow distal sampling section configured to separate a tissue sample from biological tissue by advancing axially into biological tissue while rotating at a fixed or variable rotational speed. In some embodiments, the ratio of the tangential rotational speed to the axial advancement speed of the sampling section is between 1 and 10, for example between 3.5 and 4.5, for example between 2 and 5. In some embodiments, the axial advancement and rotation of the hollow sampling section at the above ratios apply a force to a portion of biological tissue located within the inner lumen of the sampling section that is sufficient to separate a tissue sample from the biological tissue section, for example, as described in International Patent Application Publication No. WO2019155472A1, which is incorporated herein by reference in its entirety.

[0066] According to some embodiments, the sampling unit is rotated at a tangential speed in the range of 2.5 to 1000 mm / sec, for example, 2.5 to 40 mm / sec, 30 to 40 mm / sec, 35 to 45 mm / sec, 30 to 50 mm / sec, 10 to 100 mm / sec, 50 to 500 mm / sec, 300 to 1000 mm / sec, or any intermediate, smaller or larger range. Also, while rotating, the sampling unit advances axially into the tissue at an axial speed in the range of 1 to 100 mm / sec, for example, 1 to 10 mm / sec, 5 to 12 mm / sec, 5 to 15 mm / sec, 5 to 50 mm / sec, 10 to 100 mm / sec, or any intermediate, smaller or larger range. According to some exemplary embodiments, the biopsy device comprises at least one drive unit, for example, a motor, for rotating the sampling unit and / or for advancing the sampling unit axially. In some embodiments, the biopsy apparatus comprises at least two motors: at least one motor for rotating the sampling section and at least one different motor for advancing the sampling section axially. In some embodiments, a hollow distal sampling section is connected to or integrated with the distal end of a shaft, such as a flexible shaft. In some embodiments, the proximal end of a shaft, such as a flexible shaft, is connected to at least one motor. In some embodiments, the shaft is configured to deliver power and / or force from at least one motor to the sampling section. An example of a biopsy apparatus is described in International Patent Application Publication No. WO2019155472A1, which is incorporated herein by reference in its entirety.

[0067] According to some exemplary embodiments, the sampling unit comprises at least one tissue manipulator described in this patent application when it moves forward and rotates axially at the above ratio. Alternatively, the sampling unit does not include at least one tissue manipulator when it moves forward and rotates axially at the above ratio. In some embodiments, the sampling unit is the sampling unit described in this application, with or without at least one tissue manipulator.

[0068] A potential advantage of rotating the sampling unit within a specific ratio range and advancing it axially into the biological tissue is that the biopsy device can efficiently separate one or more long, complete tissue samples from a portion of the biological tissue located within the inner lumen of the sampling unit, while preventing damage to the biological tissue outside the sampling unit.

[0069] Before describing in detail at least one embodiment of the present invention, it should be understood that the present invention is not necessarily limited to the configuration and arrangement details of the components and / or methods described below and / or shown in the drawings and / or examples. Other embodiments of the present invention are possible and can be carried out or implemented in a variety of ways.

[0070] Exemplary tissue separation According to some exemplary embodiments, a biopsy apparatus comprising a sampling section has at least one tissue manipulator extending into the inner lumen of the sampling section. In some embodiments, the at least one tissue manipulator comprises two or more tissue manipulators. Optionally, the axial positions of the two or more tissue manipulators are similar along the length of the inner lumen of the sampling section.

[0071] According to some exemplary embodiments, at least one tissue manipulator is a movable tissue manipulator configured to move between, for example, a first position which is a first state and, for example, a second position which is a second state. In some embodiments, the movable tissue manipulator is an elastic tissue manipulator, for example, an elastically flexible tissue manipulator. In some embodiments, the elastically flexible tissue manipulator is a tissue manipulator configured to move from a first position to a second position when a force is applied to the tissue manipulator, and to return to the first position when the application of force stops or when the force applied to the tissue manipulator decreases.

[0072] According to some exemplary embodiments, at least one tissue manipulator is positioned, and its shape and size are set, so as to be screwed into the tissue penetrating the inner lumen, for example, when the sampling section is rotated and advanced axially into the biological tissue. In some embodiments, the penetration of at least one tissue penetration member into the tissue in the inner lumen forms a tissue separation region. In some embodiments, the tissue separation region is a region of tissue where tissue separation is likely to occur. In some embodiments, the tissue sample is separated from the biological tissue penetrating the inner lumen by applying a force, such as a tearing or shearing force, to the tissue in the tissue separation region, for example.

[0073] Refer to Figure 1a here. Figure 1a shows a tissue separation process according to some exemplary embodiments of the present invention, for example, by generating tissue separation regions in the tissue.

[0074] According to some exemplary embodiments, in block 100, biological tissue is introduced into the inner lumen of the sampling section of the biopsy device. In some embodiments, the biological tissue is introduced into the lumen as the sampling section advances axially into the biological tissue. Optionally, the biological tissue is introduced into the lumen as the sampling section advances into the biological tissue while rotating. In some embodiments, the biological tissue is introduced into the lumen through the distal opening of the sampling section.

[0075] According to some exemplary embodiments, at least one tissue manipulator penetrates the living tissue in block 101. In some embodiments, at least one tissue manipulator extends into the inner lumen of the sampling section of the biopsy device. In some embodiments, at least one tissue manipulator penetrates the living tissue entering the inner lumen as the sampling section advances into the living tissue. In some embodiments, at least one tissue penetrates the living tissue in the inner lumen as the sampling section advances axially into the living tissue outside the sampling section, with the sampling section optionally rotating.

[0076] According to some exemplary embodiments, at least one tissue manipulator penetrates the biological tissue within the inner lumen of the sampling unit when the axial advance of the sampling unit stops and the force applied to the tissue manipulator is reduced, allowing the tissue penetration member to recover from the bending.

[0077] According to some exemplary embodiments, at least one tissue manipulator forms a separation region in the biological tissue within the inner lumen of block 105. In some embodiments, the separation region is a region of tissue that is more easily separated than other regions of the tissue. In some embodiments, at least one tissue manipulator forms a separation region by, for example, forming an incision in the biological tissue, such as a circumferential or arc-shaped incision, which optionally surrounds at least a portion of the biological tissue. Alternatively, or in addition to the above, at least one tissue manipulator forms a separation region by, for example, forming a groove in the biological tissue, such as a circumferential or arc-shaped groove, which optionally surrounds at least a portion of the biological tissue. Alternatively, or in addition to the above, at least one tissue manipulator forms a separation region by gripping the biological tissue, for example, by engaging or increasing the engagement between at least one tissue manipulator and the biological tissue, and optionally increasing the friction or gripping force between them.

[0078] According to some exemplary embodiments, in block 107, the tissue sample is separated from the living tissue. In some embodiments, the tissue sample is separated from the living tissue in a separation region. In some embodiments, the tissue sample is separated from the living tissue in a separation region by applying a force to the tissue, for example, a tearing force and / or a shearing force. In some embodiments, the tissue sample is separated by rotating the sampling unit. Alternatively, or in addition to the above, the tissue sample is separated by pulling or retracting the sampling unit from the living tissue.

[0079] Refer to Figures 1b to 1e. Figures 1b to 1e illustrate a tissue sampling process by forming a separation region in tissue according to several exemplary embodiments of the present invention.

[0080] According to some exemplary embodiments, as shown, for example, in Figure 1b, at least one tissue manipulator, for example, tissue manipulators 109 and 111, penetrates a portion 113 of biological tissue 115 located within the inner lumen 117 of the sampling unit 119. In some embodiments, the tissue manipulator penetrates the tissue 113 during the axial and / or rotational movement of the sampling unit into the biological tissue 115. Alternatively, the tissue manipulator penetrates the tissue 113 when the movement of the sampling unit 119, for example, the axial movement into the biological tissue 115, stops.

[0081] According to some exemplary embodiments, the movement of tissue manipulators, for example, manipulators 109 and 111, creates a separation region 121 in a tissue portion 113 located within the lumen 117, as shown, for example, in Figure 1c. In some embodiments, the formed separation region is a region within the tissue that is more susceptible to the force applied to the tissue, causing separation of the tissue 113 in the tissue separation region 121. In some embodiments, as shown, for example, in Figure 1c, the width of the tissue in the separation region 121, e.g., the diameter, is smaller than the width of the tissue distal and / or proximal to the region 121. In some embodiments, the separation region 121 is a region where the force applied to the tissue 113 within the sampling region is concentrated, causing tearing or separation between two portions of the tissue 113 in the separation region 121.

[0082] According to some exemplary embodiments, as shown, for example, in Figure 1d, while the tissue manipulator is positioned within the separation region, the retraction and / or rotation in the rotational direction 139 of the sampling unit applies a force to the tissue 113 in the separation region 121, such as a tearing force and / or a shearing force. In some embodiments, as shown, for example, in Figure 1e, the applied force separates the tissue, for example, the tissue sample 123 located within the lumen 117 and proximal to the manipulators 111 and 109, from the rest of the tissue 113 located inside and outside the inner lumen 117. In some embodiments, the rest of the tissue 113 is located distal to the separation region and / or the manipulators 109 and 111.

[0083] According to some exemplary embodiments, the formation of the separation region 121 allows for the location of the separation plane between the remaining portion of the biological tissue 113 located within the inner lumen 117 and the tissue sample 123.

[0084] Exemplary General Tissue Sampling Process According to some exemplary embodiments, the biopsy device is used for soft tissue sampling to obtain a biopsy sample from, for example, the soft tissue of the body, such as the pancreas, liver, at least one lymph node, lungs, spleen, and / or glandular tissue such as the thyroid gland. In some embodiments, the biopsy device is used to sample tissue suspected to be cancerous. In some embodiments, the sampling section of the biopsy device, for example, a sampling needle located at the distal end of the biopsy device, advances axially while rotating synchronously into the tissue at an arbitrarily specific ratio. In some embodiments, the tissue sample is separated from the tissue entering the sampling section when the sampling section rotates in the opposite direction to the rotation used when penetrating the tissue.

[0085] Refer to Figure 1f here. Figure 1f shows a process for sampling soft tissue according to some exemplary embodiments of the present invention, for example, a process for sampling volume within soft tissue, optionally including cancerous tissue or a tumor.

[0086] According to some exemplary embodiments, in block 102, the biopsy device advances toward the target tissue. In some embodiments, a sampling section, e.g., a flexible shaft terminated by a sampling needle, advances toward the target tissue. In some embodiments, the flexible shaft terminated by the sampling section advances toward the target tissue within and / or through the working channel of the endoscope. In some embodiments, the sampling section comprises at least one tissue manipulator, e.g., a cutter, configured to extend into the inner lumen of the sampling section.

[0087] According to some exemplary embodiments, as block 102 advances toward the target tissue, the inner lumen is optionally closed by the tissue penetration member. In some embodiments, the distal tip of the tissue penetration member extends at least partially through the distal opening of the sampling section facing the tissue and is configured to form a thin incision in the tissue wall, for example, as described in WO2022003691A1, which is incorporated herein by reference as a whole. In some embodiments, once the inner lumen is closed by the tissue penetration member, the body of the tissue penetration member within the inner lumen pushes at least one tissue manipulator toward the wall, for example, toward the inner surface of the sampling section wall.

[0088] According to some exemplary embodiments, in block 103, the tissue penetration member is optionally removed from the inner lumen. In some embodiments, the tissue penetration member is removed by retracting it from the inner lumen. In some embodiments, the removal of the tissue penetration member opens the inner lumen of the sampling section, optionally allowing at least one tissue manipulator to move into the inner lumen, for example, to recover from bending of the tissue manipulator caused by the tissue penetration member.

[0089] According to some exemplary embodiments, in block 104, the sampling unit rotates around its long axis while advancing axially into the tissue, such as soft tissue. In some embodiments, the advance of the sampling unit into the tissue introduces the tissue into the internal lumen of the sampling unit. In some embodiments, the tissue enters the internal lumen through the distal opening of the sampling unit and optionally enters beyond or proximal to the axial position of at least one tissue manipulator, such as at least one cutter, in the internal lumen.

[0090] According to some exemplary embodiments, the movement of the sampling unit is stopped at block 106. In some embodiments, stopping the movement includes stopping the axial and rotational movement of the sampling unit. Alternatively, stopping the movement includes stopping the axial movement of the sampling unit toward the tissue while optionally maintaining the rotation of the sampling unit.

[0091] According to some exemplary embodiments, the sampling unit rotates in the opposite direction in block 108. In some embodiments, the sampling unit is rotated in the opposite direction to the direction of rotation used in block 104 when advancing the sampling unit axially into the tissue.

[0092] According to some exemplary embodiments, the tissue manipulator generates a separation region in the biological tissue in block 110. In some embodiments, in block 110, the tissue manipulator generates a separation region by forming incisions or grooves, such as circumferential notches or grooves, in the biological tissue within the inner lumen, for example, to separate a tissue sample from the biological tissue. In some embodiments, while the sampling unit rotates in block 108, the tissue manipulator manipulates the tissue to form incisions or grooves, for example, to separate the tissue sample from the biological tissue.

[0093] According to some exemplary embodiments, the separated tissue sample is removed from the inner lumen of the sampling unit in block 112. In some embodiments, the separated tissue sample is removed from the inner lumen through the distal opening of the sampling unit. Alternatively, the separated tissue sample is removed through the proximal opening of the sampling unit, for example, when the sampling unit is separated from the shaft used to rotate the sampling unit, or when the sampling unit is disassembled, for example, to extract the separated tissue sample.

[0094] Exemplary state of a movable cutter According to some exemplary embodiments, the sampling section of the biopsy apparatus comprises at least one internal cutter extending from the wall of the sampling section into an internal lumen into which tissue is introduced from the outside. In some embodiments, the internal cutter is integrated with or connected to the wall of the sampling section. In some embodiments, as the sampling section advances into the biological tissue, a portion of the biological tissue is introduced into the internal lumen through the distal opening of the sampling section and comes into contact with at least one internal cutter. In some embodiments, the at least one internal cutter is a movable internal cutter, a flexible internal cutter configured to move optionally between a first position and a second position, where the internal cutter extends into the internal lumen and where the internal cutter is pressed against the wall of the sampling section.

[0095] According to some exemplary embodiments, the inner cutter is configured to extend into the inner lumen of the sampling section in a relaxed state, for example, when no mechanical force is applied to the inner cutter. In some embodiments, when the inner cutter is pressed against the wall of the sampling section, the inner cutter penetrates, for example, at least a portion of an opening, which is a notched window in the wall of the sampling section.

[0096] Refer to Figure 2 here. Figure 2 shows the changes in the state of the internal cutter of the biopsy device according to the tissue sampling stage, according to some exemplary embodiments of the present invention.

[0097] According to some exemplary embodiments, in block 204, the sampling section of the biopsy device is positioned next to the biological tissue to be sampled before penetration into the biological tissue. In some embodiments, in block 204, the sampling section is stationary and the biological tissue is outside the internal volume of the sampling section. In some embodiments, in block 204, at least one movable inner cutter is bent into the internal volume of the sampling section. In some embodiments, in block 204, the movable inner cutter extends inward from the wall of the sampling section into the internal volume and is optionally in a relaxed state.

[0098] According to some exemplary embodiments, in block 206, the sampling unit advances into the biological tissue. In some embodiments, the sampling unit advances axially while rotating around its long axis. In some embodiments, as the sampling unit advances, the biological tissue enters the inner lumen of the sampling unit while remaining attached to the biological tissue outside the sampling unit. In some embodiments, the biological tissue that has entered the inner lumen pushes at least one inner cutter toward the wall of the sampling unit, for example, toward an opening in the wall. Optionally, at least one inner cutter is pushed toward the wall of the sampling unit until it is positioned at least partially substantially aligned with the wall, for example, at an angle of less than 7 degrees relative to the wall, e.g., less than 5 degrees, less than 3 degrees, or any intermediate angle, or smaller or larger.

[0099] According to some exemplary embodiments, in block 206, the biological tissue entering the internal lumen advances to a position within the internal lumen that is proximal to at least one internal cutter, for example, a position between the internal cutter and the proximal opening or proximal end of the biopsy device.

[0100] According to some exemplary embodiments, in block 208, the movement of the sampling unit into the biological tissue is stopped. In some embodiments, in block 208, the axial advance of the sampling unit into the biological tissue and / or the movement of the biological tissue within the inner lumen of the sampling unit is stopped. Also, in block 208, the rotation of the sampling unit is stopped. In some embodiments, in block 208, at least one elongated portion of the biological tissue is located between a position proximal to the inner cutter in the inner lumen and the distal opening of the sampling unit, and optionally remains connected to the biological tissue outside the sampling unit.

[0101] According to some exemplary embodiments, in block 208, when the movement of the sampling section is stopped, the cutter bends inward toward the inner lumen and enters biological tissue, such as soft tissue, within the inner lumen. In some embodiments, at the bending position, for example, when the inner cutter extends toward the inner lumen, the angle between at least one inner cutter and the wall of the sampling section is greater than 5 degrees, for example, greater than 10 degrees, greater than 20 degrees, greater than 30 degrees, greater than 45 degrees, or any intermediate angle, or a smaller or larger angle value. In some embodiments, at the bending position, the angle between the inner cutter and the wall of the sampling section is in the range of 5 to 60 degrees, for example, 15 to 50 degrees, 20 to 45 degrees, 10 to 30 degrees, or any intermediate angle range, or a smaller or larger angle range.

[0102] According to some exemplary embodiments, the sampling unit rotates in block 210 and optionally in block 206 in the opposite direction to the direction of rotation as the sampling unit advances into the biological tissue. In some embodiments, a movable cutter cuts and separates the sample at least partially from the biological tissue located inside the inner lumen of the sampling unit. In some embodiments, the rotation of the sampling unit causes the inner cutter to rotate, forming a circumferential cut through the biological tissue, thereby separating the sample of tissue located proximal to the inner cutter from the biological tissue located inside the sampling unit.

[0103] An example of a sampling section of a biopsy device. According to some exemplary embodiments, the sampling section of a biopsy device, for example, a sampling needle, has an elongated, optionally tubular body having a distal opening into an inner lumen of a tubular body. In some embodiments, the body has a tapered distal end surrounding the distal opening and is shaped and sized to allow penetration into body tissue, such as soft tissue. In some embodiments, penetration of the distal end, for example, the tapered distal end, into the tissue forms a circular notch in the tissue, allowing a portion of the biological tissue to enter the inner lumen of the body through the distal opening. In some embodiments, the sampling section includes at least one, for example, two, three, four, five, six, or more tissue manipulators, such as an internal cutter, extending from the wall of the sampling section into the inner lumen. In some embodiments, the internal cutter is configured to form a notch in the biological tissue portion located in the internal volume, thereby separating the tissue sample at least partially from the biological tissue portion.

[0104] Refer to Figure 3a here. Figure 3a shows a longitudinal cross-section of the sampling section of a biopsy device comprising at least one, for example, at least two, internal cutters, according to some exemplary embodiments of the present invention.

[0105] According to some exemplary embodiments, the biopsy device sampling unit, for example, the sampling unit 302, comprises an elongated hollow body 304 having an inner lumen 306, a long axis 308, a distal end 310, and a proximal end 312. In some embodiments, the body has a distal opening 314 at the distal end 310 to the inner lumen 306.

[0106] According to some exemplary embodiments, the distal end is a flat, straight end. In some embodiments, the distal end is substantially perpendicular to the long axis of the sampling section. As used herein, “substantially perpendicular” means having a deviation of up to 5% from an angle of 90 degrees. Alternatively, in some embodiments, the distal end is a chamfered end. In some embodiments, the sampling section body has a circular, elliptical, or ellipsoidal cross-section, for example, at the distal end 310. In some embodiments, the sampling section body is tubular, for example, to allow tissue to pass through the distal opening 314 into the inner lumen 306.

[0107] According to some exemplary embodiments, the sampling unit comprises at least one tissue manipulator, for example, at least two tissue manipulators. In some embodiments, the at least two tissue manipulators comprise at least two internal cutters 316 and 318. In some embodiments, the at least two cutters 316 and 318 are connected to the wall 320 of the body 304 surrounding the internal lumen. Alternatively, the at least two cutters 316 and 318 are partial cutouts of the wall 320. In some embodiments, connecting regions between each of the cutters 316 and 318 and the wall, for example, connecting regions 315 and 317, are located at a distance 322 from the distal end 310 or distal opening 314. In some embodiments, the connecting regions function as hinge regions. In some embodiments, the connecting regions allow the cutters 316 and 318 to elastically flex toward the wall and recover their flexion, for example, by bending inward or returning to the internal lumen 306.

[0108] In some embodiments, the distance 322, which is the axial distance between the distal end 310 of the sampling section and the axial position of one or all of the one or more inner cutters, is in the range of 0.1 mm to 50 mm, for example, 0.2 mm to 20 mm, 2 mm to 15 mm, 4 mm to 12 mm, or an intermediate value, smaller value, or larger value between these. In some embodiments, the distance 322 is 0.2 to 4 times the inner width of the sampling section 302, for example, 0.2 to 1 time the width, 0.5 to 1.5 times the width, 1 to 2 times the width, 2 to 4 times the width, or an intermediate value, smaller value, or larger value between these, or a range of such values. In some embodiments, if the sampling section 302 includes an inner sharpening section surrounding at least a portion of the distal opening, the cutter is located at a distance of 0 to 2 times the width of the sampling section following the inner sharpening section, for example, at a distance of 0 to 1 times the width, 0.5 to 1 times the width, or in a range of intermediate, smaller, or larger values ​​between these. Alternatively, or in addition to the above, the sampling section includes an outer sharpening section surrounding at least a portion of the distal opening. In some embodiments, the inner and / or outer sharpening sections are configured to form a circular incision in the biological tissue as the sampling section advances axially into the biological tissue.

[0109] According to some exemplary embodiments, the inner cutters, for example, cutters 316 and 318, extend inward into the inner lumen 306 from the wall 320 toward the proximal end 312 at a maximum angle 324 between the cutter and the wall 320. In some embodiments, the maximum angle value is in the range of 3 to 90 degrees, for example, 5 to 45 degrees, 10 to 30 degrees, or an intermediate value, a smaller value, or a larger value between these ranges.

[0110] According to some exemplary embodiments, the inner cutters, e.g., cutters 316 and 318, are flexible and configured to move between a first state and a second state, in which the cutters extend into the lumen 306 at a maximum angle 324, in which case the cutters are substantially aligned with the wall, e.g., the angle 324 with respect to the wall 320 is less than 5 degrees, e.g., less than 3 degrees, less than 2 degrees, or an intermediate value between these, a smaller value, or a larger value. In some embodiments, the cutters, e.g., cutters 316 and 318 are portions of the wall 320 that are cut out and remain connected to the wall 320 in connection regions, e.g., connection regions 315 and 317.

[0111] According to some exemplary embodiments, cutters, e.g., cutters 316 and 318, are integrated with the wall 320 and optionally formed from the same material as the wall 320. In some embodiments, the cutters, e.g., cutters 316 and 318, are thinner than the wall 320 and have a maximum thickness of up to 0.8 of the wall thickness, e.g., up to 0.6, up to 0.5, up to 0.3, or an intermediate value between these, a smaller value, or a larger value. In some embodiments, the cutters, e.g., cutters 316 and 318, are formed from a superelastic material or a shape memory alloy material, e.g., Nitinol (nickel titanium), CuAlNi (copper aluminum nickel), CuZnAl (copper zinc aluminum), Fe-Mn-Si (iron manganese silicon), NiTiCu (nickel titanium copper), CuSnZn (copper tin zinc), and TiPd (titanium palladium). In some embodiments, the material forming the cutter and / or sampling section is a biocompatible material. In some embodiments, the sampling section 302 or the main body 304 may be formed from the shape memory alloy described above, or from a material different from the shape memory alloy or the material used to form the cutters, such as the cutters 316 and 318.

[0112] According to some exemplary embodiments, the cutter is optionally elastic. In some embodiments, when the cutter is relaxed, it extends inward into the lumen 306 and acquires an extended state. In some embodiments, when a force, such as a mechanical force, is applied to the cutter in the lumen 306 radially, for example toward the wall 320, the cutter is pushed toward the wall 320 for as long as the mechanical force is applied to it. In some embodiments, a force in the tissue axis direction applies a bending moment to the cutter, for example, pushing the cutter outward radially. In some embodiments, when the application of the mechanical force is stopped, the cutter returns to a relaxed extended state and returns to the lumen 306. In some embodiments, the maximum angle 324 is acquired when the cutter is relaxed.

[0113] According to some exemplary embodiments, one or more of the cutters, for example, cutters 316 and 318, are connected to the wall 320 via at least one hinge or hinge portion. Optionally, the hinge portion is elastic and configured to allow the cutter to bend inward into the lumen 306 when the hinge portion is relaxed.

[0114] Refer to Figure 3b here. Figure 3b shows one or more internal cutters substantially aligned with the wall of the sampling section, according to some exemplary embodiments of the present invention, and Figure 3c shows one or more internal cutters extending inward into the internal lumen of the sampling section.

[0115] According to some exemplary embodiments, as shown, for example, in Figure 3b, at least one internal cutter, e.g., cutters 316 and 318, is configured to move into the opening in the wall 320. In some embodiments, at least one internal cutter moves into the wall when a mechanical force is applied from within the lumen 306 and substantially aligns with the wall. In some embodiments, a force is applied to the cutter in the proximal and / or radial direction, pushing the cutter into the opening in the wall. Alternatively, the force presses the cutter against the wall, e.g., the inner surface of the wall, and optionally attaches the cutter to the inner surface of the wall.

[0116] For example, as shown in Figure 3b, when the sampling unit is advanced into the target soft tissue of the body, a tissue penetration member 340, located inside the lumen 306 and extending through the distal opening 314, is used to penetrate the more rigid and / or elastic portion of the tissue wall. In some embodiments, when the tissue penetration member 340 is inside the lumen 306, a mechanical force is applied to at least one cutter, for example, cutters 316 and 318, to push the cutter at least partially into the wall. Alternatively, the tissue penetration member presses the cutter against the wall. In some embodiments, similarly, as biological tissue enters the lumen 306 through the distal opening, a force is applied to the cutter to push the cutter at least partially into the wall or press it against the wall.

[0117] According to some exemplary embodiments, as shown in Figure 3c, for example, when no force is applied to the cutters, for example, cutters 316 and 318, from within the lumen 306, the cutters extend into the lumen 306 and optionally extend at a maximum angle 324.

[0118] According to some exemplary embodiments, as shown, for example, in Figure 3c, a cutter, for example, a cutter 340, has a first end 342 connected to or integrated with the wall 320 and a second end 344 located away from the wall 320. In some embodiments, the second end 344 is configured to be located within the inner lumen 306 when the cutter 340 is extending inward into the lumen 306, for example, when the cutter is released from deflection or is at rest. In some embodiments, the cutter includes a cutting edge located in the region between the first end 342 and the second end 344. Optionally, the cutting edge is located at the second end 344.

[0119] According to some exemplary embodiments, as shown, for example, in Figure 3d, two or more cutters, for example, cutters 346 and 348, are connected to a wall 320, for example, the circumference of the wall. In some embodiments, cutters 346 and 348 are connected to the wall at opposite positions on the circumference of the wall. In some embodiments, each of cutters 346 and 348 extends inward into the lumen 306, and the distal end of each cutter is oriented to point to the proximal end of the sampling section. In some embodiments, each cutter is oriented at a similar angle to the wall 320.

[0120] According to some exemplary embodiments, as shown, for example, in Figure 3e, the cutters, for example, cutters 346 and 348, are oriented such that at least some, or all, of the cutting edges of cutters 346 and 348 are in the same axial position along the axis of the sampling unit, for example, enabling the formation of a single cut surface 350 in the tissue in contact with the cutting edges. In some embodiments, the cutters 346 and 348 optionally form the cut surface 350 without axial movement of the sampling unit and cutters 346 and 348 when the sampling unit and cutters 346 and 348 rotate around the long axis of the sampling unit body.

[0121] A potential advantage of having a single cutting surface 350 is that it allows for the separation of a proximal tissue sample, where flow continues within the inner lumen of the sampling section, from distal tissue, where connectivity to organ tissue continues. If the cutters are not positioned in similar axial positions relative to each other in the sampling section, after the separation of the tissue sample, the tissue may be trapped by the cutters, preventing further penetration of the tissue into the sampling section.

[0122] Exemplary biopsy device According to some exemplary embodiments, a biopsy device comprising a sampling section having an internal cutter, for example, a flexible internal cutter, is configured to remove a tissue sample, e.g., a biopsy sample, from soft tissue. In some embodiments, the soft tissue includes tissue suspected to be a tumor, and the device is configured to remove at least one sample from the suspected tissue. In some embodiments, the device cuts the tissue sample by rotating a sampling section, e.g., a needle, located at the distal end of the device and advancing it axially into the tissue (e.g., soft tissue). In some embodiments, the device allows for the separation of the tissue sample from the tissue within the sampling section by rotating the sampling section in the opposite direction, and / or allows for the separation of a continuous tissue sample from the tissue without completely withdrawing the device from the tissue after each tissue sampling.

[0123] Now refer to Figure 3f. Figure 3f shows a biopsy apparatus (also referred to herein as a biopsy system) according to some exemplary embodiments of the present invention.

[0124] According to some exemplary embodiments, a biopsy apparatus, for example, apparatus 350, comprises a control unit 352 and a sampling unit 354, for example, a needle mechanically connected to the control unit 352 via an elongated flexible shaft 356. In some embodiments, the flexible shaft 356 is a torque coil, for example, a braided torque coil configured to advance the sampling unit 354 axially and rotate it in different directions. In some embodiments, the flexible shaft is formed from a braid of interconnected wires and is optionally formed in a spiral shape.

[0125] According to some exemplary embodiments, the control unit 352 comprises a control circuit 356 functionally coupled to at least one actuator 358. In some embodiments, the at least one actuator comprises a motor, for example, an electric motor. Alternatively, or in addition to the above, the at least one actuator comprises a hydraulic actuator or a pneumatic actuator. In some embodiments, the shaft 356 is functionally coupled to at least one actuator 358.

[0126] According to some exemplary embodiments, the control unit 352 includes a memory circuit 360 that stores one or more movement parameters of the sampling unit, such as axial forward speed, rotational tangential speed, ratio of axial speed to tangential speed, rotational direction, axial forward direction, and / or duration of movement of the sampling unit.

[0127] According to some exemplary embodiments, the control unit 352 includes a user interface 362 configured to generate human-detectable instructions and / or receive input data from a user of the device 350, such as a physician, surgeon, specialist, or technician. In some embodiments, the input data includes one or more movement parameters stored in memory 360.

[0128] According to some exemplary embodiments, during the tissue sampling process, for example as shown in Figures 4 and 5d-5g, the control circuit 356 is configured to send a signal to the actuator 358 to rotate and / or advance the shaft 356 and the sampling unit 354 in the axial direction according to movement parameters stored in the memory 360.

[0129] According to some exemplary embodiments, as shown, for example, block 410 in Figure 4, and in Figures 5d and 5e, the control circuit 356 signals an actuator to advance the shaft 356 and the sampling unit 354 at the distal end of the shaft 356 axially. The control circuit 356 also signals an actuator 358 to rotate the shaft 356 and the sampling unit 354 in a first direction, for example, the direction 754 shown in Figure 7d, simultaneously with the axial advance and optionally in synchronization. In some embodiments, during axial advance and rotation, tissue enters the inner lumen 366 of the sampling unit 354 through the distal opening 354 of the sampling unit 354. In some embodiments, the tissue that has entered the lumen pushes an inner cutter, for example, a cutter 368, toward the wall 370 of the sampling unit.

[0130] According to some exemplary embodiments, as also shown in block 416 of Figure 4, after introducing tissue into the lumen 366 to a position proximal to the cutter 368, the control circuit 356 signals the actuator 358 to stop the axial advance of the shaft 356 and the sampling unit 370. In some embodiments, the control circuit 356 also signals the actuator 358 to stop the rotation of the shaft and the sampling unit in a first direction.

[0131] According to some exemplary embodiments, after a predetermined time, the control circuit signals the actuator 358 to rotate the shaft 356 and sampling unit in a second direction opposite to the first direction, for example, in the direction 746 shown in Figure 7d. In some embodiments, the control circuit signals the actuator to rotate the shaft 356 and sampling unit 354 in the second direction for a predetermined time period and / or by a different angle of rotation and / or by a selected number of rotations. Optionally, during and / or after rotation in the second direction, the control circuit 356 signals the actuator 358 to retract the shaft and sampling unit by an optionally predetermined distance, for example, in a predetermined step. In some embodiments, the retraction of the sampling unit occurs after the rotation of the sampling unit. In some embodiments, the retraction of the sampling unit allows for the separation of a tissue sample from the tissue in the lumen 366, for example, as shown in Figure 5g. In some embodiments, the retraction is manual, and the axial advance and / or rotation is electric. In some embodiments, after tissue separation, the control circuit 356 signals the actuator to repeat a sequence of (1) axially advancing while rotating in a first direction, (2) stopping the axial advance, (3) rotating in a second direction, (4) retracting the sampling unit, and optionally repeating to acquire additional tissue samples.

[0132] Exemplary detailed tissue sampling process According to some exemplary embodiments, a tissue sampling device, such as a biopsy device, is used to obtain long, continuous samples of soft tissue from the body, such as tissue from organs like the pancreas, liver, lymph nodes, spleen, lungs, glands, adrenal glands, kidneys, esophageal wall, stomach wall, and gastrointestinal tract (GI). In some embodiments, the biopsy device is used to cut and separate long tissue samples from living tissue, the length of which the tissue sample is at least 1 mm, for example, at least 2 mm, at least 3 mm, at least 4 mm, at least 5 mm, at least 6 mm, at least 7 mm, at least 8 mm, or any intermediate, smaller, or larger length of the tissue sample. Optionally, the biopsy device is used to obtain several separated long tissue samples by passing the device through the living tissue only once, or optionally without withdrawing the device from the living tissue. In some embodiments, the tissue sample includes tissue suspected to be cancerous, or tumor tissue, or tissue mass.

[0133] Now refer to Figure 4. Figure 4 shows a flowchart of the sampling process according to some exemplary embodiments of the present invention.

[0134] According to some exemplary embodiments, in block 402, the biopsy device advances toward the target tissue. In some embodiments, the biopsy device comprises a flexible shaft terminating at the distal end of the shaft with a distal sampling section, for example, a hollow needle. In some embodiments, the biopsy device comprises an elongated tissue penetration member, for example, the tissue penetration member described in WO2022003691A1, which is incorporated herein by reference in its entirety. In some embodiments, the elongated tissue penetration member passes through the shaft and the inner lumen of the sampling section and extends through the distal opening of the sampling section.

[0135] According to some exemplary embodiments, the biopsy device advances toward the tissue wall, for example, within the working channel of an endoscope.

[0136] According to some exemplary embodiments, in block 404, the biopsy device optionally penetrates the wall using a tissue penetration member. In some embodiments, the distal end of the biopsy device penetrates the tissue wall using a tissue penetration member that extends distally from the distal end of the biopsy device.

[0137] According to some exemplary embodiments, after penetrating the tissue wall, the tissue penetration member retracts from the lumen of the sampling portion in block 406.

[0138] According to some exemplary embodiments, the retraction of the tissue penetration member causes one or more inner cutters in block 408 to bend inward from the wall of the sampling section.

[0139] It should be noted that in some embodiments, there is no tissue penetration member within the lumen of the biopsy device or the sampling section, and one or more internal cutters are already bent inward from the wall into the internal lumen as the biopsy device advances. In some embodiments, when advancing to target tissue that needs to be sampled via a GI tube or trachea, there is no need to penetrate the tissue wall to reach the target tissue, and therefore there is no need to have a tissue penetration member within the lumen of the sampling section when extending distal to the sampling section. In embodiments where such a tissue penetration member is unnecessary, the process shown in Figure 4 does not include blocks 404, 406, and / or 408.

[0140] According to some exemplary embodiments, in block 410, the sampling unit advances axially into the tissue while rotating. As used herein, rotation of the sampling unit means rotating the sampling unit in any circular motion around its longitudinal central axis. In some embodiments, the sampling unit rotates at a tangential velocity in the range of 2.5 to 1000 mm / sec, for example, 2.5 to 40 mm / sec, 30 to 40 mm / sec, 35 to 45 mm / sec, 30 to 50 mm / sec, 10 to 100 mm / sec, 50 to 500 mm / sec, 300 to 1000 mm / sec, or any intermediate, smaller, or larger range. Furthermore, while rotating, the sampling unit advances axially into the tissue at an axial speed in the range of 1 to 100 mm / second, for example, in the range of 1 to 10 mm / second, 5 to 12 mm / second, 5 to 15 mm / second, 5 to 50 mm / second, 10 to 100 mm / second, or any intermediate, smaller or larger range of axial speeds. In some embodiments, the ratio of tangential rotation speed to axial speed is between 1 and 10, for example, between 3.5 and 4.5, for example, between 2 and 5, or any intermediate, smaller or larger range of values. In some embodiments, the ratio is fixed while the sampling unit advances into the tissue. An example of the sampling unit advancing into the tissue is provided in WO2019155472A1, which is incorporated in its entirety by reference herein. In some embodiments, in block 410, the sampling unit advances axially into the tissue while rotating in a direction such that the distal end of a tissue manipulator, such as a cutter, connected to the wall, becomes the leading end that first faces the tissue entering the lumen of the sampling unit.

[0141] According to some exemplary embodiments, as the sampling unit advances into the tissue, in block 412, the tissue enters the lumen of the sampling unit through the distal opening of the sampling unit. In some embodiments, the tissue entering the lumen remains connected to the tissue outside the sampling unit. Optionally, the tissue entering the lumen of the sampling unit is condensed because the inner width of the sampling unit is narrower than the width of the distal opening at the tapered distal end. In some embodiments, as the tissue enters the inner lumen, the entering tissue pushes, for example, the cutter outward towards the wall of the sampling unit.

[0142] According to some exemplary embodiments, in block 414, as the tissue advances within the medial lumen, the tissue moves proximal to the cutter.

[0143] According to some exemplary embodiments, the advance of the sampling unit into the tissue is stopped at block 416. In some embodiments, the axial advance and rotation of the sampling unit are stopped at block 416.

[0144] According to some exemplary embodiments, in block 418, the inner cutter bends inward into the tissue within the sampling section lumen. In some embodiments, the cutter bends into the tissue within the inner lumen, increasing contact and / or friction between at least one cutting edge of each cutter and the tissue within the inner lumen.

[0145] According to some exemplary embodiments, in block 420, the sampling unit rotates about its longitudinal central axis in a direction opposite to the direction used when the sampling unit advanced into the tissue in block 410. For example, during rotation, the proximal free end of the tissue manipulator is used as the leading edge, and the rotation is such that the leading edge faces the tissue. In some embodiments, in block 420, the rotation of the tissue manipulator pushes the proximal free ends of one or more tissue manipulators into the tissue.

[0146] According to some exemplary embodiments, in block 422, tissue within the inner lumen is cut by a tissue manipulator, such as a cutter. In some embodiments, as the sampling unit rotates in block 420, at least one edge, for example, the cutting edge at the proximal free end of the cutter, penetrates the tissue, forming a circular incision, optionally a circumferential incision or groove in the tissue. Instead of, or in addition to, the sampling unit is retracted with the cutter positioned inside the tissue.

[0147] According to some exemplary embodiments, in block 424, a tissue sample is separated from the tissue within the lumen of the sampling unit. In some embodiments, in block 422, a tissue sample is separated from the tissue within the sampling unit at a cut surface formed by a cutter. In some embodiments, the rotation of the sampling unit during cutting in block 422 applies forces, such as cutting, tearing, and / or shearing forces, to the cut surface, for example, the plane between the tissue distal to the cut surface and the tissue proximal to the cut surface. As a result, the proximal tissue, i.e., the tissue sample, is separated from the tissue distal to the cut surface, which remains connected to the tissue outside the sampling unit. In some embodiments, the cut surface is located in the separation region formed by the cutter. In addition to or instead of the above, the tissue sample is separated from the tissue within the sampling unit by tearing, for example, by retracting the sampling unit after or during the formation of the cut in block 422. Optionally, once the tissue sample has been separated, in block 410, the sampling unit rotates, for example, and advances axially further into the tissue to acquire at least one additional sample.

[0148] Alternatively, or in addition to the above, the retraction of the sampling unit, with or without rotation, tears or separates the tissue sample from the remaining tissue within the sampling unit.

[0149] According to some exemplary embodiments, in block 426, the tissue sample is removed from the lumen of the sampling section. In some embodiments, the tissue sample is removed from the distal opening, for example, through the lumen of an additional tube, such as a thin-walled tube, inserted through the distal opening into the inner lumen of the sampling section, by cutting a cutter toward or against the wall of the sampling section. Alternatively, the tissue sample is removed from the proximal opening of the sampling section, for example, after separating the sampling section from the flexible shaft. Alternatively, the tissue sample is removed by extracting the tissue sample by cutting the sampling section, for example, a sampling needle. Alternatively, the tissue sample is flushed out of the lumen of the sampling section, for example, through the distal or proximal opening, by introducing a fluid or air into the lumen. Alternatively, the tissue sample is removed from the lumen of the sampling section by applying a vacuum to the lumen through the distal or proximal opening. Alternatively, the tissue sample is removed from the lumen of the sampling section by introducing an elongated pressing element configured to push the sample out of the lumen through the distal or proximal opening.

[0150] Exemplary tissue sampling Refer to Figures 5a to 5f here. Figures 5a to 5f illustrate a tissue sampling process using a biopsy device having a distal sampling section, for example, a needle, which has at least one internal cutter, according to some exemplary embodiments of the present invention.

[0151] According to some exemplary embodiments, as shown in Figure 5a, for example, the sampling unit 502 advances toward the target tissue 504, which is, for example, soft tissue, having a tissue wall 506 that at least partially surrounds the target tissue 504. In some embodiments, the tissue penetration member 508 is located within the inner lumen 510 of the sampling unit and extends through the distal opening of the sampling unit 502. In some embodiments, the biopsy device, including the sampling unit 502 and the tissue penetration member 508, advances axially toward the target tissue 504 within the working channel of the endoscope.

[0152] According to some exemplary embodiments, the axial advance of the biopsy device in Figure 5a is performed manually, for example, by manually pushing the biopsy device toward the target tissue 504. Alternatively, the movement of the biopsy device in Figure 5a is motorized and performed in steps as an option. In some embodiments, the axial advance of the biopsy device may or may not include rotation of the sampling section of the biopsy device. In some embodiments, the length of each step is predetermined and arbitrarily equal. Alternatively, the length of each step is determined based on the distance between the biopsy device and the target tissue or target tissue wall. For example, the steps become shorter as the biopsy device approaches the target tissue or target tissue wall. In some embodiments, the advance of the biopsy device, for example, the biopsy device sampling section toward the target tissue, is monitored using image processing based on one or more imaging modalities, for example, using ultrasound imaging.

[0153] According to some exemplary embodiments, in Figure 5a, when the tissue penetration member 508 is inside the inner cavity 510, at least one cutter, for example, cutters 512 and 514, is at least partially attached to the inner surface of the wall 516, for example. Alternatively, in Figure 5a, at least one cutter is at least partially located within the opening of the wall 516.

[0154] According to some exemplary embodiments, as shown in Figure 5b, for example, the biopsy apparatus penetrates the wall 506 using a tissue penetration member 508. In some embodiments, during penetration, the tissue penetration member makes a thin cut in the tissue wall, for example, as described in WO2022003691A1, which is incorporated by reference in its entirety herein.

[0155] According to some exemplary embodiments, as shown in Figure 5c, for example, the tissue penetration member 508 is removed from the inner lumen 510 of the sampling section 502 after penetrating the wall 506. In some embodiments, after the removal of the tissue penetration member, at least one cutter, for example, cutters 512 and 514, remains connected to the wall 516 and bends inward into the inner lumen 510. In some embodiments, as shown in Figure 5c, for example, the distal end of the sampling section includes a distal opening 520 and faces the target tissue 504.

[0156] According to some exemplary embodiments, as shown in Figure 5d, for example, the sampling unit 502 advances axially into the target tissue 504 while rotating around its central axis 522. In some embodiments, during axial advancement, a circumferential cut surrounding the distal opening 520 cuts through the target tissue. In some embodiments, after cutting, during axial advancement, a portion of the target tissue enters the inner lumen 510 through the distal opening 520, while remaining connected to the tissue outside the sampling unit 502.

[0157] According to some exemplary embodiments, as shown in Figure 5e, for example, as the sampling unit 502 advances axially into the tissue 504, the tissue entering the lumen 510 pushes the cutters 512 and 514 toward the wall 516. In some embodiments, the cutters 512 and 514 are at least partially pushed into openings in the wall 516, and each cutter is at least partially pushed into different openings in the wall 516. Alternatively, the cutters 512 and 514 are pushed toward the inner surface of the wall 516. In some embodiments, as the sampling unit 502 advances into the tissue 504, the tissue in the lumen 510 penetrates proximal to the cutters 512 and 514.

[0158] According to some exemplary embodiments, as shown in Figure 5f, for example, the axial advance of the sampling unit 502 toward the tissue 504 is stopped after a portion of the tissue in the lumen 510 is positioned proximal to the cutters 512 and 514. The rotation of the sampling unit is also stopped. In some embodiments, when the advance of the tissue toward the lumen 510 is stopped, the dynamic radial force applied by the tissue toward the wall 516 to the cutters 512 and 514 decreases, and the cutters 512 and 514 bend inward toward the lumen 510 and toward the tissue within the lumen. In some embodiments, when the force applied to the cutters 512 and 514 by the tissue in the lumen 510 decreases, the cutters 512 and 514, which are, for example, flexible and optionally elastic cutters, return to a relaxed state and bend toward the lumen 510. In some embodiments, the cutters are elastically flexible. In some embodiments, when the force applied to the cutters by the tissue decreases, the cutters recover from the bend, and at least a portion of the cutters bend inward toward the tissue.

[0159] According to some exemplary embodiments, as cutters 512 and 514 bend into the tissue, the cutting edge of each cutter comes into contact with the tissue.

[0160] According to some exemplary embodiments, as shown, for example, in Figure 5g, the sampling section is rotated following the bending of the cutter into the tissue within the lumen. In some embodiments, the sampling section is rotated in the opposite direction to the rotational direction applied during axial advancement into the tissue, as shown, for example, in Figures 5d and 5e. In some embodiments, the rotation of the sampling section causes the cutter to move around the tissue within the lumen, forming a circumferential cut or groove in the tissue, optionally at a single cut surface. In some embodiments, during and / or after rotation, the sampling section retracts from the tissue. In some embodiments, the retraction of the sampling section tears and / or twists and / or applies shear force to the tissue in the tissue within the lumen at a single cut surface, e.g., the tissue in the formed separation region. As a result, a tissue sample located proximal to the cut surface, e.g., tissue sample 530, is separated from the tissue located distal to the cut surface, e.g., the tissue between the cut surface and the distal opening of the sampling section.

[0161] According to some exemplary embodiments, as shown in Figure 5g, for example, when the sampling section 502 retracts, the inwardly bent cutters 512 and 514 act as one-way valves, preventing the tissue sample 530 from moving distal to the cutters 512 and 514.

[0162] According to some exemplary embodiments, for example, as shown in Figure 5h, by repeating the operations shown in Figures 5e to 5g, for example, multiple tissue samples, for example, tissue samples 530, 532, 534, and 536, can be separated from tissue 504 without completely withdrawing the sampling unit from the organ.

[0163] Extraction of exemplary tissue samples According to some exemplary embodiments, one or more tissue samples located within the sampling unit are extracted at the end of the tissue sampling procedure. In some embodiments, one or more tissue samples are extracted from the sampling unit when the sampling unit is removed from the patient's body.

[0164] According to some exemplary embodiments, the cutter is removed from the lumen of the sampling section, pressed against the wall of the sampling section, or pressed against the wall of the sampling section. In some embodiments, the cutter changes its mode between a flexible state and a stable, inflexible plastic state based on the transition temperature from plastic to elastic. For example, the cutter is elastic at body temperature and plastic at room temperature. In some embodiments, as shown, for example, in Figure 6a, the cutter opener 602 is pressed into the lumen 510 through the distal opening 520. In some embodiments, the cutter opener 602 presses the cutters 512 and 514 against the wall 516 or into the opening in the wall 516. In some embodiments, the cutters 512 and 514 remain attached to the wall 516 or within the wall 516 by frictional force between the wall and each cutter, and / or by transitioning the cutter from an elastic configuration to a plastic configuration based, for example, the transition temperature from elastic to plastic of the cutter.

[0165] According to some exemplary embodiments, if the cutters 512 and 514 remain mounted in or within the wall 516, the tissue samples are moved to the distal opening 520 by applying a vacuum from the distal opening and then expelled from the distal opening 520, or, as shown in Figure 6b, for example, the tissue samples 606 and 608 are pushed out of the lumen 510 through the distal opening 520 by a pusher shaft 610 inserted into the lumen of the sampling section through the proximal opening of the sampling section. Alternatively, one or more tissue samples can be washed away using a fluid.

[0166] According to some exemplary embodiments, for example as shown in Figure 6c, a tissue extraction tube, for example, tube 612, is pushed in through the distal opening 520, pushing cutters 512 and 514 toward the wall 516. In some embodiments, for example as shown in Figure 6d, a pusher shaft 610 pushes tissue samples 606 and 608 into tube 612 and pushes them out of the sampling section.

[0167] According to some exemplary embodiments, the tissue extraction tube 612 has a chamfered tip to allow for easy insertion into the sampling section 502, for example, through a distal opening 520.

[0168] According to some exemplary embodiments, as shown in Figure 6e, for example, the sampling unit 502, e.g., the sampling needle, is connected to a flexible shaft 620. In some embodiments, the flexible shaft is configured to deliver rotational and / or axial force from at least one motor of the biopsy device and the sampling unit 502. In some embodiments, the flexible shaft is flexible enough to transmit rotational and / or axial movement when the shaft is positioned in at least a portion of the working channel of the endoscope, e.g., the working channel of a flexible endoscope.

[0169] According to some exemplary embodiments, the shaft 620 is connected to the sampling unit 502 via at least one connector 622, for example, a snap-fit ​​connector or a bayonet connector. In some embodiments, the connector is a circumferential connector. In some embodiments, in order to extract tissue samples 606 and 608 from the lumen of the sampling unit, the sampling unit 502 is released from the shaft 620 by releasing the sampling unit 502 and / or the shaft 620 from the connector 622, as shown, for example, in Figure 6f, or by cutting the sampling unit 502. In some embodiments, when the sampling unit 502 is detached from the shaft 620, the proximal opening 624 of the sampling unit 502 allows access to the lumen 510 and / or the tissue samples 606 and 608. In some embodiments, as shown in Figure 5g, for example, the pusher shaft 630 is inserted into the lumen 510 through the distal opening 520, and the cutters 512 and 514 are moved toward the wall 516 to push out tissue samples, for example, samples 606 and 608 in the lumen 510, from the sampling section 502 through the proximal opening 624.

[0170] Alternatively, a fluid, such as saline solution, is injected through the distal opening 520 to push out samples, such as samples 606 and 608, from the sampling unit 502 through the proximal opening 624, and / or wash them out through the proximal opening of a shaft connected to the sampling unit, or through the proximal opening of a handle connected to the shaft.

[0171] Alternatively, tissue can be removed by applying a vacuum to remove it through the opening at the proximal end of the sampling section or biopsy device, or by pushing a shaft or tube into the lumen and guiding it towards the proximal end.

[0172] Exemplary biopsy device sampling section and inner cutter According to some exemplary embodiments, each cutter, for example, each flexible or elastic cutter, is a portion of the wall of the sampling section, partially cut out from the wall. (See Figures 7a–7e.) Figures 7a–7e show one or more cutters, which are partial cutouts of the biopsy apparatus sampling section, according to some exemplary embodiments of the present invention.

[0173] According to some exemplary embodiments, for example as shown in Figure 7a, the biopsy device sampling section 702 includes an elongated body 704 having a distal end 706 and a proximal end 708. In some embodiments, the body is a hollow body having an inner lumen extending between the distal end 706 and the proximal end 708. In some embodiments, the body 704 is tubular. In some embodiments, the inner lumen of the body 704 includes a distal opening 710 at the distal end 706.

[0174] According to some exemplary embodiments, the distal end 706 is a flat, straight distal end, as also shown in Figure 7b, which is an enlarged view of the region 712 shown in Figure 7a. In some embodiments, the sampling section 702 includes at least one tissue manipulator, for example, at least one cutter 714 which is optionally flexible or elastically flexible. In some embodiments, the cutter 714 is a cutout of the wall of the body, for example, wall 716. In some embodiments, an arc-shaped notch, for example, a U-shaped notch 718, is formed in the wall 716 at a distance 720 from the distal end 706. In some embodiments, the value of the distance 720 is in the range of 0.5 mm to 10 mm, for example, in the range of 0.5 mm to 3 mm, in the range of 1 mm to 5 mm, or in the middle of these values, or in a range smaller than these values, or in a range larger than these values.

[0175] According to some exemplary embodiments, a cutter 714 is formed, and the long axis 717 of the cutter 714 is oriented at an angle 719 with respect to the transverse axis 720 of the body 704, for example, an axis perpendicular to the long axis 722 of the body 704. In some embodiments, the value of the angle 719 is in the range of 5 to 20 degrees, for example, in the range of 5 to 12 degrees, in the range of 8 to 15 degrees, in the range of 10 to 14.5 degrees, in the range of 12 to 14.5 degrees, or in the middle of these values, or in a range smaller than these values, or in a range larger than these values.

[0176] According to some exemplary embodiments, the value of angle 719(α) depends on the ratio of the axial velocity to the tangential velocity of the sampling unit and / or is determined, for example, according to the following calculation. D = Diameter of the sampling unit body ω = rotational speed (revolutions / second) π × D = circumference Vtangential = ω × π × D α = tan -1 (Vaxial / Vtangential)

[0177] For example, if ω = 13 rotations / second, Vaxial = 9 mm / second, and D = 1 mm, then Vtangential = π × 1 × 13 = 40.84, and angle α = tan -1 (0.22) = 12.4 degrees.

[0178] According to some exemplary embodiments, as shown in Figure 7c, a transparent view of the sampling section 702, the sampling section comprises two spaced-apart cutters 714 and 730, which are partial cutouts of the wall 716. In some embodiments, each cutter, for example, a flexible and optionally elastic cutter, is formed by forming a U-shaped cut in the wall. In some embodiments, the cutters are located on opposite sides of the wall from each other. In some embodiments, the cutters are aligned in the same direction from each other.

[0179] According to some exemplary embodiments, as shown in Figure 7c, the distal end 706 is a tapered end surrounding the distal opening 710. In some embodiments, the distal end has sharp edges on the inside and / or outside so that it can cut tissue as the distal end advances axially into the tissue, as shown, for example, in Figures 5d and 5e. In some embodiments, as shown in Figure 7c, the maximum inner width 740 of the sampling portion at the distal end 706, for example, the inner diameter, is in the range of 0.4 to 10 mm, for example, 0.4 to 5 mm, 0.5 to 2 mm, 0.5 to 3 mm, 1 to 5 mm, 3 to 10 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, the minimum inner width 742 of the sampling section in the narrow part of the sampling section, for example, the inner diameter, is within the range of 0.5 to 8 mm, for example, 0.5 to 2 mm, 1 to 2 mm, 1.5 to 5 mm, 2 to 8 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, the maximum thickness 744 of the wall 716 is within the range of 0.04 to 2 mm, for example, 0.04 to 1 mm, 0.05 to 0.1 mm, 0.05 to 0.2 mm, 0.1 to 2 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these.

[0180] Refer to Figures 7d and 7e here. Figures 7d and 7e show the arrangement of cutters along the circumference of the biopsy device sampling section according to some exemplary embodiments of the present invention.

[0181] According to some exemplary embodiments, as shown, for example, in Figures 7d and 7e, two cutters 714 and 730 are aligned in the same circumferential direction 746. In some embodiments, each cutter has a distal end having, for example, a base region 750 connected to and optionally integrated with the wall 716, and a proximal free end 752 configured to be located within the lumen 729 of the sampling section 702. In some embodiments, each cutter has at least one cutting edge between the base 750 and the proximal free end 752, and optionally on the proximal free end 752.

[0182] According to some exemplary embodiments, the distal end 750 of the tissue manipulator is closer to the distal end and / or distal opening of the sampling section than the proximal end 752 of the tissue manipulator. In some embodiments, the radius of curvature of the tissue manipulator between the distal end 750 and the proximal end 752 is about the same as the radius of curvature of the wall of the sampling section. Alternatively, the radius of curvature of the tissue manipulator is less or greater than the radius of curvature of the wall of the sampling section by a percentage value of up to 50%, e.g., up to 40%, up to 30%, up to 15%, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. Alternatively, the tissue manipulator between the distal end 750 and the proximal end 752 is linear.

[0183] According to some exemplary embodiments, as the sampling unit advances axially into the tissue, the sampling unit is rotated in direction 754, as shown in Figures 5d and 5e, for example, with the base 750 being the leading end of the rotating cutter. In some embodiments, as the sampling unit advances axially into the tissue, the tissue entering the lumen of the sampling unit pushes each cutter toward and optionally into the opening in the wall. For example, cutter 714 is pushed toward and optionally into the opening 718 shown in Figure 7b. In some embodiments, the rotation in direction 754 pushes each cutter at least partially into the opening in the wall.

[0184] According to some exemplary embodiments, in order to cut the tissue within the lumen of the sampling unit, the sampling unit is rotated in direction 746, which is the opposite direction to direction 754, so that the distal end 752 becomes the leading end of the cutter, as shown in Figure 5g, for example, to cut the tissue.

[0185] Refer to Figure 8a here. Figure 8a shows the tubular body of the sampling section in an open and planar state according to some exemplary embodiments of the present invention.

[0186] According to some exemplary embodiments, each cutter, for example, cutters 802 and 804, is formed and positioned at a distance of 806 from the distal end 808 of the sampling unit body. In some embodiments, the value of distance 806 is within the range of 0.1 to 15 mm from the distal end of the sampling unit, for example, 0.1 to 5 mm, 1 to 4 mm, 2 to 10 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, if the sampling unit has an inner or outer sharpening region that at least partially surrounds the distal opening, the distance between the cutter and the inner sharpening region is within the range of 0 to 2 mm, for example, 0 to 1 mm, 0.1 to 1.5 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, as shown, for example, in Figure 8a, cutters 802 and 804 are located in the same axial position on the body 810. In some embodiments, cutters 802 and 804 each form arc-shaped notches, e.g., U-shaped notches, e.g., notches 812 and 814, respectively, in the wall 816. In some embodiments, the notches, e.g., laser notches, have a width 825 in the range of 0.005 to 0.05 mm, e.g., 0.01 to 0.05 mm, 0.015 to 0.03 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these.

[0187] Now refer to Figure 8b. Figure 8b is an enlarged view of the portion 820 shown in Figure 8a, according to some exemplary embodiments of the present invention.

[0188] According to some exemplary embodiments, each cutter, for example, cutter 802, is oriented with respect to the transverse axis 824 of the sampling unit body at an angle 822, which is, for example, the angle α calculated above. In some embodiments, the angle 822 is within the range of 5 to 20 degrees, for example, 5 to 12 degrees, 8 to 15 degrees, 10 to 14.5 degrees, 12 to 14.5 degrees, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, as described above, the angle 822 is determined based on the ratio of the axial forward speed to the tangential speed of the sampling unit.

[0189] According to some exemplary embodiments, the length 826 between the base 828 and the tip 830 of each cutter is in the range of 0.4 mm to 8 mm, for example, 0.4 mm to 3 mm, 1 mm to 5 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, the length is determined based on the number of cutters and according to the circumference.

[0190] The length 826 = [1 / (2 × number of cutters)] of the circumference. For example, with two cutters, the length 826 is 1 / 4 of the circumference.

[0191] In some embodiments, the width 832 of the base region 828 of each cutter connecting the cutter to the wall is in the range of 0.2 mm to 2 mm, for example, in the range of 0.5 mm to 1 mm, in the range of 1 mm to 2 mm, or an intermediate value between these, or a value smaller than the intermediate value between these, or a value larger than the intermediate value between these. In some embodiments, the width 832 is about 1 / 3 of the length 826.

[0192] While it is expected that many related sampling needles will be developed during the term of this patent application as it matures, the term "sampling unit" is intended to encompass all such new technologies.

[0193] In this specification, the term “approximately” used in reference to a quantity or value means “within ±10%.”

[0194] The terms "comprises," "comprising," "includes," "including," and "having," along with their conjugations, all mean "including but not limited to."

[0195] The term "consisting of" means "to include or be limited to."

[0196] The term "substantially derived from" means that the composition, method, or structure may include additional components, steps, and / or parts, provided that these additional components, steps, and / or parts do not substantially alter the basic and novel properties of the composition, method, or structure described in the claim.

[0197] In this specification, the singular pronouns "a," "an," and "the" also refer to plural nouns unless the context clearly indicates otherwise. For example, "a compound" or "at least one compound" may include multiple compounds, and may also include mixtures thereof.

[0198] Throughout this application, embodiments of the present invention may be described in range form. It should be understood that the use of range form is merely for convenience and brevity, and not as a limitation that restricts the flexibility of the scope of the invention. Therefore, a range description should be considered to specifically disclose all possible sub-ranges and the individual numerical values ​​within those ranges. For example, a range description such as 1-6 specifically discloses not only sub-ranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, but also the individual numerical values ​​within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the size of the range.

[0199] Where a numerical range is indicated herein (for example, “10-15”, “10 to 15”, or any pair of numbers linked by such other range designations), unless the context explicitly indicates otherwise, it shall include the range limits and any numbers (decimals or integers) within the limits of the indicated range. The phrases “range between the first indicated number and the second indicated number / between the first indicated number and the second indicated number / the range between the first indicated number and the second indicated number” and “range from the first indicated number to the second indicated number / between the first indicated number and the second indicated number / the range between the first indicated number and the second indicated number (or other terms indicating such a range)” are used interchangeably herein and are intended to include the first indicated number and the second indicated number, as well as all decimals and integers between them.

[0200] Unless otherwise indicated, the numbers used herein and any range of numbers derived therefrom are approximations within reasonable measurement and rounding error tolerances as understood by those skilled in the art.

[0201] Features of the present invention described in specific embodiments are described in the context of separate embodiments for clarity, but it is understood that they are also provided in combination within a single embodiment. Conversely, several features of the present invention described in relation to a single embodiment for brevity may also be provided separately, in any preferred partial combination, or in any other appropriate described embodiment. Certain features described in relation to various embodiments should not be considered essential requirements of an embodiment unless the particular embodiment is inoperable without that element.

[0202] Although this disclosure has been described in relation to its specific embodiments, numerous alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, all such alternatives, modifications, and variations are intended to be included in the spirit and broader scope of the appended claims.

[0203] It is the applicant's intention that all publications, patents, and patent applications referenced herein be incorporated herein by reference in the same manner as each individual publication, patent, and patent application is incorporated herein by specific and individual reference. In addition, any reference or specification in this application should not be construed as an acceptance that such references may be used as prior art of the present invention. Nor should the titles of each section be construed as limitations to the extent in which they are used. Furthermore, if there are priority documents for this application, they are incorporated herein by reference in their entirety.

Claims

1. A hollow sampling section comprising a long axis, a proximal end, a distal end, and an internal lumen, and including an elongated body positioned along the long axis, The distal end of the sampling section is provided with a distal opening whose shape and size are set to allow the tissue to enter the inner lumen when the hollow sampling section advances axially into the biological tissue. At least one movable tissue manipulator extending from the wall of the sampling unit body into the inner lumen and toward the proximal end of the sampling unit, The at least one tissue manipulator is configured to move outward toward the wall and inward toward the inner lumen, A biopsy device equipped with the following features.

2. The apparatus according to claim 1, wherein the shape and size of the at least one movable tissue manipulator are set such that they are pushed toward the inner surface of the wall of the sampling section by the tissue entering the inner lumen, and return toward the inner lumen to apply force to the tissue within the inner lumen.

3. The apparatus according to claim 1, wherein the at least one tissue manipulator is configured to return to the inner lumen when the axial advance of the hollow sampling section stops.

4. The apparatus according to claim 2, wherein the at least one tissue manipulator is an elastically flexible tissue manipulator configured to elastically bend toward the inner surface of the wall when the tissue enters the inner lumen through the distal opening, and to recover from the bending when the axial advance of the hollow sampling portion into the biological tissue stops.

5. The apparatus according to claim 1, wherein the at least one tissue manipulator is a partial cutout of the wall of the sampling section.

6. The apparatus according to claim 5, wherein the at least one tissue manipulator is formed from the wall material.

7. The apparatus according to claim 5, wherein the at least one tissue manipulator is formed by forming an arc-shaped notch in the wall, the width of the notch being 0.005 mm to 0.05 mm.

8. The apparatus according to claim 1, wherein the at least one tissue manipulator comprises a distal end adjacent to the distal end of the sampling section and connected to or integrated with the wall, and a proximal end configured to be located within the inner lumen, the distal end of the at least one tissue manipulator being located at a distance of 0.1 mm to 20 mm from the distal end of the sampling section, or at a distance of four times the inner width of the sampling section from the distal end of the sampling section.

9. The apparatus according to claim 8, wherein the distal end of the at least one tissue manipulator is located at the level of the wall of the hollow sampling section and / or is aligned with the wall of the hollow sampling section.

10. The apparatus according to claim 8, wherein the radius of curvature of the at least one tissue manipulator between the distal end and the proximal end is the same as the radius of curvature of the wall of the hollow sampling section.

11. The apparatus according to claim 8, wherein the radius of curvature of the at least one tissue manipulator between the distal end and the proximal end is up to 30% smaller or larger than the radius of curvature of the wall of the hollow sampling section.

12. The apparatus according to claim 8, wherein the at least one tissue manipulator between the distal end and the proximal end is linear.

13. The apparatus according to claim 1, wherein the pitch angle between the at least one tissue manipulator and the plane perpendicular to the long axis of the sampling unit is 5 degrees to 30 degrees.

14. The apparatus according to claim 1, wherein the at least one tissue manipulator is formed from a superelastic material and / or a shape memory alloy.

15. The apparatus according to claim 1, wherein the at least one tissue manipulator is configured to return toward the inner lumen and apply force to the tissue within the inner lumen, thereby forming a tissue separation region in the tissue, the tissue separation region being a region more prone to tissue separation than other regions of the biological tissue.

16. The apparatus according to claim 1, wherein the at least one tissue manipulator is configured to return toward the inner lumen and penetrate the tissue within the inner lumen to form a tissue separation region in the tissue, the tissue separation region being a region more prone to tissue separation than other regions of the biological tissue.

17. The apparatus according to claim 15, wherein when the hollow sampling section rotates and / or retracts, the hollow sampling section applies sufficient force to the tissue in the inner lumen to separate the tissue sample from the tissue in the tissue separation region.

18. The apparatus according to claim 15, wherein the hollow sampling section advances axially into the biological tissue while rotating in a first direction, and when the axial advancement stops and the hollow sampling section rotates in a second opposite direction, the at least one movable tissue manipulator is configured to form the tissue separation region.

19. The apparatus according to claim 15, wherein the at least one tissue manipulator includes a tissue penetration edge configured to form the separation region by contacting the tissue in the inner lumen and forming at least a partial circumferential groove or at least a partial circumferential slit in the tissue when the hollow sampling portion rotates.

20. The apparatus according to claim 1, wherein the at least one tissue manipulator comprises at least two tissue manipulators, each having a tissue contact end configured to contact the tissue in the inner lumen, the tissue contact ends of the at least two tissue manipulators are located on a single plane substantially perpendicular to the long axis when each of the at least two tissue manipulators is fully extended into the inner lumen.

21. The apparatus according to claim 1, further comprising at least one actuator and a shaft having a distal end and a proximal end, wherein the at least one actuator is connected to the proximal end of the shaft, the hollow sampling section is connected to the distal end of the shaft, and the shaft is configured to rotate and / or advance the hollow sampling section axially within the biological tissue.

22. The apparatus according to claim 21, wherein the shaft rotates the sampling unit in a first direction while the sampling unit advances axially into the biological tissue, and the rotation of the sampling unit by the shaft in a second opposite direction causes the at least one tissue manipulator to form a tissue separation region and / or separate the tissue sample from the tissue in the inner lumen.

23. The apparatus according to claim 21, wherein the at least one actuator is configured to rotate the sampling unit at a tangential speed of 2.5 to 1000 mm / second.

24. The apparatus according to claim 21, wherein the at least one actuator is configured to advance the sampling unit axially at an axial speed of 1 to 100 mm / second.

25. The apparatus according to claim 21, wherein the ratio of the axial speed to the tangential speed of the sampling unit is 1 to 10.

26. The apparatus according to claim 21, wherein the ratio of the axial speed to the tangential speed of the sampling unit is 2 to 5.

27. The apparatus according to claim 21, wherein the shaft is a flexible shaft.

28. The apparatus according to claim 1, wherein the sampling unit is shaped and sized to advance toward the biological tissue within the working channel of the endoscope.

29. The apparatus according to claim 1, wherein the hollow sampling section is equipped with a sampling needle.

30. The apparatus according to claim 1, wherein the distal end of the sampling unit is substantially perpendicular to the long axis of the sampling unit.

31. The apparatus according to claim 1, wherein the distal end of the sampling portion has an inner and / or outer sharp edge configured to form a circular notch that penetrates the biological tissue during the axial advance and / or rotation of the sampling portion into the biological tissue, and the edge surrounds the distal opening.

32. The biopsy device advances the sampling unit axially into the living tissue, and during this axial advancement, a portion of the living tissue enters the inner lumen of the sampling unit, pushing at least one tissue manipulator extending from the wall of the sampling unit into the inner lumen outward toward the wall, thereby advancing the device. When the at least one tissue manipulator returns to the inner lumen, force is applied to the biological tissue portion by the at least one tissue manipulator, The method involves forming a tissue separation region in the biological tissue portion, wherein the tissue separation region is a region where tissue separation is more likely to occur compared to other regions of the biological tissue portion within the inner lumen, in response to the application of separation force to the biological tissue portion. By applying the separation force to the biological tissue portion, the tissue sample is separated from the biological tissue portion in the tissue separation region. A method for sampling tissue, including the following.

33. The method according to claim 32, wherein the at least one tissue manipulator comprises two or more tissue manipulators, and the granting includes the two or more tissue manipulators grasping the biological tissue portion in the inner lumen when the two or more tissue manipulators return to the inner lumen.

34. The method according to claim 32, wherein forming the tissue separation region with the at least one tissue manipulator includes forming at least a partial circumferential groove or slit in the biological tissue by rotating the at least one tissue manipulator while applying the force.

35. The method according to claim 34, further comprising rotating the sampling unit and the at least one tissue manipulator while the at least one tissue manipulator applies the force to the biological tissue unit and forms at least a partial circumferential groove or slit in the biological tissue unit.

36. The method according to claim 34, wherein advancing in the axial direction includes advancing in the axial direction while rotating the sampling unit in a first direction relative to the biological tissue, and forming includes forming the tissue separation region by rotating the sampling unit and the at least one tissue manipulator in a second opposite direction while applying the force to the biological tissue by the at least one tissue manipulator.

37. The method according to claim 32, comprising stopping the axial advancement before forming the tissue separation region.

38. The method according to claim 32, wherein the separation includes separating the tissue sample by applying a shear force to the biological tissue by rotating the sampling unit with respect to the biological tissue located outside the sampling unit.

39. The method according to claim 32, wherein the separation includes separating the tissue sample by retracting the sampling portion from the biological tissue and applying a tearing force to the biological tissue portion.

40. The method of claim 32, comprising advancing in the axial direction, granting, forming, and separating to obtain at least one additional tissue sample from the biological tissue.

41. The method according to claim 32, wherein advancing in the axial direction includes advancing the sampling unit axially into the biological tissue at an axial speed of 1 to 100 mm / second.

42. The method according to claim 41, wherein advancing in the axial direction includes rotating the sampling unit at a tangential speed of 2.5 to 1000 mm / second while advancing in the axial direction.

43. The method according to claim 42, wherein the ratio of the axial speed to the tangential speed is in the range of 3 to 5.

44. A long, slender handle equipped with a gripping member, A slender, flexible shaft mechanically equipped with a hollow distal sampling section having an internal lumen and a distal opening facing soft tissue, A soft tissue biopsy apparatus comprising: at least one drive unit configured to rotate the sampling unit while advancing the sampling unit axially into the soft tissue, A soft tissue biopsy device in which the ratio of the tangential rotation speed to the axial forward speed of the sampling unit is 1 to 10.

45. The apparatus according to claim 44, wherein the at least one drive unit rotates the elongated flexible shaft at a tangential speed in the range of 2.5 to 1000 mm / second.

46. The apparatus according to claim 44, wherein the at least one drive unit advances the sampling unit in the axial direction at an axial speed in the range of 1 to 100 mm / second.

47. The apparatus according to claim 44, wherein the distal opening is located at the distal end of the sampling section, and the distal end of the sampling section is a flat, straight end or is substantially perpendicular to the long axis of the sampling section.

48. The apparatus according to claim 44, wherein the ratio is the ratio between 2 and 5.

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