JP7333030B2 - fistula treatment instrument - Google Patents

Description

The present invention relates to an ostomy treatment device. More particularly, it relates to therapeutic instruments that can be used to treat fistulas such as bronchial stump fistulas.

Bronchial stump fistula is a serious complication after pulmonary resection, occurring in 0.5% after lobectomy and 4.5-20% after pneumonectomy, with a mortality rate of 16-70%. Are known.

Treatment methods for bronchial stump fistula are roughly divided into surgical treatment and bronchoscopic treatment. However, surgical therapy is highly invasive, and if inflammation spreads over a wide area, more invasive secondary surgery including fenestration drainage is required, requiring long-term treatment. On the other hand, bronchoscopic therapy is relatively less burdensome to the patient than surgical therapy and does not require general anesthesia, so various therapeutic methods have been reported.

For example, as one of the bronchoscopic treatments, a method has been proposed in which a silicone filling material called EWS (Endobronchial Watanabe Spigot) is temporarily indwelled at the bronchial stump to promote fistula closure (non-patent literature 1).

As another method, for example, a method for promoting fistula closure by isolating autologous adipose stem cells and injecting them into the bronchial stump under bronchoscope has been proposed (Non-Patent Documents 2 and 3).

Bronchology JJSB 23(6):510-515, 2001 Thorax 2008;63:374-376 Cytotherapy, 2016;18:36-40 Sayako Morikawa et al. Ther Adv Respir Dis 2016, Vol. 10(6): 518-524

However, the method of Non-Patent Document 1 has problems of low closure rate and occurrence of complications. Specifically, the fistula closure rate by EWS is said to be 83%, but this includes cases in which some kind of therapeutic intervention such as pleurodesis was performed before EWS, and the actual EWS alone The success rate is estimated to be around 33%. In addition, although it is considered a relatively less invasive local treatment that does not require general anesthesia, serious complications such as myocardial infarction, arrhythmia, and obstructive pneumonia have been reported (Non-Patent Document 4). In addition, EWS itself is a non-biomaterial, and mechanical stimulation due to its low biocompatibility may cause the above complications. On the other hand, the methods of Non-Patent Documents 2 and 3 are in the form of injecting a liquid, so there is a possibility that the liquid may leak into the thoracic cavity from the target bronchus stump. As described above, none of the methods have good therapeutic results, and development of a new therapeutic method for effectively treating bronchial stump fistula has been desired.

Under such circumstances, the present inventors conducted extensive research and found that if a solidified cell structure obtained by fusing spheroids could be supplied to the bronchial stump, fistula closure would be promoted and the bronchial stump could be treated. A novel idea was obtained that fistula could be treated effectively.

However, in this case, since the cell construct cannot be directly held by a bronchoscope, etc., it was considered necessary to develop a new instrument for reliably transporting and supplying the cell construct to a predetermined position. .

The present invention has been made in view of the above circumstances, and provides a fistula treatment instrument for transporting and supplying a cell structure for closing a fistula such as a bronchial stump fistula to a predetermined position. The challenge is to

In order to solve the above problems, the fistula treatment instrument of the present invention is a fistula treatment instrument for transporting and supplying a cell structure for closing a fistula to a predetermined position,
an exterior portion having a substantially cylindrical through hole;
a bottomless cylindrical body inserted into the through hole of the exterior part;
an extrusion member axially slidable inside the cylindrical body;
with
The cylindrical body has one end protruding outside the exterior part and can hold a solidified cell structure inside the other end,
When the pushing member is slid from the one end side of the cylindrical body toward the other end side, the cell structure held inside the other end side is pushed outward and can be detached from the cylindrical body. It is characterized by

In this fistula treatment instrument, the cylindrical body includes a first cylindrical portion and a second cylindrical portion having a larger diameter than the first cylindrical portion,
The first cylindrical portion has a protruding portion that protrudes outward from the exterior portion at one end and is connected to the second cylindrical portion at the other end,
It is preferable that the second cylindrical portion is inserted into the through-hole and capable of holding the cell structure inside.

In this fistula treatment instrument, the extrusion member
a substantially cylindrical body portion inserted through the first cylindrical portion and the second cylindrical portion;
A substantially disk-shaped flange portion provided at one end of the main body portion and exposed to the outside of the first cylindrical portion;
A substantially disk-shaped extruding portion provided at the other end of the main body portion and located inside the second cylindrical portion;
with
The outer diameters of the flange portion and the extruded portion are preferably larger than the inner diameter of the first cylindrical portion.

In this instrument for gastrostomy, it is preferable that the pushing member has a handle protruding from the vicinity of the center of the flange.

The assembly kit of the present invention is an assembly kit for the fistula treatment instrument,
an exterior portion having a substantially cylindrical through hole;
a bottomless cylindrical body inserted into the through hole of the exterior part;
an extrusion member that is axially slidable inside the cylindrical body;
It is characterized by comprising

INDUSTRIAL APPLICABILITY The therapeutic instrument for fistula of the present invention can reliably transport and supply a cell structure for closing a fistula to a predetermined position, and can effectively treat various diseases associated with fistula.

1 is an internal see-through perspective view illustrating one embodiment of a fistula treatment instrument of the present invention; FIG. 2 is a cross-sectional view taken along the line A-A' in FIG. 1; FIG. 2 is a perspective view showing an exterior part of the fistula treatment instrument shown in FIG. 1. FIG. FIG. 2 is a perspective view showing a cylindrical body in the fistula treatment instrument shown in FIG. 1; FIG. 2 is a schematic diagram illustrating an outline of a process for assembling the fistula treatment instrument shown in FIG. 1 and a process for holding the cell structure; FIG. 2 is a schematic diagram illustrating a state in which the fistula treatment instrument of the present invention is carried to the fistula of a bronchial stump fistula using forceps of a bronchoscope. FIG. 4 is a schematic diagram illustrating a form of detaching a cell structure from a transported fistula treatment instrument and supplying it to a fistula. FIG. 4 is a schematic diagram illustrating a state in which the forceps are pulled out from the fistula treatment instrument that has been transported.

The fistula treatment instrument of the present invention is a fistula treatment instrument for transporting and supplying a cell structure for closing a fistula to a predetermined position.

The fistula therapeutic instrument of the present invention can be suitably used for closing fistulas formed in various organs such as the digestive system, respiratory system, and circulatory system. Specifically, bronchial stump fistula, gastrointestinal cutaneous fistula (Crohn's disease, inflammatory bowel disease such as ulcerative colitis, fistula due to delayed postoperative gastrointestinal insufficiency, postoperative biliary fistula, postoperative pancreatic juice fistula), anal fistula, vesicovaginal fistula, rectovaginal fistula, tracheoesophageal fistula, and the like. It may also be applied to bronchoscopic lung volume reduction therapy (BLVR) for emphysema.

An embodiment of the fistula treatment instrument of the present invention will be described with reference to the drawings. FIG. 1 is an internal see-through perspective view illustrating one embodiment of the fistula treatment instrument of the present invention. 2 is a cross-sectional view taken along the line A-A' in FIG. 1. FIG. 3 is a perspective view showing an exterior part of the fistula treatment instrument shown in FIG. 1. FIG. 4(A) and 4(B) are perspective views showing a cylinder in the fistula treatment instrument shown in FIG. 1. FIG.

A fistula treatment instrument 1 includes an exterior portion 2 , a cylindrical body 3 , and an extrusion member 4 .

The exterior part 2 has a substantially cylindrical through hole 21 . In this embodiment, the exterior part 2 has a substantially cylindrical shape having a top surface part 23 and a bottom surface part 24, and the outer diameter decreases from the top surface part 23 side toward the bottom surface part 24 side. Further, the through-hole 21 penetrates vertically through the vicinity of the center of the top surface portion 23 and the bottom surface portion 24 .

The size of the exterior part 2 can be appropriately designed, but for example, the outer diameter is 5 mm to 10 mm, and the length (length from the top part to the bottom part) is 8 mm to 12 mm. can be done.

Although the material of the exterior part 2 is not particularly limited, it is preferably made of resin such as silicon. When the exterior part 2 is made of a resin such as silicone, it is easy to handle and suppresses adverse effects on the patient during fistula treatment.

The cylindrical body 3 has a cylindrical shape (substantially bottomless cylindrical shape) that does not have a bottom portion, and is inserted into the through hole 21 of the exterior portion 2 . In addition, one end 3A side (upper end side) of the cylindrical body 3 protrudes outside the exterior part 2, and the other end 3B side (lower end side) of the cylindrical body 3 can hold the solidified cell structure 5 inside. . The material of the cylindrical body 3 is not particularly limited, and can be designed as appropriate. Examples thereof include metals such as stainless steel, titanium alloys, and cobalt alloys.

More specifically, in this embodiment, the cylindrical body 3 has a first cylindrical portion 31 and a second cylindrical portion 32 having a larger diameter than the first cylindrical portion 31, which are vertically connected.

One end of the first cylindrical portion 31 is formed with a protruding portion 31a protruding to the outside of the exterior portion 2 . In addition, the other end of the first cylindrical portion 31 is connected to the second cylindrical portion 32, and the outer circumference between the first cylindrical portion 31 and the second cylindrical portion 32 extends outward in the circumferential direction. A widening stepped portion 33 is formed. Furthermore, the space inside the first cylindrical portion 31 and the space inside the second cylindrical portion 32 communicate with each other.

The second cylindrical portion 32 is entirely inserted into the through-hole 21 and is capable of holding the cell structure 5 inside from the open end portion 32a. The inner and outer diameters of the second cylindrical portion 32 are designed to be larger than the inner and outer diameters of the first cylindrical portion 31 . Also, the length of the second cylindrical portion 32 is designed to be longer than the length of the first cylindrical portion 31 .

The dimensions of the first cylindrical portion 31 and the second cylindrical portion 32 are not particularly limited, and can be designed as appropriate. Ranges can be exemplified. Further, the inner diameter of the second cylindrical portion 32 can be exemplified in the range of 3 mm to 7 mm, and the outer diameter thereof can be exemplified in the range of 4 mm to 8 mm.

In this embodiment, the extrusion member 4 includes a body portion 41 , a flange portion 42 and an extrusion portion 43 .

The body portion 41 has a vertically long, substantially columnar shape, and is inserted through the insides of the first cylindrical portion 31 and the second cylindrical portion 32 . The body portion 41 is designed to have an outer diameter substantially equal to the inner diameter of the first cylindrical portion 31 and is in contact with the inner peripheral surface of the first cylindrical portion 31 . The main body portion 41 is slidable in the axial direction (longitudinal direction) while being in contact with the first cylindrical portion 31 , so that the pushing member 4 slides in the cylindrical body 3 in the axial direction.

The flange portion 42 is provided at one end (upper end) of the main body portion 41 and exposed to the outside (upper side) of the first cylindrical portion 31 . The flange portion 42 has a substantially disk shape with an outer diameter larger than the inner diameter of the first cylindrical portion 31 . In this embodiment, the outer diameter of the flange portion 42 is designed to be approximately equal to the outer diameter of the first cylindrical portion 31 . A handle portion 44 is provided on the upper surface of the flange portion 42 so as to protrude from the vicinity of the center. The handle portion 44 is designed to have a shape and size that can be grasped by forceps of a bronchoscope, for example.

The push-out portion 43 is provided at the other end (lower end) of the body portion 41 and positioned inside the second cylindrical portion 32 . The extruded portion 43 has a substantially disk shape with an outer diameter larger than the inner diameter of the first cylindrical portion 31 . In this embodiment, the outer diameter of the extrusion portion 43 is designed to be slightly smaller than the inner diameter of the second cylindrical portion and substantially equal to the outer diameter of the first cylindrical portion 31 . The push-out portion 43 can be formed integrally with the body portion 41 or can be formed as a separate body.

The material of the extruded member 4 is not particularly limited and can be designed as appropriate. Examples thereof include metals such as stainless steel, titanium alloys, and cobalt alloys.

Next, an overview of the process of assembling the therapeutic instrument for fistula and the process of holding the cell structure of the present invention will be described. FIG. 5 is a schematic diagram illustrating an outline of the steps of assembling the fistula treatment instrument shown in FIG. 1 and the steps of holding the cell structure.

As illustrated in FIGS. 5A and 5B, the cell structure 5 is held inside the second cylindrical portion 32 by inserting the cell structure 5 into the open end portion 32a of the second cylindrical portion 32. . Then, as illustrated in FIG. 5(C), the fistula treatment instrument 1 can be obtained by inserting the cylindrical body 3 holding the cell structure 5 through one of the through holes 21 of the exterior part 2 . Due to the elasticity of the exterior part 2, the through hole 21 of the exterior part 2 and the periphery of the cylindrical body 3 can be brought into close contact with each other, and the cylindrical body 3 can be stably fixed.

In this way, the fistula treatment instrument 1 of the present invention can be assembled by the user as appropriate. Therefore, as described above, the assembly kit of the fistula treatment instrument 1 of the present invention includes the exterior part 2 having the substantially cylindrical through hole 21 and the bottomless cylinder fitted into the through hole 21 of the exterior part 2. and a push member 4 that is axially slidable within the cylindrical body 3 .

Next, a cell structure that can be held and used in the fistula treatment instrument of the present invention will be described.

The cell structure 5 is solidified by fusing spheroids containing mesenchymal stem cells. Mesenchymal Stem Cells (MSCs) are pluripotent cells that can differentiate into various types of cells and have the ability to self-renew. Mesenchymal stem cells can be obtained, for example, from test animals (e.g., experimental animals such as mice, rabbits, rats, guinea pigs, dogs, pigs, goats, and cows) or human bone marrow by the Dexter method, magnetic bead method, cell sorting method, and the like. can be collected by a known method of Furthermore, mesenchymal stem cells can also be collected from skin, subcutaneous fat, muscle tissue, and the like.

Examples of mesenchymal stem cells include human bone marrow-derived mesenchymal stem cells, human umbilical cord matrix-derived mesenchymal stem cells, and human adipose tissue-derived mesenchymal stem cells. Also, the mesenchymal stem cells are preferably autologous cells of a patient in need of treatment for bronchial stump fistula.

A "spheroid" refers to a spherical cell aggregate in which cells aggregate and aggregate.

Spheroids can contain various types of cells other than mesenchymal stem cells, and the types thereof are not particularly limited. Specifically, the cells constituting the spheroids can be exemplified by one or more of fibroblasts, vascular endothelial cells, chondrocytes, iPS cells, and the like. It preferably contains cells or vascular endothelial cells. In this case, the proportion of mesenchymal stem cells contained in the spheroids is more preferably 50% or more. Moreover, the various cells that constitute the spheroids are preferably autologous cells of a patient in need of fistula treatment.

A method for producing spheroids is not particularly limited, and conventionally known methods can be employed. For example, when cells are cultured on a Teflon (registered trademark)-treated plate, the cells seek scaffolds and adhere to each other to form cell aggregates, ie, spheroids. Furthermore, when the spheroids adhere to each other and fuse together, the spheroids become even larger. Also, for example, when cells are seeded and cultured on a cell non-adhesive plate, the cells spontaneously aggregate to form spheroids. The culture time until spheroid formation is approximately 6 to 48 hours, preferably 24 to 48 hours.

The method for producing spheroids is not limited to the methods described above, and may be a swirling culture method in which a cell suspension is placed in a swirling solution, a method in which a cell suspension is placed in a test tube and sedimented in a centrifuge, or A number of methods are known, such as the alginate bead method. Among them, a method of placing a cell suspension in a water-repellent or non-cell-adhesive multiwell can be preferably exemplified in that a large amount of homogenous spheroids can be processed and recovered.

The cell structure 5 is a structure solidified by adhesion of a plurality of spheroids containing mesenchymal stem cells. The cell structure 5 can be obtained, for example, by collecting spheroids that have been brought into contact and fused by the procedure described above. Since the cell structure 5 contains mesenchymal stem cells, it has excellent strength and stability. In addition, here, "solidified" refers to having a certain shape rather than a liquid state, but a semi-solid state (semi-fluid) that has the attributes of both liquid and solid may also include the form of

In manufacturing the cell structure 5, it is preferable to use a known 3D bioprinting technique. 3D bioprinting is a method of creating cell patterns in a limited space using 3D printer technology. As the “biological “ink” (bioink), the above-described mesenchymal stem cells or the like or a gel containing the same can be used to create a cell structure 5 with a desired shape in which spheroids are fused. . Moreover, in order to obtain such a cell structure 5, for example, the description of Japanese Patent No. 4517415 can be referred to.

In addition, a commercially available 3D bioprinter can be used for manufacturing the cell structure 5, for example, Regenova manufactured by Cyfuse Inc. can be exemplified. By using these 3D bioprinters, it is possible to fuse spheroids and obtain spatially arranged cell structures 5 of arbitrary shape.

The shape of the cell structure 5 is not particularly limited, but preferred examples include a spherical shape and a substantially cylindrical shape. Also, the size of the cell structure 5 can be appropriately designed.

A cell structure 5 containing two or more types of cells can be obtained by fusing spheroids formed from different types of cells. In particular, from the viewpoint of its strength and stability, the cell structure 5 can contain fibroblasts or vascular endothelial cells in addition to mesenchymal stem cells.

Next, an embodiment of the method of using the therapeutic instrument for fistula of the present invention will be described by taking the treatment of bronchial stump fistula as an example. FIG. 6 is a schematic diagram illustrating a state in which the fistula treatment instrument of the present invention is carried to the fistula of a bronchial stump fistula using forceps of a bronchoscope. FIG. 7 is a schematic diagram illustrating a form in which the cell structure is detached from the transported fistula treatment instrument and supplied to the fistula. FIG. 8 is a schematic diagram illustrating a state in which the forceps are pulled out from the transported fistula treatment instrument.

As illustrated in FIG. 6 , the forceps 61 of the bronchoscope 6 can be used to grasp the handle portion 44 of the pushing member 4 of the fistula treatment instrument 1 . Since the handle portion 44 protrudes upward from the vicinity of the center of the flange portion 42, it can be easily grasped using the forceps 61 of the bronchoscope 6, and the bronchial stump fistula S to be treated can be reliably transported. can do. In addition, since the outer diameters of the flange portion 42 and the pushing portion 43 of the pushing member 4 are larger than the inner diameter of the first cylindrical portion 31 , the pushing member 4 does not come off from the first cylindrical portion 31 . Therefore, even when the handle portion 44 is gripped by the forceps 61 of the bronchoscope 6 or the like to operate and transport the fistula treatment instrument 1, the operation and transportation can be performed stably.

As illustrated in FIG. 7(A), the handle portion 44 is grasped by the forceps 61 of the bronchoscope 6 or the like, and the fistula treatment instrument 1 of the present invention is transported to the bronchial stump fistula S to be treated. As illustrated in (B), the pushing member 4 can be pushed into the cylindrical body 3 (the first cylindrical portion 31 and the second cylindrical portion 32). As a result, the pushing member 4 slides toward the open end portion 32 a of the second cylindrical portion 32 . At this time, the flange portion 42 comes into contact with the upper end 3A of the first cylindrical portion 31, and the extruding portion 43 reaches the vicinity of the open end portion 32a of the second cylindrical portion 32. As shown in FIG. Along with this, the cell structure 5 is pushed out by the pushing portion 43, and the cell structure 5 is detached from the cylindrical body 3 (second cylindrical portion 32). After that, the forceps 61 can be released from the grip of the handle portion 44 and the forceps 61 can be pulled out. Thereby, the cell structure 5 can be reliably transported and supplied to the bronchial stump fistula S.

Then, as illustrated in FIG. 8, the fistula treatment instrument 1 of the present invention can leave the cell structure 5 in the bronchial stump for a predetermined period after supplying the cell structure 5 to the bronchial stump fistula S. As a result, the fistula treatment instrument 1 serves as a weight, and the cell structure 5 supplied to the bronchial stump fistula S can be stabilized. After the improvement of the bronchial stump fistula S is confirmed, the bronchoscope 6 is introduced again, and the fistula treatment instrument 1 is recovered by grasping the handle portion 44 of the fistula treatment instrument 1 with the forceps 61 and pulling it out. be able to.

As described above, the fistula treatment instrument 1 of the present invention consists of the exterior part 2 having the substantially cylindrical through hole 21 and the bottomless cylindrical body 3 fitted into the through hole 21 of the exterior part 2 . and an extrusion member 4 that is slidable in the inner axial direction of the cylindrical body 3 . One end side of the cylindrical body 3 protrudes outside the exterior part 2, and the other end side of the cylindrical body 3 can hold the solidified cell structure 5 inside. When the pushing member 4 is slid from one end side to the other end side, the cell structure 5 held inside the other end side is pushed out and can be detached from the cylindrical body 3 . Therefore, the cell structure 5 for closing the fistula can be reliably transported and supplied to a predetermined position, and various diseases associated with the fistula can be treated effectively.

The fistula treatment instrument and its assembly kit of the present invention are not limited to the above embodiments. For example, the cylindrical part is not limited to the form constituted by the first cylindrical part and the second cylindrical part described above, as long as it can hold the solidified cell structure inside. Moreover, the push-out member is not limited to the above-described form, as long as it is slidable in the axial direction inside the cylindrical body and can push out the cell structure.

1 fistula treatment instrument 2 exterior portion 21 through hole 3 cylindrical body 31 first cylindrical portion 31a protruding portion 32 second cylindrical portion 4 pushing member 41 body portion 42 flange portion 43 pushing portion 44 handle portion 5 cell structure

Claims (3)

A fistula treatment device for transporting and delivering a cell structure for closing a fistula to a predetermined location, comprising:
an exterior portion having a substantially cylindrical through hole;
a bottomless cylindrical body inserted into the through hole of the exterior part;
an extrusion member axially slidable inside the cylindrical body;
with
The cylindrical body includes a first cylindrical portion located on one end side and a second cylindrical portion located on the other end side, and the second cylindrical portion has a larger diameter than the first cylindrical portion. ,
The first cylindrical portion has a protruding portion that protrudes outward from the exterior portion at one end and is connected to the second cylindrical portion at the other end,
The second cylindrical portion is inserted into the through-hole and can hold a solidified cell structure inside,
The extrusion member is
a substantially cylindrical body portion inserted through the first cylindrical portion and the second cylindrical portion;
A substantially disk-shaped flange portion provided at one end of the main body portion and exposed to the outside of the first cylindrical portion;
A substantially disc-shaped extruding portion provided at the other end of the main body portion and located inside the second cylindrical portion;
with
The outer diameters of the flange portion and the extruded portion are larger than the inner diameter of the first cylindrical portion,
When the pushing member is slid from the one end side of the cylindrical body toward the other end side, the cell structure held inside the second cylindrical portion is pushed outward and detached from the cylindrical body. A therapeutic instrument for a fistula, characterized in that it is capable of 2. The instrument for fistula treatment according to claim 1 , wherein said pushing member has a handle protruding from the vicinity of the center of said flange. The fistula treatment instrument assembly kit of claim 1, comprising:
an exterior portion having a substantially cylindrical through hole;
a bottomless cylindrical body inserted into the through hole of the exterior part;
an extrusion member that is axially slidable inside the cylindrical body;
with
The cylindrical body includes a first cylindrical portion and a second cylindrical portion having a larger diameter than the first cylindrical portion,
The extrusion member is
a substantially cylindrical body portion inserted through the first cylindrical portion and the second cylindrical portion;
A substantially disk-shaped flange portion provided at one end of the main body portion and exposed to the outside of the first cylindrical portion;
A substantially disc-shaped extruding portion provided at the other end of the main body portion and positioned inside the second cylindrical portion;
with
The outer diameters of the flange portion and the extruded portion are larger than the inner diameter of the first cylindrical portion.
An assembly kit characterized by

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