WO2025084436A1 - Marker, marker placement tool, and marker detection device - Google Patents

Abstract

Provided are: a marker that poses no risk of dislodgement, does not become a noise source for MRI or CT, can be easily and reliably placed at a lesion, and allows for precise detection of the placed position; a placement tool therefor; and a marker detection device. The marker placement tool comprises a catheter or an injection needle 11 in which a marker is loaded in the lumen, and a pusher 23 that is pushed into the lumen. A marker 1 contains a fluorescent dye. The surface or the inside of the marker 1 is provided with at least one of surface irregularities (a protrusion 5, flare shapes 6a, 6b) and a through hole 7c as fluid passages 7a, 7b, 7c so that the marker 1 can be held in the lumen when the marker 1 is not directly pressed by the pusher 23 but receives the pressing force of a fluid with which the lumen is filled. When directly pressed by the pusher 23, the marker 1 is pushed out from the injection needle 11, inserted into the living tissue, and placed. The marker detection device 60 is of a probe type and uses a light receiving element to detect the intensity of fluorescence emitted by the marker.

Description

Marker, marker placement device, and marker detection device

The present invention relates to a marker to be placed in biological tissue, a marker placement device, and a marker detection device.

In surgical procedures, medical clips are used as markers to pinpoint the location of the affected area in advance by attaching them to an endoscopic clipping device. For example, a clip (Patent Document 1) is used that consists of a clip body made of a metal leaf spring such as stainless steel bent into an approximate ">" shape, and a crimping ring that fits over the clip body to close it.

However, when a clip consisting of a metal leaf spring and crimping ring is used as a marker for the affected area during surgery, if the clip bites into an automatic stapler used to cut off the affected area, the clip will not break because it is made of metal, causing the stapler to become stuck.

In response to this, the present inventor has proposed a clip made of resin containing a fluorescent dye (Patent Document 2). This clip solves the problem that the stapler cannot move even if it bites into the clip because it is made of resin. Furthermore, there is an advantage that the position of the clip can be clearly confirmed from the serosal side by irradiating excitation light from the serosal side after clamping the mucosa of a hollow organ with the clip to cause the fluorescent dye to emit light. However, this clip has a weaker force for clamping biological tissue than conventional metal clips.

On the other hand, in gastrointestinal polyp surgery, endoscopic mucosal resection (EMR) is performed in which a bulge is formed by injecting saline into the submucosa of the lesion using an endoscopic needle, and the bulge is then used as a marker to squeeze and resect with a snare (Patent Document 3). However, even when an endoscopic needle is used to pierce the lesion, the angle of the needle's entry into the mucosal surface is not constant because the orientation of the needle changes depending on the puncture position. As a result, the needle tip may penetrate the gastrointestinal tract, making it impossible to form a bulge. In addition, the bulge disappears when the injected saline is absorbed in the body. There is also a demand for the ability to more clearly identify the lesion, as in the case of marking the lesion with a clip containing a fluorescent dye as described in Patent Document 2.

In addition, embedded markers with a diameter of 1 to 2 mm and a length of 5 to 15 mm are used as markers for non-palpable cancers. In other words, the location of non-palpable cancers is identified by MRI, mammography, ultrasound, etc. Non-palpable cancers include those that are non-palpable at the time of diagnosis and those that were palpable at the time of diagnosis but became non-palpable after chemotherapy. However, non-palpable cancers cannot be surgically removed while their location is identified by MRI, etc. Therefore, in order to determine the resection range including non-palpable cancers using a means that is easy to use during surgery, a method is used in which the location of the non-palpable cancer is observed in advance by MRI, etc., while an embedded marker is embedded in the biological tissue surrounding the non-palpable cancer, and the location of the marker is identified by a marker detection means during surgery. This method is useful for minimizing the resection range, and the marker embedded in the biological tissue is also useful for accurately identifying the area to be monitored after surgery.

Known types of implantable markers and methods for identifying their positions include a system that uses a probe that uses a coil of magnetic wire with an inner diameter of less than 2 mm, excites the marker with an alternating magnetic field, and detects the marker from changes in magnetic flux density (Patent Document 4), a method that uses nanoparticles of ferromagnetic material such as iron oxide dispersed in a bioabsorbable gel as a marker and identifies the marker's position with a handheld magnetometer (Patent Document 5), a system that uses a passive tag equipped with a photosensitive diode as a marker and an ultra-wideband radar as a probe (Patent Document 6), and a system that uses a passive RFID (Radio Frequency Identification) tag as a marker (LOCalizer (registered trademark), Hologic).

However, these implantable markers contain metal, which can be a source of noise in MRI and CT scans.

Patent No. 6572229 Patent No. 6675674 Patent No. 6382444 Patent Publication No. 2021-523751 Patent Publication No. 2015-524689 Patent Publication No. 2018-524059

The present invention provides a marker with a new configuration that is placed in the affected area or in the vicinity thereof, uses a marking method different from conventional clips, bulges caused by injections, and embedded metal markers, is not likely to fall off, does not become a noise source in MRI or CT, and can be placed in the affected area simply and reliably, and provides a placement tool for the marker. It also aims to provide a marker detection device that can accurately detect a marker placed in the affected area or in the vicinity thereof and can be easily used during surgery.

The inventors discovered that making the embedded marker a molded product containing a fluorescent dye is preferable because it allows the marker to be detected without becoming a noise source in MRI or CT, and that providing a fluid flow path on the surface or inside the product is preferable because it makes it easier to place the marker. They also discovered that the method of detecting a marker containing a fluorescent dye is preferably to identify the embedded position by the intensity of fluorescence using a probe-type device that can be pressed against biological tissue, rather than identifying the embedded position by creating a fluorescent image, and thus completed the present invention.

That is, the present invention provides a marker containing a fluorescent dye, which is loaded into the inner cavity of a catheter or an injection needle, pushed out by a pusher, inserted into biological tissue, and left in place,
a molded product having at least one of surface irregularities and through holes as a fluid flow path on the surface or inside of the marker so that the marker loaded in the cavity is not directly pressed by a pusher and the marker is held in the cavity when the fluid filled in the cavity is subjected to an extrusion force,
To provide a marker which is pushed out from an injection needle when the marker loaded in the inner cavity is directly pressed by a pusher.

The present invention also provides a first marker placement device for inserting and placing the marker in biological tissue, comprising:
Injection needles,
a tube having the injection needle attached to one end;
a cylinder in communication with the other end of the tube;
A piston sliding inside a cylinder,
a pusher having one end inserted into the tube and the other end connected to the piston in the cylinder, and a liquid supplying part for supplying an injection liquid to the cylinder;
The tube or needle falls under the following items (a1) and (a2):
(a1) When the marker is loaded into the tube or injection needle and the cylinder is filled with the injection liquid from the liquid supply unit, even if the pusher is pushed in by the piston, the marker is held in the tube or injection needle before the pusher directly presses the marker.
(a2) in a state where the marker is loaded in a tube or an injection needle, a pusher directly presses the marker to push the marker out of the injection needle;
The present invention provides a marker placement device having an inner diameter or shape that enables the above.

In addition, as a second marker placement device,
The injection needle includes a pusher that slides within the injection needle,
The injection needle is as follows: (b1) and (b2)
(b1) Even if the pusher is pushed into the injection needle with the marker loaded in the injection needle, the marker is held in the injection needle before the pusher directly presses the marker.
(b2) a pusher directly presses the marker while the marker is loaded into the injection needle, thereby pushing the marker out of the injection needle;
The present invention provides a marker placement device having an inner diameter or shape that enables the above.

Furthermore, the present invention provides a probe-type marker detection device for detecting a marker containing a fluorescent dye placed in a biological tissue, comprising:
A cylindrical inner cylinder portion formed of a light-impermeable material;
an excitation light emitting portion disposed around the inner cylindrical portion;
an excitation light cut filter provided within the inner cylindrical portion and closer to the rear than the tip surface of the inner cylindrical portion;
A marker detection device is provided that has a light receiving element provided in the inner cylindrical portion closer to the rear than the excitation light cut filter, and an output section for outputting the intensity of the fluorescence received by the light receiving element.

When the marker of the present invention and the first marker retention device are used endoscopically on biological tissue such as the mucosa of a hollow organ, an injection needle is inserted into the lesion and injection fluid is injected. If a bulge is formed there, the marker can be pushed out on the spot, allowing the marker to be retained at the lesion. On the other hand, if a bulge is not formed when an injection needle is inserted into a lesion in biological tissue and injection fluid is injected, it is clear that the injection needle has penetrated the biological tissue, and the needle can be inserted again. Therefore, the marker can be reliably retained at the lesion.

Furthermore, the marker of the present invention can be inserted and placed in biological tissues such as the breast, lungs, and bronchi by using the second marker placement device of the present invention.

There is no risk of the markers being placed in biological tissue in this way falling off. In addition, since there is no need to use metal, which is a source of noise in MRI and CT, in the material used to make the markers, the markers do not cause artifacts in MRI or CT images. In addition, since the markers contain fluorescent dyes, they can be made to emit fluorescence by irradiating them with excitation light, and the location where the marker was embedded can be identified by searching for areas with strong fluorescent intensity.

There are no particular limitations on the fluorescence detection device for detecting the marker of the present invention embedded in biological tissue, but the marker detection device of the present invention uses a light receiving element rather than an imaging element as the light receiving sensor, and the light receiving element is located behind the tip surface of the cylindrical inner tube, which increases the directionality when detecting the marker and improves the accuracy of the detection position of the marker.

Also, because it is a probe type, the marker detection device of the present invention can be pressed against biological tissue during surgery and moved up and down and left and right, or pushed in, and the embedded position of the marker can be identified based on the intensity of the received fluorescent light at that time. In particular, if a sound whose volume or pitch changes depending on the intensity of the received light is made to sound when the probe is moved to find the embedded position, the detector can know the position where the received light intensity is strong without taking his or her eyes off the biological tissue over which the probe is being moved, and the embedded position of the marker can be easily identified.

FIG. 1A is a side view of an embodiment of a marker 1A. FIG. 1B is a view of the marker 1A of the embodiment taken along the line A. FIG. 1C is a cross-sectional view of the marker 1A of the embodiment taken along the line BB. FIG. 2A is a side view of the marker 1B of the embodiment. FIG. 2B is a view of the marker 1B of the embodiment taken along the arrow C. FIG. 2C is a cross-sectional view of the marker 1B of the embodiment taken along the line DD. FIG. 3A is a side view of a marker 1C according to an embodiment of the present invention. FIG. 3B is a view of the marker 1C of the embodiment as seen from the arrow E. FIG. 3C is a cross-sectional view of the marker 1C of the embodiment taken along the line FF. FIG. 4 is a diagram showing the overall configuration of a first embodiment of the marker placement device. FIG. 5 is an explanatory diagram of the operation of the liquid supply unit. FIG. 6 is an explanatory diagram of the function of the first marker retaining device. FIG. 7 is an explanatory diagram of the function of the first marker retaining device. FIG. 8A is a side view of an injection needle having a reduced diameter portion as a movement resistance adjusting portion. FIG. 8B is a perspective view of an injection needle having a portion of the needle tip curved inward as a movement resistance adjusting portion. FIG. 9A is an explanatory diagram of a method of using the first marker placement device. FIG. 9B is an explanatory diagram of a method of using the first marker placement device. FIG. 9C is an explanatory diagram of a method of using the first marker placement device. FIG. 9D is an explanatory diagram of a method of using the first marker placement device. FIG. 9E is an explanatory diagram of a method of using the first marker placement device. FIG. 10 is an explanatory diagram of a method of using the first marker placement device. FIG. 11 is an explanatory diagram of a method of using the first marker placement device. FIG. 12 is an explanatory diagram of a method of using the first marker placement device. FIG. 13A is a cross-sectional view of a second marker placement device. FIG. 13B is a cross-sectional view of the second marker retaining device. FIG. 13C is a cross-sectional view of the second marker placement device. FIG. 14A is an explanatory diagram of a method of using the second marker placement device. FIG. 14B is an explanatory diagram of how to use the marker. FIG. 15 is a perspective view of an embodiment of a marker detection device. FIG. 16A is a cross-sectional view of a marker detection device. FIG. 16B is an enlarged cross-sectional view and a front view of the tip of the probe of the marker detection device. FIG. 17 is an explanatory diagram of a method for using the marker detection device.

Below, an embodiment of the present invention will be described in detail with reference to the drawings. Note that in each drawing, the same reference numerals represent the same or equivalent components.

[marker]
Fig. 1A is a side view of a marker 1A according to an embodiment of the present invention, Fig. 1B is a view taken along the line A, and Fig. 1C is a cross-sectional view taken along the line B-B. The marker 1A contains a fluorescent dye. The marker 1A is a molded product formed into a specific shape so that it is loaded into the inner cavity of a catheter or injection needle 11, pushed out by a pusher, inserted into biological tissue, and retained therein.

In other words, even if the marker 1 of the present invention including the above-mentioned marker 1A is loaded into the inner cavity of the first marker holder 10A shown in FIG. 4 or the second marker holder 10B shown in FIG. 13A and the pusher 23 starts to be pushed toward the injection needle 11, the marker 1 is not directly mechanically pressed by the pusher 23, and when the injection liquid, air, or other fluid filled in the inner cavity receives a pushing force, the fluid is pushed out from the injection needle 11 of the marker holder, but the marker 1 is held in the inner cavity by the movement resistance of surface friction, etc. On the other hand, when the marker 1 is directly pressed by the pusher 23, the marker 1 is also pushed out from the injection needle of the marker holder. In order to have the mobility in the inner cavity such that the marker is held in the inner cavity or pushed out from the inner cavity, the marker of the present invention has a shape that adjusts the movement resistance in the inner cavity, and also has surface irregularities or through holes that serve as a fluid flow path. The details of the shape of the marker will be described later.

(Materials for forming markers)
The marker 1 of the present invention can be made of various materials such as resin, ceramics, cellulose molded products, and metals such as titanium that do not become noise sources in MRI or CT, as long as the fluorescent dye can be contained in the marker 1. It is preferably molded from a flexible resin that can deform its external shape. If the marker 1 is made of a hard material, there is a risk that when the marker is placed in the stomach, intestines, etc., the marker may move from its initial placement position due to peristalsis.

The hardness of the marker 1 is preferably in the range of A10 to A90 as Shore A (JIS K 6253) or D40 to D70 as Shore D (JIS K 6253) measured with a durometer.

Such flexible resins include resins used in medical devices, such as soft polyvinyl chloride, thermoplastic polyurethane, silicone, and ethylene-vinyl acetate copolymer.

Marker 1 contains a fluorescent dye. This allows the location of the lesion to be identified during surgery as a location where the fluorescence emitted by the marker is strong, and also makes it possible to visually confirm the location using a fluorescent camera. Marker 1 may contain a radiopaque contrast agent such as barium sulfate. This allows the location of the lesion to be confirmed using X-ray photography.

The fluorescent dye is preferably one that emits fluorescence in the red or near-infrared wavelength range of 600 to 1400 nm, and more preferably in the red or near-infrared wavelength range of 700 to 1100 nm. Light in such wavelength ranges is highly permeable to human tissues such as skin, fat, and muscle, and can easily reach, for example, the mucous membrane and serosal surface of tubular human tissues such as the rectum.

Examples of fluorescent dyes that emit fluorescence in the above-mentioned wavelength range include riboflavin, thiamine, NADH (nicotinamide adenine dinucleotide), indocyanine green (ICG), the azo-boron complex compounds described in JP 2011-162445 A, dyes having a condensed ring structure described in WO 2016/132596 A, dyes having a boron dipyrromethene skeleton described in Japanese Patent No. 5,177,427 A, dyes that chemically bond to silica particles described in JP 2020-74905 A, and phthalocyanine dyes described in JP 2020-105170 A.

A specific example of how to incorporate a fluorescent dye into the marker 1 is to mix the fluorescent dye into the resin using a twin-screw kneader, and then mold the marker 1 by injection molding. In this case, the preferred concentration of the fluorescent dye in the resin can be set according to the type of fluorescent dye and resin, and is usually preferably 0.001 to 1% by mass.

Also, a coating film containing a fluorescent dye may be formed on the surface of the marker 1 made of a flexible resin or the like.

(Marker shape)
In the present invention, the shape of the marker 1 can be roughly cylindrical, rectangular or other columnar or tubular, bullet-shaped, spiral or coil-shaped, but as described above, it is preferable to provide the marker with a movement resistance adjustment part so that after the marker 1 is loaded into the inner cavity of the first marker holder 10A shown in FIG. 4 or the second marker holder 10B shown in FIG. 13A, the marker 1 is not directly mechanically pressed by the pusher 23 and is not pushed out of the injection needle 11 only by the hydraulic or pneumatic pressure of the fluid such as the injection solution or air filled in the inner cavity.

In the marker of the present invention, the movement resistance adjustment section may be, for example, a plurality of semi-spherical protrusions 5 that slide against the inner surface of the injection needle 11 or tube, provided on the circumferential surface of the bullet-shaped marker 1A, as in the marker 1A of the embodiment shown in Figures 1A and 1B. These protrusions 5 increase the movement resistance of the marker 1A due to friction with the inner surface of the injection needle 11 or tube. In addition, as a movement resistance adjustment section, a flare shape 6a that slides against the inner surface of the injection needle 11 or tube may be provided at the end of the marker 1A. In this marker 1A, the flare shapes 6a are provided radially.

On the other hand, in this marker 1A, the peripheral surface of the marker 1A where the protrusion 5 is not formed becomes a flow path 7a for fluid such as an injection solution. Therefore, when the marker 1 is loaded into the first marker retention device 10A shown in FIG. 4 and the piston 21 is pushed in, it becomes possible to eject only the injection solution A from the injection needle 11 through the flow path 7a, and this ejection also allows the liquid pressure applied to the marker 1 to be relieved. Also, when the marker 1 is loaded into the second marker retention device 10B shown in FIG. 13A and the pusher 23 is pushed in, if the pusher 23 does not reach the marker 1, it becomes possible to eject only air from the injection needle 11 through the flow path 7a (FIG. 1A).

The marker 1B shown in Figures 2A, 2B, and 2C also has a roughly bullet-shaped outer shape, and has a flare shape 6b at the end of the bullet shape that slides against the inner surface of the injection needle 11 or tube as a movement resistance adjustment section. The flare shape 6b of this marker 1B is formed in a semicircular arc shape with a central angle θ of approximately 180°, so it is less likely to deform than the radial flare shape 6a of the marker 1A shown in Figures 1A and 1B, and the movement resistance of the marker can be increased.

The marker 1B also has a groove 7b formed in the longitudinal direction on the circumferential surface of the marker as a flow path. The groove 7b extends linearly and not helically.

The marker 1C shown in Figures 3A, 3B, and 3C also has a roughly bullet-shaped outer shape, and has a flare shape 6c formed around the entire circumference of the end of the bullet shape as a movement resistance adjustment section. This flare shape 6c can further increase movement resistance than the semicircular arc flare shape 6b described above.

The marker 1C also has a through hole 7c formed in the axial direction that passes through the center of the marker as a flow path.

The marker 1A shown in Figure 1A is preferred because of ease of manufacture.

[Marker placement device]
(First marker placement device)
4 is an overall configuration diagram of one embodiment of the first marker retaining device of the present invention, showing a state in which the marker 1 is loaded. The first marker retaining device 10A can be used by being inserted through the forceps hole of an endoscope, and includes the marker 1 of the present invention which is inserted into and retained in living tissue such as a hollow organ, an injection needle 11 of a tube diameter through which the marker 1 can be passed, a tube (also called an inner tube) 12 to one end of which the injection needle 11 is attached, a cylinder 20 which communicates with the other end of the tube 12, and a piston 21 which slides within the cylinder 20. A rubber piston head 22 is attached to the end of the piston 21 on the cylinder side.

In the first marker retaining device 10A, the marker 1 can be inserted into the tube 12 from the open end of the tube 12 on the cylinder 20 side, and is loaded near the end of the tube 12 closer to the injection needle 11 or into the inner cavity of the injection needle 11. Alternatively, the marker 1 can be loaded into the needle tube of the injection needle 11, and then the injection needle 11 can be attached to the tube 12.

In FIG. 4, the marker 1 is loaded into the injection needle 11, but in the present invention, the marker 1 may also be loaded into the tube 12.

The size of the injection needle 11 can be the same as that of a typical endoscopic injection needle, for example, a 19 gauge (inner diameter 0.70 mm, outer diameter 1.06 mm), length 3 to 10 mm, or a 20 gauge (inner diameter 0.58 mm, outer diameter 0.88 mm), length 3 to 10 mm can be used.

However, as described above, when the marker 1 is pressed only by the liquid pressure of the injection solution, it is not pushed out of the injection needle 11, and the inner diameter or shape of the injection needle 11 is determined so that the marker 1 generates a movement resistance that keeps it in the injection needle 11. The same applies to the tube 12. For example, the size or shape of the inner diameter of the injection needle 11 or the tube 12 is determined so that the marker 1 slides inside the injection needle 11 or the tube 12. Also, as shown in FIG. 8A, the movement resistance adjustment part may be formed by one or more narrowed parts 11a formed on the injection needle 11. The narrowed parts 11a can be formed, for example, by making a recess in the injection needle 11 with a punch or the like. In addition, as the movement resistance adjustment part, a part in which the needle tip 11b of the injection needle 11 is curved inward may be provided as shown in FIG. 8B.

On the outside of the tube 12 is an outer tube 13, and the tube 12 can be extended from the outer tube 13 or retracted into the outer tube 13 by an operating unit (not shown). The tube 12 and the outer tube 13 are also referred to as a catheter.

A disposable product can be formed by the injection needle 11, the tube 12, the marker 1 loaded into the injection needle 11 or the tube 12, the outer tube 13, the cylinder 20, the pusher 23, and the piston 21.

The tube 12, the outer tube 13, and the pusher 23 may be flexible or rigid depending on the part of the biological tissue in which the first marker retention device 10A is used. For example, they can be rigid when used with a cystoscope, and are preferably flexible when used with a gastrointestinal endoscope.

An end of a pusher 23 is connected to the piston 21 via a piston head 22. The pusher 23 is inserted into the tube 12, and the end of the pusher 23 reaches the vicinity of the injection needle 11. Therefore, when the piston 21 is pushed into the cylinder 20, the pusher 23 directly and mechanically presses the marker 1, so that the marker 1 is pushed out of the injection needle 11.
The piston 21 and the pusher 23 may be formed integrally or separately.

The cylinder 20 is provided with a liquid supply section 30 that supplies injection liquid A. As injection liquid A, for example, saline solution, hyaluronic acid solution, etc. can be used.

The liquid supply unit 30 has a syringe 31 and a plunger 32, and is connected to the cylinder 20 via a valve 33 such as a two-way valve. As shown in FIG. 5, by opening the valve 33 and pushing the injection liquid A in the syringe 31 with the plunger 32, an amount of injection liquid A suitable for forming a bulge (usually 1 to 2 mL) can be injected into the cylinder 20. Note that in the present invention, the liquid supply unit 30 is not limited to being composed of a syringe and a plunger, and a fixed amount of injection liquid may be discharged using a trigger mechanism.

With this first marker retaining device 10A, as shown in FIG. 6, when the marker 1 is loaded into the inner cavity of the injection needle 11 or the tube 12 and the cylinder 20 and the tube 12 are filled with injection fluid A, and the piston 21 is pushed into the cylinder 20 with the valve 33 closed, if the pusher 23 does not reach the marker 1 due to the amount of pushing (i.e., the marker is not directly pressed by the pusher), the injection fluid A is dispensed from the injection needle 11, but the marker 1 is retained in the inner cavity of the tube 12 or the injection needle 11. In other words, the marker 1 is not pushed out of the injection needle 11 by the fluid pressure alone when the injection fluid A is pushed in by the piston 21. On the other hand, when the piston 21 is pushed further into the cylinder 20 and the pusher 23 mechanically presses the marker 1 directly, as shown in FIG. 7, the marker 1 is pushed out of the injection needle 11.

(Method of using the first marker placement device)
(How to use 1)
The first marker retaining device 10A is preferably used when retaining a marker in the biological tissue of a hollow organ. In this case, the marker retaining device 10A is first inserted into the forceps hole of the endoscope and set. The injection liquid A is supplied from the liquid supply unit 30 to the cylinder 20, and the injection needle 11, the tube 12, and the cylinder 20 are filled with the injection liquid A. The valve 33 is closed, the piston 21 is slightly pushed into the cylinder 20, and it is confirmed that the injection liquid is dispensed from the injection needle 11.

Then, the injection needle 11 is inserted into the hollow organ through a natural opening such as the mouth, nose, or anus, an incision, or other opening, and under endoscopic observation, the injection needle 11 is inserted near the diseased area 42 of the mucosa 41 of the hollow organ, as shown in Figure 9A. Then, as shown in Figure 9B, the piston 21 is pushed to inject injection liquid A into the mucosa 41, and it is confirmed that a bulge 43 is formed. The formation of the bulge 43 indicates that the injection needle 11 has not penetrated the wall of the hollow organ, and after this confirmation, the piston 21 is further pushed to push the marker 1 with the pusher 23, as shown in Figure 9C, thereby forcing the marker 1 into the mucosa 41 and leaving it there.

In contrast, if no bulge is formed even after injection of injection fluid A, it is considered that the injection needle 11 has penetrated the wall of the tubular organ and injection fluid A has been injected outside the serosal surface 44, as shown in FIG. 9D. In this case, the injection needle 11 should be inserted again.

The bulge formed in the mucosa 41 by the injection of injection solution A generally disappears about one hour after injection.

After placing the marker 1 in the mucosa 41, as shown in FIG. 9E, excitation light L1 is irradiated from the serosal surface 44 side using a near-infrared fluorescence endoscope 50, and the position of the marker 1 can be precisely visually confirmed by the fluorescence L2 emitted by the marker 1. This makes it easy to precisely identify the location of the affected area during surgery.

(How to use 2)
As a method of using the first marker retaining device 10A of the present invention, a plurality of markers 1a, 1b may be loaded into an injection needle 11 or a tube 12 as shown in FIG.

In this case, after the first marker 1a on the needle tip side is placed on the mucosa 41 as described above, the injection needle 11 is pulled out from the mucosa, the piston 21 is pulled back, and the pusher 23 is separated from the second marker 1b inside the injection needle 11. Next, the valve 33 of the liquid supply unit 30 is opened to supply injection liquid A into the cylinder 20. Thereafter, as described above, the valve 33 is closed and the injection needle 11 is inserted into the mucosa 41, the piston 21 is pushed to inject injection liquid A into the mucosa 41, and after the bulge is confirmed, the piston 21 is further pushed to push the second marker 1b into the mucosa 41.

In this way, if multiple markers 1a and 1b are stored in the injection needle 11 or tube 12 of the first marker retainer 10A, the markers 1a and 1b can be fired continuously by setting the marker retainer 10A once in the forceps hole of the endoscope. Therefore, for example, as shown in FIG. 11, when identifying the location of a cancer in the digestive tract, the first marker 1a can be placed on the oral side of the lesion 42 and the second marker 1b can be placed on the anal side, and as shown in FIG. 12, by irradiating excitation light L1 from the serosal surface 44 of the digestive tract using a near-infrared fluorescence endoscope 50, the location of the cancer in the digestive tract can be accurately identified by the fluorescence L2 emitted by the first marker 1a and the second marker 1b.

Furthermore, by storing multiple markers 1a and 1b in the first marker retention device 10A, markers can be placed in multiple locations in biological tissue with one marker retention device, which reduces the burden on the doctor and also makes it possible to cut costs for the marker retention device. Therefore, the present invention also includes retention device 10A in which multiple markers are stored.

(Second marker placement device)
13A is a cross-sectional view of one embodiment of the second marker retaining device of the present invention, showing a state in which the marker 1 is loaded into an injection needle. The second marker retaining device 10B comprises an injection needle 11 and a pusher 23 that slides inside the injection needle 11. The end of the pusher 23 opposite to the injection needle 11 is a large-diameter pressing part 23a.

It is preferable to provide a finger hook 24 at the end of the outer circumferential surface of the injection needle 11. In addition, a temporary plug 25 made of bleached beeswax or the like is provided inside the injection needle 11 near the needle tip to prevent the marker 1 from accidentally falling out of the injection needle 11.

When placing a marker inside the wall of a hollow organ, there is a risk that the injection needle loaded with the marker will penetrate the wall of the hollow organ, so as mentioned above, a bulge in the injection fluid is formed to check whether the needle tip is in the correct position (Figures 9A to 9E). However, if the site where the marker is to be placed is not susceptible to such risk, such as the breast, or is a site where it is not desirable to inject the injection fluid, such as the lungs or bronchi, it is preferable to use the second marker placement device 10B, which pushes out the marker without injecting the injection fluid.

The injection needle 11 of the second marker retaining device 10B has an inner diameter that generates a movement resistance to the marker 1 of the present invention, similar to the injection needle 11 of the first marker retaining device 10A. In addition, the marker 1 of the present invention has surface irregularities or through holes that serve as an air flow path, as described above. Therefore, as shown in FIG. 13A, when the pusher 23 is pushed into the injection needle 11 loaded with the marker 1, the marker 1 does not pop out at the same time as the pusher 23 is pushed in. Even if the pusher 23 is pushed in, it does not reach the marker 1, and in the state before the marker 1 is directly pressed, a fluid such as air is pushed out of the injection needle 11 through the flow path of the marker 1, and the marker 1 is held in the injection needle 11. Next, as shown in FIG. 13B, when the pusher 23 begins to directly press the marker 1, the marker 1 moves together with the pusher 23, and is pushed out of the injection needle 11 as shown in FIG. 13C.

(Method of using the second marker placement device)
When the marker 1 of the present invention is placed in a lesion of a breast, for example, using the second marker placement device 10B, as shown in Fig. 14A, the pusher 23 is pushed in to move the marker 1 to the tip of the injection needle 11, and then the skin is punctured, and the marker 1 is placed in the lesion or in its vicinity while confirming the lesion and the injection needle 11 on an image by ultrasound examination or mammography. During surgery to remove the lesion, the fluorescence emitted from the marker 1 by irradiation with excitation light L1 is observed with a fluorescence camera (not shown). It is preferable that the fluorescence camera not only displays a fluorescent image of red or infrared fluorescence L2, but also displays a visible light image superimposed on the fluorescent image.

Furthermore, multiple markers can also be loaded into the injection needle 11 of the second marker placement device 10B, so multiple markers 1 can be easily placed around the lesion.

When marker 1 is placed in biological tissue in this way, even if the original lesion becomes non-palpable due to chemotherapy, radiation therapy, etc., marker 1 emits fluorescence when irradiated with excitation light, as shown in Figure 14B, so the location of the original lesion can be easily identified. Furthermore, by using the position of the marker as a guide during surgery, the area of resection can be kept to the minimum necessary.

[Marker detection device]
(Configuration of the marker detection device)
FIG. 15 is an oblique view of one embodiment of a probe-type marker detection device 60 of the present invention, FIG. 16A is a cross-sectional view of the marker detection device 60, and FIG. 16B is an enlarged cross-sectional view and a front view (viewed in the direction of arrow G) of the tip of the probe of the marker detection device 60.

This marker detection device 60 is a probe-type device that detects a marker containing a fluorescent dye that is placed in biological tissue, and is suitable for detecting the above-mentioned marker 1 of the present invention. The marker detected by this marker detection device 60 may be any material that contains a fluorescent dye, and may be made of resin, ceramic, or metal, or may be a liquid containing a fluorescent dye. It is not limited to the marker of the present invention in which the movement resistance is adjusted as described above.

The probe 61 of the marker detection device 60 has a cylindrical inner tube portion 62 made of a light-impermeable material such as metal, an excitation light emitting portion 63 arranged around the inner tube portion 62 and toward the rear of the tip surface 62a of the inner tube portion 62, an excitation light cut filter 64 (64a, 64b) provided within the inner tube portion 62 toward the rear of the tip surface 62a of the inner tube portion 62, and a light receiving element 65 provided within the inner tube portion 62 toward the rear of the excitation light cut filter 64. Air is present in the gap between the excitation light cut filter 64 and the light receiving element 65.

The outermost surface of the probe 61 is formed of a cylindrical outer tube portion 66 made of a light-impermeable material such as metal, and surrounds the excitation light emitting portion 63. The excitation light emitting portion 63 and the light receiving element 61 are provided in the portion where the inner tube portion 62 and the outer tube portion 66 form a double structure. The tip surface 62a of the inner tube portion 62 is located closer to the rear than the tip surface 66a of the outer tube portion 66.

A transparent glass member 67 is provided on the front surface of the excitation light emitting portion 63 inside the outer tube portion 66, and the tip surface 67a of the transparent glass member 67 is the excitation light emitting surface. There is no optical fiber between the excitation light emitting portion 63 and the excitation light emitting surface. On the tip side of the probe 61 closer to the tip portion 63a of the excitation light emitting portion 63, the transparent glass member 67 fills the gap between the outer tube portion 66 and the inner tube portion 62. Air exists in the gap between the excitation light emitting portion 63 and the transparent glass member 67. The light receiving element 65 and the excitation light emitting portion 63 are connected to a substrate 68.

Meanwhile, a gripping portion 70 is formed at the rear end of the probe 61, and a battery box 71 and a speaker 72 are provided inside the gripping portion 70. The speaker 72 emits a sound whose volume or pitch corresponds to the intensity of the fluorescent light received by the light receiving element 65. A circuit board 73 is provided on the back of the battery box 71. In addition, a main switch 74 of the marker detection device 60 is provided on the rear end surface of the gripping portion 70.

Here, it is preferable to provide an LED as the excitation light emitter 63, which emits light of a red to near-infrared wavelength that excites the fluorescent dye contained in the marker 1. A plurality of LEDs 63 can be provided around the inner tube 62. It is also preferable to provide the tip 63a of the LED 63 closer to the rear than the tip surface 66a of the outer tube 66. This can increase the directionality of the excitation light. For example, when the excitation light emitter 63 is formed of a bullet-shaped LED and the inner diameter D1 of the outer tube 66 is 10 to 16 mm, it is preferable that the distance K1 between the tip 63a of the excitation light emitter 63 and the tip surface 66a of the outer tube 66 is 2 to 4 mm.

In contrast, guiding light from a light source outside the probe to the excitation light emitting unit 63 using an optical fiber is not preferable because it complicates the configuration of the marker detection device and also causes light loss.

The light receiving element 65 is preferably a photodiode, phototransistor, or the like that is sensitive to light of red to near-infrared wavelengths. It is not necessary to provide an imaging element such as a CCD in which the light receiving elements are arranged in an array. By providing a single light receiving element such as a photodiode, the intensity of the received fluorescent light can be increased. Furthermore, by not providing an imaging element, there is no need for optical systems such as a lens system for focusing or an aperture for adjusting the amount of light, which simplifies the configuration of the marker detection device and makes it possible to manufacture it inexpensively.

In addition, by providing the tip 65a of the light receiving element 65 closer to the rear than the tip surface 62a of the inner tube portion 62, the directivity of the fluorescence received by the light receiving element 65 can be improved, and the positional accuracy when detecting a marker placed in biological tissue can be improved. For example, when the inner diameter D2 of the inner tube portion 62 is 3 to 6 mm and the light receiving element 65 is a bullet-shaped photodiode, the distance K2 between the tip surface 62a of the inner tube portion 62 and the tip 65a of the light receiving element 65 is preferably 5 to 9 mm, and the distance K3 between the tip surface 66a of the outer tube portion 66 and the tip 65a of the light receiving element 65 is preferably 8 to 15 mm.

The excitation light cut filter 64 disposed in front of the light receiving element 65 can be provided with overlapping filters 64a and 64b having different cut wavelengths as necessary. The tip surface of the excitation light cut filter 64 becomes the tip surface of the fluorescence receiving side in the marker detection device 60.
In the marker detection device of the present invention, there is no optical fiber between the fluorescent light receiving tip face and the light receiving element 65 .

In place of the speaker 72, or together with the speaker 72, a Bluetooth or Wi-Fi transmitter may be provided as an output section for the intensity of the fluorescent light detected by the light receiving element 65, or a display may be provided.

(Method of using the marker detection device)
As a method of using the marker detection device, for example, when detecting a marker placed in advance at or near a breast lesion when surgically removing the lesion, it is preferable to press the tip of the probe 61 against the breast and move it back and forth, left and right, or up and down to find a location where the detection intensity of the fluorescence emitted by the marker 1 is strong, as shown in Fig. 17. By pressing the tip of the probe 61 against the milk and moving it, the distance to the probe 61 is shortened even for a marker 1 embedded deep under the skin, and the light receiving intensity at the light receiving element 65 is increased, making detection easier. In addition, by pressing the probe 61, blood between the marker 1 and the probe 61 can be eliminated, so that scattering or absorption of the excitation light or fluorescence by the blood can be suppressed, and this also increases the light receiving intensity at the light receiving element 65.

If the marker detection device 60 is equipped with a speaker 72, the surgeon can easily find the location where the marker has been placed by the pitch or intensity of the sound. In addition, if the marker detection device 60 is equipped with a Bluetooth or Wi-Fi transmitter, the output waveform of the fluorescence intensity can be displayed on the display 81 of the receiver 80, such as a personal computer, tablet, or smartphone, that receives radio waves from the transmitter.

With this marker detection device 60, the fluorescence emitted by the marker is detected by a light receiving element such as a stand-alone photodiode, without being detected by an imaging element, and furthermore, the directionality during detection is improved. Moreover, since the probe 61 can be moved back and forth, left and right, or up and down while being pressed against the biological tissue, the marker 1 placed in the biological tissue can be detected with high positional accuracy and high sensitivity. Therefore, for example, a marker placed at a depth of up to 4 cm from the surface of the biological tissue can be reliably detected.

Generally, when a marker placed in biological tissue is photographed with a fluorescent camera, markers at a depth of up to about 2 cm can be detected, but markers deeper than 2 cm cannot be detected, so it can be seen that the detection sensitivity of the marker detection device of the present invention is superior to that of a fluorescent camera.

In addition, the location where the marker is placed in the biological tissue can be detected by the marker detection device 60, and after an incision is made near the detection location so that the marker can be detected by the fluorescent camera, the position of the marker can be confirmed with the fluorescent camera while the affected area is excised. In this case, it is preferable for the fluorescent camera to be one that can simultaneously display the fluorescent image emitted by the marker and the visible light image from the biological tissue, and for example, the HyperEye Medical System (Mizuho Corporation) can be used.

1, 1a, 1b, 1A, 1B, 1C Marker 5 Protruding portion 6a, 6b, 6c Flare shape 7a, 7b Flow path, groove 7c Flow path, through hole 10A First marker retaining device 10B Second marker retaining device 11 Injection needle 11a Diameter-reduced portion 11b Needle tip 12 Tube (inner tube)
13 Outer tube 20 Cylinder 21 Piston 22 Piston head 23 Pusher 23a Pressing portion 24 Finger hook portion 25 Temporary plug 30 Liquid supply portion 31 Syringe 32 Plunger 33 Valve 41 Mucous membrane of hollow organ 42 Lesion portion 43 Bulging portion 44 Serous surface of hollow organ 45 Milk 50 Near-infrared fluorescence endoscope 60 Marker detection device 61 Probe 62 Inner tube portion 62a Tip surface of inner tube portion 63 Excitation light emission portion, LED
63a Tip of excitation light emitting part 64, 64a, 64b Excitation light cut filter 65 Light receiving element 65a Tip of light receiving element 66 Outer cylinder part 66a Tip surface of outer cylinder part 67 Transparent glass member 67a Tip surface of transparent glass member 68 Board 70 Grip part 71 Battery box 72 Speaker 73 Board 74 Main switch 80 Receiving device 81 Display A Injection solution D1 Inner diameter D2 of outer cylinder part Inner diameter K1 of inner cylinder part Distance K2 between excitation light emitting part and tip surface of outer cylinder part Distance K3 between tip surface of inner cylinder part and light receiving element Distance L1 between tip surface of outer cylinder part and light receiving element Excitation light L2 Fluorescence

Claims (14)

A marker containing a fluorescent dye that is loaded into the lumen of a catheter or an injection needle together with a fluid, and is pushed out by a pusher to be inserted into biological tissue and left in place,
The marker has a sliding contact portion that is in sliding contact with the inner cavity, and has a fluid flow path on the surface or inside of the marker, and the sliding contact portion and the flow path have the following (i) and (ii):
(i) when the marker is loaded into the inner cavity together with a fluid and the tip of the pusher is pushed into the inner cavity in the axial direction of the injection needle, the fluid is pushed out of the injection needle through the flow path before the marker is directly pressed by the pusher because the pusher does not reach the marker, but the marker is held in the inner cavity by friction between the sliding portion and the inner cavity;
(ii) when the pusher is pushed further than in (i) and the marker loaded in the lumen is directly pressed in the axial direction of the injection needle by the tip of the pusher, the marker is pushed out of the injection needle;
A marker that allows. The marker according to claim 1, in which the sliding contact part is made of a flexible resin with a Shore D hardness of 40 to 70 so that it can be deformed. The marker according to claim 1 has a cylindrical, columnar or bullet-shaped outer shape, and the sliding portion has a flare shape that slides against the inner surface of the injection needle. The marker according to claim 1 has a cylindrical, columnar or bullet-shaped outer shape, and has a plurality of semi-spherical protrusions on the periphery of the marker as sliding contact parts that come into sliding contact with the inner surface of the injection needle. The marker of claim 4, wherein the liquid flow path is formed in the non-formed portion of the peripheral surface of the marker. The marker according to claim 1, wherein the marker has a cylindrical, columnar or bullet-shaped outer shape, and a non-helical linear groove extending in the longitudinal direction of the marker is formed on the circumferential surface as a fluid flow path. The marker according to claim 1, wherein the marker has a cylindrical, columnar or bullet-shaped external shape, and has an axially extending through-hole that the pusher does not penetrate as a fluid flow path. A marker retention device for inserting and retaining the marker according to claim 1 in biological tissue,
Injection needles,
a tube having the injection needle attached to one end;
a cylinder in communication with the other end of the tube;
A piston sliding inside a cylinder,
A pusher, one end of which is inserted into a tube and the other end of which is connected to a piston within a cylinder;
and a liquid supplying part for supplying an injection liquid to the cylinder,
The lumen of the tube or injection needle is capable of sliding against the sliding contact portion of the marker, and the lumen is caused to slide against the sliding contact portion by friction with the sliding contact portion, and the following (a1) and (a2) are satisfied:
(a1) When the marker is loaded into the inner cavity of a tube or a syringe needle and the cylinder is filled with an injection liquid from a liquid supply unit, the tip of the pusher is pushed in the axial direction of the syringe needle by the piston. Before the pusher directly presses the marker because the pusher does not reach the marker, the injection liquid is pushed out of the syringe needle through the flow path of the marker, but the marker is held in the inner cavity by friction between the sliding portion and the inner cavity,
(a2) when the marker is loaded in the tube or the lumen of the injection needle, the tip of the pusher is pushed in the axial direction of the injection needle further than (a1) to directly press the marker in the axial direction of the injection needle, thereby pushing the marker out of the injection needle;
A marker placement device having an inner diameter or shape that enables the above. A marker retention device for inserting the marker according to claim 1 into a biological tissue and retaining it therein, comprising an injection needle and a pusher that slides within the injection needle,
The lumen of the injection needle is capable of slidingly contacting the sliding portion of the marker, and the lumen is configured to have the following properties (b1) and (b2) due to friction between the lumen and the sliding portion.
(b1) When the tip of the pusher is pushed into the injection needle in a state in which the marker is loaded into the injection needle together with the injection liquid, before the pusher directly presses the marker, the injection liquid is pushed out of the injection needle through the flow path of the marker, but the marker is held in the injection needle by friction with the sliding contact portion,
(b2) when the marker is loaded in the injection needle, the tip of the pusher is pushed further into the injection needle than in (b1) to directly press the marker in the axial direction of the injection needle, thereby pushing the marker out of the injection needle;
A marker placement device having an inner diameter or shape that enables the above. A probe-type marker detection device for detecting a marker containing a fluorescent dye placed in a biological tissue, comprising:
A cylindrical inner cylinder portion formed of a light-impermeable material;
an excitation light emitting portion disposed around the inner cylindrical portion;
a cylindrical outer cylinder portion formed of a light-impermeable material and surrounding the excitation light emission portion;
an excitation light cut filter provided within the inner cylindrical portion and closer to the rear than the tip surface of the inner cylindrical portion;
a light receiving element provided in the inner cylindrical portion closer to the rear than the excitation light cut filter, and an output section that outputs the intensity of the fluorescence received by the light receiving element,
The light receiving element and the excitation light emitting part are provided in the part where the inner and outer cylinders have a double structure,
A marker detection device in which a tip surface of an inner cylinder is provided rearward of a tip surface of an outer cylinder, and an excitation light emitting portion is provided rearward of the tip surface of the inner cylinder. The marker detection device according to claim 10, wherein no optical fiber is interposed between the excitation light exit end face of the marker detection device and the excitation light exit section, and no optical fiber is interposed between the fluorescent light receiving end face of the marker detection device and the light receiving element. The marker detection device according to claim 10, wherein an LED is provided as the excitation light emitter. The marker detection device according to any one of claims 10 to 12, which has a speaker as an output section and changes the volume or pitch of the sound depending on the intensity of the fluorescence. The marker detection device according to any one of claims 10 to 12, which has a display as an output unit and displays the fluorescence intensity on the display.

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