JP7370981B2 - In-vivo indwelling device manufacturing method and indwelling system - Google Patents

Description

TECHNICAL FIELD The present invention relates to an in-vivo indwelling device containing cell fibers made of cells in the form of fibers, and an indwelling system thereof.

Until now, cells have been administered intravenously to treat disease areas such as cerebral infarction, cardiac neuropathy, myocardial infarction, arteriosclerosis, retinitis pigmentosa, diabetic retinopathy, head and neck aneurysms, and vascular lesions such as diabetes. Research has been conducted on activating endogenous stem cells by introducing methods or drug administration. However, intentional delivery to the target disease site is difficult, and no specific in-vivo indwelling device or indwelling system has been found.

For example, as a prior art, Patent Document 1 discloses a structure containing cells or cell cultures in fibers. Further, Patent Document 2 discloses a non-liquid type therapeutic element containing a nucleotide-based drug and an indwelling system thereof.

International Publication No. 2011-046105 International Publication No. 2015-166648

An object of the present invention is to provide an in-vivo indwelling device, an indwelling system, a method for manufacturing an in-vivo indwelling device, and a method for using the indwelling system, which includes a connector that enables intentional delivery to a target disease site. It is.

In order to solve the above problems, as a result of intensive studies, the present invention has been completed.
[1] The present invention is an in-vivo indwelling device, which is equipped with a cell fiber made of a plurality of cells in the form of a fiber, and the cell fiber is equipped with a connector.
[2] The connector is preferably located at the proximal end of the cell fiber.
[3] The connector is preferably tube-shaped.
[4] It is preferable that the connector has a tube shape at the distal portion and a plate-like member at the proximal portion.
[5] The connector preferably includes a fiber fixing part containing a cell scaffolding material.
[6] Preferably, the connector includes a fiber fixing portion that includes a radiopaque material.
[7] The connector is preferably made of a biocompatible material selected from resin and metal.
[8] The cell fibers preferably have a spiral shape, a nonwoven structure, or a three-dimensional structure.
[9] The diameter of the cell fibers is preferably 100 nm to 1000 μm.
[10] The cell fibers are preferably composed of non-neural cells.
[11] The cell fibers are preferably composed of nerve cells.
[12] The cell fibers preferably include neural stem cell differentiation-inducing fibers that are differentiated from neural stem cells into neurons and glial cells.
[13] The present invention is an indwelling system that includes an indwelling device and a delivery tube, where the delivery tube includes a housing section that accommodates a connector.
[14] The delivery tube preferably includes a syringe in the proximal portion of the delivery tube, and is preferably equipped with a release mechanism that releases the indwelling object from the delivery tube by a fluid flow generated by the syringe.
[15] Preferably, the indwelling system includes a release mechanism including a pusher at least partially disposed within the delivery tube.
[16] Preferably, the connector is connected to the distal end of the pusher and is a detachment mechanism that causes the connector to detach from the pusher by electrical or thermal energy supplied through the pusher.
[17] The present invention provides an in-vivo indwelling device that includes the steps of preparing a cylindrical body having an inner layer having extracellular organs and cells and an outer layer, growing cells in the inner layer, and dissolving the outer layer. This is a manufacturing method.
[18] Preferably, the extracellular organ contains collagen or fibroin.
[19] The outer layer preferably contains sodium alginate or calcium alginate.
[20] The present invention provides the steps of: placing the distal end of a delivery tube with an indwelling object disposed on the distal side at a target site; generating a fluid flow at the proximal end of the delivery tube; A method of using an indwelling system includes the step of arranging an indwelling object at a target site by the flow of the indwelling system.

The present invention can provide an in-vivo indwelling device, an indwelling system, a method for manufacturing an in-vivo indwelling device, and a method for using the indwelling system, which include a connector that enables intentional delivery to a target disease site.

FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 3 is a diagram showing the shape of the proximal end of the connector of the in-vivo indwelling device according to the embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention. FIG. 1 is a schematic cross-sectional view of an indwelling system for indwelling items in a living body according to an embodiment of the present invention.

Hereinafter, the present invention will be explained in more detail based on the following embodiments. However, the present invention is not limited by the following embodiments, and modifications may be made as appropriate within the scope that fits the spirit of the above and below. Of course, additional implementations are also possible, and all of these are included within the technical scope of the present invention. In addition, in each drawing, hatching, member codes, etc. may be omitted for convenience, but in such cases, the specification and other drawings shall be referred to. Further, the dimensions of various members in the drawings are given priority to help understanding the features of the present invention, and therefore may differ from actual dimensions.

The gist of the in-vivo indwelling device of the present invention is that it includes a cell fiber in which a plurality of cells are configured in a fiber shape, and that the cell fiber is provided with a connector.

FIG. 1 is a schematic cross-sectional view of an in-vivo indwelling device 1 according to an embodiment of the present invention, showing a state in which a portion of cell fibers 2 are linearly expanded outside a delivery tube 4.

The in-vivo indwelling device 1 has a distal side and a proximal side. The proximal side of the in-vivo indwelling device 1 refers to the direction toward the user's (operator's) hand with respect to the extending direction of the in-vivo indwelling device 1, and the distal side refers to the direction opposite to the proximal side ( In other words, it points in the direction of the treatment target. The indwelling device 1 includes at least cell fibers 2 extending in the far-to-near direction and a connector 3 connected to the proximal end of the cell fibers 2, and the indwelling system includes the indwelling device 1 and the delivery system. At least a tube 4 is provided. A cell mass composed of a plurality of cells disposed in the inner lumen of the delivery tube 4 in the form of fibers is referred to as a cell fiber 2. According to the present invention, the cell fibers 2 can be reliably delivered to the target disease site in the body. The cell fiber 2 and part or all of the connector 3 connected to the cell fiber 2 are delivered to the target disease site.

Moreover, it is preferable that the connector 3 is arranged at the proximal end of the cell fiber 2. That is, it is preferable that the in-vivo indwelling device 1 includes the connector 3 at the proximal end of the cell fiber 2. By providing the connector 3 at the proximal end of the cell fiber 2, when the in-vivo indwelling device 1 is delivered to the target disease site, the load applied to the in-vivo indwelling device 1 for delivery is transferred to the vicinity of the cell fiber 2. The connector 3 located at the distal end receives the indwelling device 1, and the in-vivo indwelling device 1 can be efficiently delivered to the target disease site.

There is no particular restriction on the cell type constituting the cell fiber 2, and it can be appropriately selected depending on the purpose. For example, it is composed of nerve cells such as cerebral cortex cells, muscle cells such as skeletal muscle cells and cardiac muscle cells, fibroblasts, epithelial cells, hepatocytes, pancreatic islet cells, photoreceptor cells, blood monocytes, and the like. The cell fiber 2 is preferably composed of stem cells (muscle stem cells, reproductive stem cells, hepatic stem cells, etc.) that have unipotency. In addition, various stem cells with multipotency (neural stem cells, hematopoietic stem cells, mesenchymal stem cells, Muse cells, etc.), embryonic stem cells (ES cells) with pluripotency, and induced pluripotent stem cells (iPS cells) , somatic cell-derived ES cells (ntES cells), and multipotent stem cells (hematopoietic stem cells, neural stem cells, mesenchymal stem cells, etc.). These cell types may be used alone or in combination of two or more types. Furthermore, not only autologous cells but also allogeneic cells may be used. In this application, cells other than nerve cells are referred to as non-neuron cells.

When treating a brain injury site, the cell fibers 2 are preferably formed from cells containing neural stem cell differentiation-inducing fibers that have been differentiated into neurons and glial cells from neural stem cells. This accelerates nerve regeneration at the treatment target site. For treatment of other areas, non-neural cell fibers 2 can be used.

Cell fiber 2 contains BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial growth factor), EGF (epidermal growth factor), FGF (fibroblast growth factor), IGF (insulin-like growth factor), and PDGF (platelet growth factor). It may be composed of cells into which cell growth factors such as NGF (derived growth factor), NGF (nerve growth factor), physiologically active substances such as cytokines, gene plasmids, antibodies, and drug-containing capsules have been introduced.

The method for producing the cell fiber 2 is not particularly limited, but includes a step of preparing an inner layer having an extracellular matrix and cells and a cylindrical body having an outer layer, a step of growing cells in the inner layer, and a step of dissolving the outer layer. , is preferably included. The step of dissolving the outer layer is performed after cells are grown in the inner layer. Moreover, it is preferable that the cylindrical body has a structure in which an inner layer is disposed inside the outer layer. Furthermore, a part of the inner layer may face the outside of the cylindrical body.

Examples of the extracellular matrix included in the inner layer include collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptide. Among these, it is preferable that the extracellular matrix of the inner layer contains collagen or fibroin. Preferably, the outer layer comprises sodium alginate or calcium alginate.

The cell fibers 2 may be provided with a cell support. Examples of the material for the support include bioabsorbable polymers, natural polymers, decellularized biological tissues and cells, and combinations thereof. For example, the bioabsorbable polymer can be poly-L-lactic acid (PLLA), polyglycolic acid (PGA), a copolymer of lactic acid and glycolic acid (PLGA), or polycaprolactone (PCL). Examples of natural polymers include collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptide.

The diameter of the cell fiber 2 is preferably 100 nm to 1000 μm. Note that the diameter of the cell fiber 2 can be selected depending on the delivery performance and the shape and size of the target site. It is preferable that the cell fiber 2 is composed of cells over its entire length in the axial direction. Further, if necessary, the cell fiber 2 may contain substances or drugs other than cells. Examples of substances other than cells include substances that promote cell growth and substances that promote cell adhesion at target sites.

The in-vivo indwelling device 1 may be one using one or more long cell fibers 2 in the far-to-near direction, or may be an aggregate of short cell fibers 2. When the in-vivo indwelling device 1 is an aggregate of short cell fibers 2, the in-vivo indwelling device 1 may include an intermediate member that connects the cell fibers 2. In addition to the materials used for the cell fibers 2 described above, proteins such as gelatin can also be used as the intermediate member. The structure of the cell fiber 2 is preferably a columnar structure, but there is no particular limitation, and as shown in FIGS. It may be a three-dimensional structure such as a cylindrical bundle shape 25 in which a plurality of cylindrical cell fibers 2 are bundled, a cylindrical stack shape 26 in which another cell fiber 2 is arranged inside the cylindrical cell fiber 2, a coil shape 27, etc. . The cell fiber 2 can also be formed into a hollow shape and used. Further, the cell fiber 2 formed in a sheet shape can be rolled into a columnar shape or folded for use. The shape of the cell fiber 2 can be selected depending on the delivery performance and the shape and size of the target site. In particular, when the cell fibers 2 have a spiral shape, a nonwoven fabric structure, or a three-dimensional structure, the rate of fixation to the tissue and the compatibility with the tissue are increased, and the therapeutic effect is enhanced. Furthermore, by shaping the cell fibers 2 in advance to match the target tissue, treatment time can be shortened.

As shown in FIG. 9, the distal end of the cell fiber 2 is preferably provided with a hemispherical or semi-ellipsoidal head 7. This is because the tip of the cell fiber 2 reduces friction with the inner wall of the blood vessel, contributing to improving the delivery performance of the cell fiber 2 and suppressing the generation of debris at the distal end of the cell fiber 2. Note that debris refers to unnecessary material generated when the cell fibers 2 come into contact with a blood vessel wall or the like.

As shown in FIG. 10, the proximal end of the cell fiber 2 is preferably shaped to match the connector 3 to facilitate release from the delivery tube 4. For example, when the distal end of the connector 3 is a tapered connector 31 that tapers toward the distal side, the proximal end of the cell fiber 2 also has the same taper shape as the tapered connector 31. One example is that it has a tapered structure. By forming the proximal end of the cell fiber 2 into such a shape, the cell fiber 2 can be made difficult to separate from the connector 3.

As shown in FIG. 11, when the cell fiber 2 is extremely small in diameter compared to the diameter of the connector 31, in order to prevent the cell fiber 2 from breaking and detaching from the connector 31 during delivery, Preferably, the distal end has a tapered shape.

In the in-vivo indwelling device 1 of the present invention, since the connector 3 is connected to the proximal end of the cell fiber 2, when the in-vivo indwelling device 1 is placed in the delivery tube 4, the cell fiber 2 may unintentionally It is possible to suppress deviation from the delivery tube 4.

The cell fibers 2 and the connectors 3 connected to the proximal ends of the cell fibers 2 can be bonded by, for example, press-fitting, welding, caulking, adhesion with glue or adhesive, engagement, connection, bonding, ligation, etc. Connection and fixation can be performed by a method such as physical fixation, a fixation method using the adhesive property of cells, or a combination thereof. The connector 3 can be provided with a fiber fixing part to which the cell fibers 2 are fixed. The fiber fixing part is preferably located on the proximal end side of the cell fiber 2.

Preferably, the in-vivo indwelling device 1 is produced by co-cultivating cells with the connector 3 during production of the cell fibers 2. Cells adhere to the connector 3 while secreting adhesion proteins such as fibronectin and laminin to form an extracellular matrix. Furthermore, a tissue adhesive may be used to join the cell fibers 2 and the connectors 3. As the tissue adhesive, fibrin and fibrin polymers formed by mixing fibrinogen, which is a type of blood product, and thrombin can be used. Specific examples of fibrin and fibrin polymers include Volhir, Tisil, Veriplast, and the like. As other tissue adhesives, adhesives composed of dextran, dextrin, polylysine, etc. are preferred. As the adhesive composed of dextran, dextrin, polylysine, etc., for example, LYDEX is preferable. This is because blood products may not be able to completely inactivate or remove viruses such as hepatitis C and human parvovirus B19, but LYDEX has high adhesiveness and safety.

The outer shape of the connector 3 may be any shape as long as it can be moved in the far-to-near direction through the inner cavity of the delivery tube 4, and the cross-sectional shape in the far-to-near direction can be designed to have any shape such as a circle, a polygon, or a curved shape. can. Further, the connector 3 may be hollow or solid.

As shown in FIG. 1, the connector 3 preferably includes a tube shape. Examples of the tube shape include a cylindrical shape and a polygonal cylindrical shape. Among these, it is more preferable that the connector 3 has a cylindrical tube shape. By forming the tube shape in this way, a part of the cell fibers 2 can be placed in the tube lumen, and the cell fibers 2 can be easily held.

As shown in FIGS. 10 and 11, the distal end of the connector 3 including the tube shape may have a hollow tapered shape. The tapered shape may taper distally. By forming the tapered shape in this manner, the cell fiber 2 can be easily held at the tapered portion of the tapered connector 31.

It is preferable that the connector 3 has a tube shape at the distal portion and a plate-like member at the proximal portion. Since the connector 3 has a tube shape at the distal portion and a plate-like object at the proximal portion, it is added to the in-vivo indwelling device 1 in order to deliver the in-vivo indwelling device 1 to the target disease site. The load can be efficiently received by the plate-shaped object at the proximal part of the connector 3, and the in-vivo indwelling object 1 can be efficiently delivered.Furthermore, since the distal part of the connector 3 has a tube shape, It becomes possible to prevent the connector 3 from coming off from the cell fiber 2 when a load is applied to the connector 3.

As shown in FIG. 12, it is more preferable that the distal part of the connector 3 has a hollow tube shape and the proximal part has a sealing structure 6. By forming the sealed structure 6 in this way, the load when releasing the indwelling object 1 is easily applied to the proximal part of the indwelling object 1, so that the indwelling object 1 can be released from the delivery tube 4. become more susceptible to

As shown in FIGS. 13(a) to (d), the cross-sectional structure in the axial direction of the proximal end of the connector 3 has a hexagonal shape as shown in aspect (a) and a hexagonal shape as shown in aspect (b), in addition to the sealed structure 6. It may have a rectangular shape, a cross shape as shown in aspect (c), or a mesh structure as shown in aspect (d). Further, the cross-sectional structure of the connector 3 may have such a shape over the entire length.

Preferably, the connector 3 includes a fiber fixing part, at least a part of which is made of a cell scaffolding material. The cell fibers 2 can be fixed to the connector 3 via such a scaffold material. As the scaffold material, bioabsorbable polymers, natural polymers, decellularized living tissue or cells, or a combination thereof can be used. For example, poly-L-lactic acid (PLLA), polyglycolic acid (PGA), a copolymer of lactic acid and glycolic acid (PLGA), and polycaprolactone (PCL) are used as bioabsorbable polymers. Further, examples of natural polymers include collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptide.

It is preferable that the scaffold material is processed into a porous body and used. Processing into a porous material makes it easier for many cells to enter the porous material, and also enables the supply of sufficient oxygen and nutrients. Moreover, it is more preferable to process it into a hydrogel and use it in a laminated manner.

Moreover, it is more preferable that the scaffold material is a decellularized tissue in which only cellular components are removed and the extracellular matrix is left behind. Decellularized tissue is expected to have a higher tissue regeneration effect because it closely resembles the structure of living tissue and contains abundant physiologically active substances such as cell growth factors. The scaffold materials exemplified above may contain cells, such as FGF (fibroblast growth factor), VEGF (vascular endothelial growth factor), EGF (epidermal growth factor), IGF (insulin-like growth factor), PDGF. It is more preferable if the material is made of a material into which cell growth factors such as (platelet-derived growth factor) and NGF (nerve growth factor), physiologically active substances such as cytokines, and gene plasmids have been introduced.

The connector 3 may also be made of synthetic resin material or metal material. Examples of such materials include fluororesins such as polytetrafluoroethylene, perfluoroalkoxyalkanes, ethylenetetrafluoroethylene copolymers, and polyvinylidene fluoride, olefin resins such as polyethylene and polypropylene, and polyester resins such as polyethylene terephthalate. Examples include resin materials such as polyamide resins such as nylon, polyimide, and polysilicone, and metal materials such as platinum, gold, rhodium, palladium, rhenium, gold, silver, titanium, tantalum, tungsten, alloys thereof, and stainless steel. The connector 3 can be made of a combination of various synthetic resins, metals, and scaffolding materials. Preferably, the material of the connector 3 is a biocompatible material. That is, the connector 3 is preferably made of a biocompatible material selected from resin and metal. Thereby, safety when the indwelling member is placed inside the body can be improved.

Preferably, the proximal end of the connector 3 has a contrast marker. The contrast marker is made of an X-ray opaque metal material such as platinum or palladium, or a non-metallic material that hardly transmits X-rays with few artifacts, and may be ring-shaped or coil-shaped. The contrast marker may be a portion of the connector that includes radiopaque material. Preferably, the fiber fixing portion includes a radiopaque material. That is, it is preferable that the connector 3 includes a fiber fixing part containing an X-ray opaque material. Thereby, the portion where the cell fiber 2 is fixed to the connector 3 can be confirmed in the X-ray image.

Furthermore, the connector 3 moves inside the delivery tube 4 when delivering the indwelling object 1 to the target site. At this time, it is preferable to cover the inner layer of the delivery tube 4 or the outer surface of the connector 3 with a hydrophilic polymer substance in order to improve slipperiness. This reduces the coefficient of friction and provides lubricity when inserting or withdrawing the indwelling object 1. The hydrophilic polymeric substance is not particularly limited, but includes, for example, natural or synthetic polymeric substances, or derivatives thereof. In particular, fluorine-containing materials such as cellulose-based polymer substances (e.g., cellulose acetate, hydroxypropyl cellulose), polyethylene oxide-based polymer substances (polyethylene glycol), maleic anhydride-based polymer substances, acrylamide-based polymer substances, polytetrafluoroethylene, etc. The water-soluble nylon resin has a low coefficient of friction, and the sliding properties of the delivery tube 4 are further improved.

As an indwelling system for indwelling the above-mentioned in-vivo indwelling object 1 in a living body, a delivery tube 4 that can place the in-vivo indwelling object 1 in its internal cavity is used.

As shown in FIG. 14, the delivery tube 4 includes a connector accommodating portion 5 that accommodates the connector 3 of the indwelling device 1. As shown in FIG. The connector accommodating portion 5 is a distal portion including the distal end of the delivery tube 4 . The indwelling device 1 is released into the body from the distal outlet of the delivery tube 4 . The delivery tube 4 may be inserted directly into the body cavity, or may be delivered to the target site through an instrument that has been previously placed within the body cavity. The cell fibers 2 may be placed in the delivery tube 4 until the delivery tube 4 passes through the body cavity or the like and the delivery port of the delivery tube 4 is delivered to the target site, and a portion of the cell fibers 2 is delivered from the delivery port. It may come out of tube 4.

The delivery tube 4 has torque transmittance and blood vessel characteristics to ensure that the rotational force applied at the proximal end of the delivery tube 4 is transmitted when the operator inserts and withdraws the delivery tube 4 into a blood vessel or the like. It is preferable to have pushability that allows the operator's pushing force to be reliably transmitted from the proximal end to the distal end in order to advance the inside.

Further, it is preferable that the inner layer of the delivery tube 4 exhibits the lubricity of a wire so that it can be inserted and withdrawn smoothly along a leading wire through a blood vessel or the like that is curved in a complicated shape without damaging the inner wall of the blood vessel or the like. Further, it is preferable that the delivery tube 4 has wire followability and affinity for blood and tissue in the outer layer of the delivery tube 4. In addition, in order for the tip of the delivery tube 4 to reach the target location of the target affected area, for example in the thin and meandering blood vessels in the brain, it is necessary to make the delivery tube 4 thinner and to apply a high-frequency current. When used, a delivery tube 4 is required that can be used safely without leakage when the conductive wire is energized. The materials constituting the delivery tube 4 include various elastomers such as polyamide elastomer, polyester elastomer, polyurethane elastomer, polystyrene elastomer, fluorine-based elastomer, silicone rubber, and latex rubber, fluorine-based resins such as polytetrafluoroethylene, platinum, gold, and rhodium. , palladium, rhenium, silver, titanium, tantalum, tungsten, stainless steel, or a combination of two or more of these. Among these, the material constituting the delivery tube 4 is preferably polyamide elastomer in terms of flexibility and ease of processing. As the polyamide elastomer, for example, PEBAX (registered trademark) manufactured by ARKEMA is suitable.

Further, from the viewpoints of pushability, followability, kink resistance, and safety, it is preferable to cover the outer surface of the delivery tube 4 with a hydrophilic polymeric substance. As a result, when the outer surface of the delivery tube 4 comes into contact with blood, physiological saline, etc., the coefficient of friction is reduced and lubricity is imparted. The hydrophilic polymeric substance is not particularly limited, but includes, for example, natural or synthetic polymeric substances, or derivatives thereof. In particular, fluorine-containing materials such as cellulose-based polymer substances (e.g., cellulose acetate, hydroxypropyl cellulose), polyethylene oxide-based polymer substances (polyethylene glycol), maleic anhydride-based polymer substances, acrylamide-based polymer substances, polytetrafluoroethylene, etc. The water-soluble nylon resin has a low coefficient of friction, and the sliding properties of the delivery tube 4 are further improved.

The delivery tube 4 preferably includes a release mechanism for releasing the indwelling device 1 into the body. Possible methods for releasing the indwelling object 1 include, for example, a hydraulic method, an electric method, a mechanical method, and the like. Among these, it is preferable to release the indwelling device 1 into the body using a hydraulic release mechanism or an electric release mechanism. Furthermore, for organs capable of receiving gas, the in-vivo indwelling device 1 can be released into the body using, for example, a pneumatic release mechanism instead of the hydraulic release mechanism.

The method of releasing the in-vivo indwelling device 1 from the delivery tube 4 using liquid or gas includes the steps of placing the distal end of the delivery tube 4 with the in-vivo indwelling device 1 disposed on the distal side at a treatment target site; The method includes the steps of generating a fluid flow at the proximal end of the delivery tube 4 and positioning the in-vivo indwelling device 1 at the treatment target site by the fluid flow. Methods of use of the invention include such release methods. A fluid flow is a flow of fluid, such as a flow of liquid or a flow of gas.

FIG. 15 shows a release mechanism using the syringe 8. It is preferable that the delivery tube 4 includes a syringe 8 at the proximal portion of the delivery tube 4 and includes a release mechanism that releases the indwelling object 1 from the delivery tube 4 by a fluid flow generated by the syringe. The hydraulic discharge mechanism is connected to the delivery tube 4 after filling the syringe 8 with a fluid such as sterilized physiological saline and removing air from the syringe 8 . If there is air inside the delivery tube 4, it is completely removed. After the syringe and delivery tube 4 are connected, the in-vivo indwelling object 1 can be moved within the delivery tube 4 by pressurizing the syringe 8. When the tip of the delivery tube 4 is delivered to the treatment target site in the living body, the in-vivo indwelling article 1 can be released to the treatment target site by further applying pressure with the syringe 8. In addition, when repositioning the in-vivo indwelling object 1 to the target site, it is possible to return the in-vivo indwelling object 1 into the delivery tube 4 by applying negative pressure to the syringe 8. The release mechanism is suitable for proper placement of the indwelling device 1.

Further, the electric discharge mechanism supplies a discharge current from the outside between the conductive delivery tube 4 and the counter electrode connected to the living body, thereby disassembling and fusing the connecting member. In particular, when a heat-soluble material such as heat-meltable polyvinyl alcohol is used as the connector 3, the tip of the conductive delivery tube 4 is used as a heating electrode, and the connector 3 is heated by high-frequency current supplied between it and the counter electrode. The indwelling material 1 is thermally melted and released.

Further, as shown in FIG. 14, a pusher 9 connected to the connector 3 may be provided in the inner cavity of the delivery tube 4. That is, the indwelling system for indwelling the indwelling device 1 in the living body preferably includes a release mechanism including the pusher 9 at least partially disposed within the delivery tube 4. Further, it is preferable that the pusher 9 includes a mechanism for supplying electrical or thermal energy to the connector 3. The energy supplied to the connector 3 via the pusher 9 releases the connection between the pusher 9 and the connector 3, thereby realizing a detachment mechanism for detaching the indwelling object 1 from the pusher 9. That is, the connector 3 is preferably connected to the distal end of the pusher 9 and includes a detachment mechanism for detaching the connector 3 from the pusher 9 by electrical or thermal energy supplied via the pusher 9. A detachment section can be provided between the pusher 9 and the connector 3, which is disconnected by energy supplied via the pusher 9.

The material of the pusher 9 is preferably a biocompatible and electrically conductive metal wire material, and examples thereof include platinum, tungsten, titanium, gold, iridium, palladium, tantalum, alloys thereof, and stainless steel. In that case, a discharge current is supplied from the outside between the conductive delivery pusher and the counter electrode connected to the living body, and the connector 3 is disassembled and fused. In particular, when a thermofusible material such as polyvinyl alcohol that can be melted by heat is used as the connector 3, the tip of the conductive delivery tube is used as a heating electrode, and the connector 3 is heated by the high frequency current supplied between it and the counter electrode. The indwelling object 1 is then released. It is preferable to connect the pusher 9 to the connector 3 because it is possible to return it to the delivery tube 4 by pulling the pusher 9 at the hand when relocating it to the target site.

This application claims the benefit of priority based on Japanese Patent Application No. 2018-139982 filed on July 26, 2018. The entire contents of the specification of Japanese Patent Application No. 2018-139982 filed on July 26, 2018 are incorporated by reference into this application.

1: In-vivo indwelling object 2, 21, 22, 23, 24, 25, 26, 27: Cell fiber 3, 31: Connector 4: Delivery tube 5: Connector housing part 6: Sealed structure 7: Head 8: Syringe 9: pusher

Claims (14)

An indwelling system comprising an in-vivo indwelling object and a delivery tube, the delivery tube including a housing section for accommodating a connector ,
The in-vivo indwelling device includes a cell fiber composed of a plurality of cells in a fiber shape, and the cell fiber is provided with the connector ,
the connector is located at the proximal end of the cell fiber;
The connector has a tube shape at a distal portion and a plate-like object at a proximal portion,
The connector includes a fiber fixing part containing the cell scaffolding material,
The delivery tube is an indwelling system that is disposed in a proximal portion of the delivery tube or in a lumen of the delivery tube, and includes a release mechanism that applies a load to the in-vivo indwelling object. The indwelling system of claim 1 , wherein the fiber fixing portion includes a radiopaque material. The indwelling system according to claim 1 or 2 , wherein the connector is made of a biocompatible material selected from resin and metal. The indwelling system according to any one of claims 1 to 3 , wherein the cell fiber has any one of a spiral shape, a nonwoven fabric structure, and a three-dimensional structure. The indwelling system according to any one of claims 1 to 4 , wherein the cell fiber has a diameter of 100 nm to 1000 μm. The indwelling system according to any one of claims 1 to 5 , wherein the cell fibers are composed of non-neural cells. The indwelling system according to any one of claims 1 to 5 , wherein the cell fibers are composed of nerve cells. The indwelling system according to any one of claims 1 to 5 , wherein the cell fibers include neural stem cell differentiation-inducing fibers that are differentiated from neural stem cells into neurons and glial cells. 9. The delivery tube includes a syringe at a proximal portion of the delivery tube, and the release mechanism releases the indwelling object from the delivery tube by a fluid flow generated by the syringe. An indwelling system according to any one of the preceding paragraphs . 10. An indwelling system according to any one of claims 1 to 9 , wherein the release mechanism includes a pusher located at least partially within the delivery tube. 11. The indwelling system of claim 10 , wherein the connector includes a detachment mechanism connected to a distal end of the pusher to cause the connector to detach from the pusher by electrical or thermal energy supplied through the pusher. . A method for manufacturing the in-vivo indwelling device according to any one of claims 1 to 11, comprising:
Production of an in-vivo indwelling device comprising the steps of preparing an inner layer having an extracellular matrix and cells, and a cylindrical body having an outer layer, growing the cells in the inner layer, and dissolving the outer layer. Method. 13. The method for producing an indwelling device according to claim 12 , wherein the extracellular matrix contains collagen or fibroin. The method for manufacturing an indwelling device according to claim 12 or 13, wherein the outer layer contains sodium alginate or calcium alginate.

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