WO2020261828A1 - In vivo indwelling object - Google Patents

Abstract

Provided is an in vivo indwelling object which can assess the state of cells before and after the indwelling of a cell tissue at a target site for therapy or the environment of the target site for therapy after the indwelling of the cell tissue at the target site for therapy. An in vivo indwelling object (1) comprising: a cell fiber (10) composed of a plurality of cells that are formed in a fiber-like form; and a functional material.

Description

In vivo indwelling

The present invention relates to an in vivo indwelling containing cell fibers in which a plurality of cells are formed into fibers.

Conventionally, in the treatment of stroke and the like, images of the target site of treatment have been taken by computed tomography (CT) examination, magnetic resonance angiography (MRA) examination, magnetic resonance imaging (MRI) examination, angiography, or the like. Later, administration of a drug or transplantation of cell tissue by injection has been performed. In addition, when sensing is performed to obtain information on the target site in treatment, the coronary blood flow reserve ratio (FFR), which measures the blood pressure of the vascular stenosis using a guide wire, and intravascular ultrasound are used. Intravascular ultrasonography (IVUS) may be performed to image the vascular lumen using. Regarding transplantation of cell tissue in the treatment of a lesion site such as a stroke, for example, Patent Documents 1 to 3 disclose the method.

Special Table 2009-514950 Japanese Patent Publication No. 2004-533277 International Publication No. 2011/046105

In the treatment of lesion sites such as stroke, it is required to understand the state of cells before and after placement of the cell tissue at the target site and the environment of the target site after the placement of the cell tissue. With the methods disclosed in Patent Documents 1 to 3, it is not possible to sufficiently grasp the state of cells before and after the placement of the cell tissue at the target site and the environment of the target site after the placement of the cell tissue, which is improved. There was room for.

The present invention has been made in view of the above circumstances, and an object of the present invention is the state of cells before and after placement of cell tissue at a target site for treatment, and the treatment after placement of cell tissue. The purpose of the present invention is to provide an in-vivo indwelling that can grasp the environment of a target site.

The in-vivo indwelling that was able to solve the above-mentioned problems is characterized by having a cell fiber in which a plurality of cells are formed into a fiber shape and a functional material.

In the in-vivo indwelling of the present invention, it is preferable that the cell fiber has a layer structure including an outer layer and an inner layer, and the functional material is arranged inside the inner layer.

In the in-vivo indwelling of the present invention, the functional material is preferably a luminescent substance that emits light when irradiated with light. That is, it is preferable that the in-vivo indwelling substance has a cell fiber in which a plurality of cells are formed into a fiber, and a luminescent substance that emits light when irradiated with light.

In the in-vivo indwelling of the present invention, the luminescent substance is preferably present on the surface of the cell fiber.

In the in-vivo indwelling substance of the present invention, the luminescent substance is preferably a substance that fluoresces when irradiated with excitation light in the presence of oxygen.

In the in-vivo indwelling of the present invention, the luminescent substance contains an oxygen sensor protein having a property of binding and dissociating oxygen molecules and a fluorescent protein that fluoresces when irradiated with excitation light, and contains the oxygen sensor protein and fluorescence. The protein is preferably linked by a polypeptide linker.

In the in-vivo indwelling of the present invention, it is also preferable that the functional material is an oxygen sensor that measures the concentration of oxygen. That is, it is also preferable that the in-vivo indwelling object has a cell fiber in which a plurality of cells are formed into a fiber, and an oxygen sensor for measuring the oxygen concentration.

In the in-vivo indwelling of the present invention, the oxygen sensor is preferably fixed to the cell fiber.

In the in-vivo indwelling of the present invention, the oxygen sensor is preferably located at the distal end of the cell fiber.

In the in-vivo indwelling object of the present invention, it is preferable that the oxygen sensor has a light emitting unit that emits light and a light receiving unit that receives light emitted from the light emitting unit.

In the in-vivo indwelling object of the present invention, it is preferable to have a transmitter that transmits information detected by the oxygen sensor.

In the in-vivo indwelling of the present invention, it is also preferable that the functional material is TRPA1, which is an ion channel protein. That is, it is also preferable that the in-vivo indwelling substance has cell fibers in which a plurality of cells are formed into fibers and TRPA1 which is an ion channel protein.

In the in-vivo indwelling of the present invention, TRPA1 is preferably present on the surface of cell fibers.

The in-vivo indwelling object of the present invention preferably further has an electrode.

In the in-vivo indwelling object of the present invention, the electrode is composed of at least a first electrode and a second electrode, and the first electrode is arranged on the outer surface of the proximal end of the cell fiber, and the first electrode Two electrodes are located inside the distal end of the cell fiber, or the first electrode is located inside the proximal end of the cell fiber and the second electrode is distal to the cell fiber. It is preferably located on the outer surface of the end.

It is preferable that the in-vivo indwelling substance of the present invention further has a luminescent substance that emits light when irradiated with light.

In the in-vivo indwelling product of the present invention, the cell fiber is preferably composed of a plurality of cells including cells that differentiate into living tissue after being placed in the living body in the form of fibers.

According to the in-vivo indwelling object of the present invention, the state of the cells before and after the in-vivo indwelling is placed and the state of the cells before and after the in-vivo indwelling is provided by having the cell fiber composed of a plurality of cells in the form of fibers and the functional material. It is possible to grasp the environment of the target site of the treatment in which the in-vivo indwelling object is placed. Specifically, according to the in-vivo indwelling substance of the present invention, the in-vivo indwelling is performed by having a cell fiber in which a plurality of cells are formed into a fiber shape and a luminescent substance that emits light when irradiated with light. By irradiating light before and after the indwelling of the object and measuring the luminescence intensity of the in vivo indwelling, the state of cells before and after the in vivo indwelling and the target site of the treatment in which the in vivo indwelling is placed. You can grasp the environment of. Further, according to the in-vivo indwelling object of the present invention, the in-vivo indwelling object is placed by having a cell fiber in which a plurality of cells are formed into a fiber shape and an oxygen sensor for measuring the oxygen concentration. It is possible to measure the oxygen concentration in the in-vivo indwelling object before, and the oxygen concentration in the in-vivo indwelling object and the target site for treatment after the in-vivo indwelling object is placed. Furthermore, according to the in-vivo indwelling product of the present invention, by having a cell fiber in which a plurality of cells are formed into a fiber shape and TRPA1 which is an ion channel protein, before the in-vivo indwelling material is placed, By measuring the ion current generated from TRPA1 after indwelling, the oxygen concentration in the in-vivo indwelling object before indwelling the in-vivo indwelling object, and in the in-vivo indwelling object after indwelling the in-vivo indwelling object and the target site for treatment. You can check the oxygen concentration.

A schematic diagram of a first in-vivo indwelling object according to an embodiment of the present invention is shown. The II-II cross-sectional view of the in vivo indwelling shown in FIG. 1 is shown. A schematic diagram of a second in-vivo indwelling object according to an embodiment of the present invention is shown. A schematic diagram of a third in-vivo indwelling object according to an embodiment of the present invention is shown. The VV cross-sectional view of the in vivo indwelling shown in FIG. 4 is shown. The VI-VI cross-sectional view of the in-vivo indwelling shown in FIG. 4 is shown.

Hereinafter, the present invention will be described in more detail based on the following embodiments, but the present invention is not limited by the following embodiments as well as the present invention, and appropriate changes are made to the extent that it can be adapted to the purpose of the above and the following. In addition, it is of course possible to carry out, all of which are within the technical scope of the invention. In each drawing, hatching, member reference numerals, and the like may be omitted for convenience, but in such cases, the specification and other drawings shall be referred to. In addition, the dimensions of various members in the drawings may differ from the actual dimensions because priority is given to contributing to the understanding of the features of the present invention.

The in vivo indwelling of the present invention is used for delivering and indwelling a cell tissue to a target site in treatment. The in vivo indwelling has cell fibers. A cell fiber contains a cell mass that constitutes a plurality of cells in a fibrous form.

In the present invention, the proximal side refers to the direction toward the hand side of the user (operator), and the distal side refers to the direction toward the treatment site, which is the opposite direction to the proximal side.

First, the first in-vivo indwelling object 1 of the present invention will be described below. FIG. 1 shows a schematic view of the in-vivo indwelling object 1, and FIG. 2 shows an II-II cross-sectional view of the in-vivo indwelling object 1. As shown in FIGS. 1 and 2, the first in-vivo indwelling object 1 has a cell fiber 10 in which a plurality of cells are formed into a fiber shape, and a functional material. It is a luminescent substance 20 that emits light when irradiated with light.

The in-vivo indwelling object 1 may have one or a plurality of long cell fibers 10 in the perspective direction, or may have an aggregate of short cell fibers 10. When the in-vivo indwelling object 1 has an aggregate of short cell fibers 10, the in-vivo indwelling object 1 may include an intermediate member for fixing the plurality of cell fibers 10 to each other. As the intermediate member, in addition to the material used for the cell fiber 10, for example, a protein such as gelatin can be used.

The cell type constituting the cell fiber 10 is not particularly limited, and can be appropriately selected depending on the purpose. Examples of cells constituting the cell fiber 10 include nerve cells such as cerebral cortex cells, muscle cells such as skeletal muscle cells and myocardial cells, fibroblasts, epithelial cells, hepatocytes, pancreatic islet cells, photoreceptor cells, and blood monospheres. Examples include cells. The cell fiber 10 is preferably composed of monogenic stem cells (muscle stem cells, germ stem cells, hepatic stem cells, etc.), and various pluripotent stem cells (nerve stem cells, hematopoietic stem cells, mesenchymal stem cells, etc.). , Muse cells, etc.), embryonic stem cells (ES cells) with pluripotency, artificial pluripotent stem cells (iPS cells), somatic cell-derived ES cells (ntES cells), stem cells with pluripotency (hematopoietic stem cells, It is more preferable to be composed of nerve stem cells, mesenchymal stem cells, etc.). As the cell fiber 10, only one of these cell types may be used, or two or more of these cell types may be used in combination. Further, the cell fiber 10 may use an autologous cell or an allogeneic cell. In the present application, cells other than nerve cells are referred to as non-nerve cells.

For treatment of brain damage sites, cell fiber 10 preferably contains neural stem cell differentiation-inducing fibers that have differentiated from neural stem cells into neurons and glial cells. Since the cell fiber 10 contains the neural stem cell differentiation-inducing fiber differentiated into neurons and glial cells, it is possible to accelerate nerve regeneration at the target site of treatment. In the treatment of other sites, cell fiber 10 containing non-nerve cells can be used.

Cell fiber 10 is BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial cell growth factor), EGF (epithelial growth factor), FGF (fibroblast growth factor) insulin-like growth factor (IGF), PDGF (platelet-derived). It may be composed of cells into which cell growth factors such as growth factors) and NGF (nerve growth factor), physiologically active substances such as cytokines, gene plasmids, and antibodies or drug-encapsulating capsules have been introduced.

The method for producing the cell fiber 10 is not particularly limited, but is a step of preparing an inner layer having an extracellular matrix and cells and a tubular body having an outer layer, a step of growing cells in the inner layer, and a step of lysing the outer layer. And are preferably included. The step of lysing the outer layer is performed after the cells have been grown in the inner layer. Further, the tubular body preferably has a structure in which the inner layer is arranged inside the outer layer. Further, a part of the inner layer may face the outside of the tubular body.

Examples of the extracellular matrix contained in the inner layer include collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptides. Above all, the extracellular matrix contained in the inner layer preferably contains collagen or fibroin. The outer layer preferably contains sodium alginate or calcium alginate.

The cell fiber 10 preferably has a layered structure including at least an outer layer and an inner layer. The outer layer is preferably a material having a stronger structure than the inner layer and decomposing in the body in order to maintain the strength of the cell fiber 10 at the time of preparation or transplantation of the cell fiber 10. The inner layer is preferably composed of an extracellular matrix and has a structure in which a cell layer is present inside the extracellular matrix. Functional materials such as luminescent substances and ion channel proteins are preferably contained in the cell layer inside the inner layer. Since the functional material is contained in the cell layer, the functional material can be reliably introduced into the body at the time of transplantation of the in-vivo indwelling object 1 into the body. When the in-vivo indwelling object 1 has an electrode 60 described later, it is preferable that the electrode 60 is contained in the outer layer. In addition, another layer may exist between the outer layer and the inner layer. Further, between the outer layer and the inner layer, the outer layer component and the inner layer component may be mixed. This is also the case between the inner layer and the cell layer.

The cell fiber 10 may include a cell support. Examples of the material of the support include bioabsorbable polymers and natural polymers, decellularized biological tissues and cells, and combinations thereof. As the bioabsorbable polymer, for example, polyL-lactic acid (PLLA), polyglycolic acid (PGA), a copolymer of lactic acid and glycolic acid (PLGA), polycaprolactone (PCL) and the like can be used. Examples of natural polymers include collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptides.

As shown in FIGS. 1 and 2, the in-vivo indwelling object 1 has a luminescent substance 20. The luminescent substance 20 indicates a substance that emits light when irradiated with light. Since the in-vivo indwelling object 1 has the luminescent substance 20, the in-vivo in-vivo object 1 is irradiated with light before or after the in-vivo indwelling object 1 is placed, and the luminescence intensity is measured. Before and after the placement of the indwelling object 1, the state of the cells contained in the cell fiber 10 can be confirmed and managed. Furthermore, even after the in-vivo indwelling object 1 is placed at the target site for treatment, the state of cells contained in the in-vivo indwelling object 1 can be grasped by measuring the luminescence intensity of the in-vivo indwelling object 1. It will be possible.

In order to configure the in-vivo indwelling substance 1 to have the cell fiber 10 and the luminescent substance 20, for example, co-culturing the cell fiber 10 with a gel having the luminescent substance 20 can be mentioned. When a gel having a luminescent substance 20 is used for the in-vivo indwelling object 1, a porous gel can be used as the gel.

The diameter of the in-vivo indwelling object 1 can be selected according to the delivery performance, the shape and size of the target site, and is preferably 100 nm or more and 1000 μm or less, for example. The in-vivo indwelling object 1 preferably contains cells over the entire length in the long axis direction of the in-vivo indwelling object 1. In addition, the in-vivo indwelling substance 1 may contain a substance or a drug other than cells, if necessary. Examples of substances other than cells include substances that promote cell growth, substances that promote cell adhesion at therapeutic target sites, and the like.

The structure of the in-vivo indwelling object 1 is preferably a cylindrical structure, but is not particularly limited. For example, a plurality of spiral-shaped, double-helical, non-woven, sheet-shaped, cylindrical, and string-shaped cell fibers 10 are bundled. It may have a three-dimensional structure such as a cylindrical bundle shape, a cylindrical stack shape in which the cell fiber 10 is further arranged inside the tubular cell fiber 10, or a coil shape. Hollow cell fibers 10 can also be formed and used in the construction of in vivo indwelling material 1. Further, the cell fiber 10 can be formed into a sheet shape, and the sheet-shaped cell fiber 10 can be wound into a columnar shape, or can be folded and used. The shape of the in-vivo indwelling object 1 can be selected according to the delivery performance, the shape and size of the target site, and the like. In particular, when the shape of the in-vivo indwelling object 1 is a spiral shape, a non-woven fabric structure, or a three-dimensional structure, the fixation rate and compatibility of the treatment target site with the tissue are increased, and the therapeutic effect can be enhanced. In addition, the treatment time can be shortened by making the shape of the in-vivo indwelling object 1 suitable for the tissue of the target site for treatment.

Although not shown, it is preferable that the distal end of the in-vivo indwelling object 1 is formed in a hemispherical or semi-elliptical sphere. Since the distal end of the in-vivo indwelling object 1 is formed in a hemispherical or hemi-elliptical sphere, the friction between the tip of the in-vivo indwelling object 1 and the inner wall of the blood vessel is reduced, and the in-vivo indwelling object 1 It can contribute to the improvement of delivery performance and the suppression of debris generation at the distal end of the in-vivo indwelling object 1. The debris refers to an unnecessary substance that is generated when the distal end of the in-vivo indwelling object 1 comes into contact with the blood vessel wall or the like and collapses and is separated from the in-vivo indwelling object 1.

The luminescent substance 20 may be wrapped in the cell fiber 10, or a part thereof may be exposed on the surface of the cell fiber 10. As shown in FIGS. 1 and 2, the luminescent substance 20 is preferably present on the surface of the cell fiber 10. By arranging the luminescent substance 20 on the surface of the cell fiber 10, the light irradiated to the in-vivo indwelling object 1 can easily hit the luminescent substance 20, and the luminescence intensity of the in-vivo indwelling object 1 can be increased.

Examples of the luminescent substance 20 include green fluorescent protein (GFP), fluorescent protein such as luciferase and calcium-sensitive Cameleon, 2', 7'-Dichlorodihydrofluorescin diacenate (DCFH-DA), BESH ₂ O ₂ , Alexa Fluor (registered). Includes cell-penetrating fluorescent probes such as ™, Hoechst®, flura, and Calcium Green.

The luminescent substance 20 is preferably a substance that fluoresces when irradiated with excitation light in the presence of oxygen. Since the luminescent substance 20 is a substance that fluoresces when irradiated with excitation light in the presence of oxygen, the oxygen concentration can be grasped by measuring the intensity of the fluorescence emitted from the in-vivo indwelling object 1. Therefore, the state of the cells constituting the cell fiber 10 and the state of the cells of the cell fiber 10 after the in vivo indwelling substance 1 is placed at the target site for treatment can be easily confirmed, and the treatment can be performed efficiently. It becomes possible.

The luminescent material 20 contains an oxygen sensor protein having a property of binding and dissociating oxygen molecules and a fluorescent protein that fluoresces when irradiated with excitation light, and the oxygen sensor protein and the fluorescent protein are bound by a polypeptide linker. Is preferable. The oxygen sensor protein is a protein containing heme, like hemoglobin, which is a protein that transports oxygen in blood, and has a property of binding and dissociating oxygen molecules according to the oxygen concentration in the environment. By converting the hem binding region of the oxygen sensor protein and the fluorescent protein into a binding protein by a polypeptide linker, the absorption change caused by the oxygen sensor protein when the oxygen molecule is bound can be converted into the degree of disappearance of fluorescence of the fluorescent protein. .. Since the luminescent substance 20 is a substance in which an oxygen sensor protein and a fluorescent protein are bound by a polypeptide linker, the oxygen sensor protein binds oxygen molecules to the fluorescent protein when the in vivo indwelling substance 1 is in the presence of oxygen. Since the extinction of fluorescence is weakened and the intensity of fluorescence emitted when the in-vivo indwelling object 1 is irradiated with light is increased, the oxygen concentration can be easily measured by measuring the fluorescence intensity.

The second in-vivo indwelling object 1 of the present invention will be described below. FIG. 3 shows a schematic view of the in-vivo indwelling object 1. In FIG. 3, the right side of the figure is the distal side and the left side of the figure is the proximal side. The description of the structure similar to that of the first in-vivo indwelling object 1 of the present invention will be omitted.

As shown in FIG. 3, the second in-vivo indwelling object 1 has a cell fiber 10 in which a plurality of cells are formed into a fiber shape, and a functional material, and the functional material has an oxygen concentration. It is an oxygen sensor 30 for measuring. Since the in-vivo indwelling object 1 has the oxygen sensor 30, it is possible to measure the oxygen concentration inside or in the peripheral portion of the in-vivo indwelling object 1. Therefore, the state of the cells constituting the cell fiber 10 before the in vivo indwelling substance 1 is placed at the target site of the treatment, the state of the cells constituting the cell fiber 10 after being placed at the target site of the treatment, and the state of the cells of the treatment. It becomes possible to grasp the state of the target site, and it is possible to perform treatment efficiently.

The oxygen sensor 30 is preferably fixed to the cell fiber 10. Since the oxygen sensor 30 is fixed to the cell fiber 10, the oxygen sensor 30 and the cell fiber 10 are integrated. Therefore, when the in-vivo indwelling object 1 is delivered to the target site for treatment or after the indwelling, the oxygen sensor 30 is less likely to separate from the cell fiber 10, and the oxygen concentration at the target site for treatment can be sufficiently measured. The oxygen sensor 30 may be wrapped in the cell fiber 10 or may be exposed on the surface.

Examples of fixing the oxygen sensor 30 to the cell fiber 10 include adhesion using an adhesive, engagement, connection, binding, ligation, or a combination thereof. Another example is that the oxygen sensor 30 is provided with a scaffolding material for cells, and the oxygen sensor 30 is fixed to the cell fiber 10 by co-culturing with the oxygen sensor 30 when the cell fiber 10 is cultured. Above all, it is preferable to fix the oxygen sensor 30 and the cell fiber 10 with a tissue adhesive. As the tissue adhesive, for example, fibrin and fibrin polymers formed by mixing fibrinogen and thrombin, which are a kind of blood products, dextran, dextrin, polylysine and the like can be used. Since the oxygen sensor 30 is fixed to the cell fiber 10 by adhesion, the fixing between the oxygen sensor 30 and the cell fiber 10 can be easily strengthened.

As shown in FIG. 3, the oxygen sensor 30 is preferably located at the distal end of the cell fiber 10. Since the oxygen sensor 30 is arranged at the distal end of the cell fiber 10, the distance between the treatment target site and the oxygen sensor 30 becomes close when the in vivo indwelling object 1 is delivered to the treatment target site. , The oxygen concentration in the vicinity of the target site of treatment can be accurately measured. Further, it is possible to prevent the distal end of the cell fiber 10 from coming into contact with the inner wall of the blood vessel or the like during delivery of the in-vivo indwelling object 1 and prevent the distal end of the cell fiber 10 from being damaged.

As shown in FIG. 3, the oxygen sensor 30 preferably includes a light emitting unit 31 that emits light and a light receiving unit 32 that receives light emitted from the light emitting unit 31. Since the oxygen sensor 30 has a light emitting unit 31 and a light receiving unit 32, the oxygen sensor 30 becomes a so-called pulse oximeter. That is, when light is emitted from the light emitting unit 31 and the light receiving unit 32 receives this light, it is possible to easily measure the hemoglobin bonded to oxygen among the hemoglobin contained in the red blood cells in the blood. Therefore, it becomes easy to perform the treatment while confirming the oxygen concentration of the target site of the treatment.

It is preferable that the in-vivo indwelling object 1 has a transmitter 40 that transmits information detected by the oxygen sensor 30. Since the in-vivo indwelling object 1 has the transmitter 40, the oxygen concentration can be easily grasped based on the information detected by the oxygen sensor 30.

Examples of the transmitter 40 include those that perform communication using radio waves. Above all, the transmitter 40 having a Bluetooth (registered trademark) function is preferable. Since the transmitter 40 has the Bluetooth (registered trademark) function, the in-vivo indwelling object 1 such as the oxygen concentration sensed by the oxygen sensor 30 was obtained after the in-vivo indwelling object 1 was placed in the target site for treatment. Information can be received immediately, and the condition of the target site for treatment can be confirmed immediately.

Although not shown, the oxygen sensor 30 and the transmitter 40 preferably have a power source. Examples of the power source for the oxygen sensor 30 and the transmitter 40 include a battery used in a pacemaker or the like. When the oxygen sensor 30 and the transmitter 40 do not have a power source, the oxygen sensor 30 and the transmitter 40 may be electrically connected to an external device (not shown) by using wireless power supply. Examples of the wireless power supply include a non-radiating type such as an electromagnetic induction type and a magnetic field resonance type, and a radiating type such as a microwave type. Above all, the wireless power supply is preferably a non-radiative type.

Although not shown, the in-vivo indwelling object 1 may have a sensor of a different type from the oxygen sensor 30. Examples of the type of sensor different from the oxygen sensor 30 include a temperature sensor, a pressure sensor, a distance measuring sensor, and the like. Since the in-vivo indwelling object 1 has a plurality of types of sensors, the state of cells contained in the in-vivo indwelling object 1 and the in-vivo indwelling object before and after the in-vivo indwelling object 1 are placed. Various information related to the condition around the target site of treatment after the placement of 1 can be obtained. As a result, it is possible to improve the efficiency of treatment and shorten the treatment time.

The third in-vivo indwelling object 1 of the present invention will be described below. FIG. 4 shows a schematic view of the in-vivo indwelling object 1, FIG. 5 shows a VV cross-sectional view of the in-vivo indwelling object 1, and FIG. 6 shows a VI-VI cross-sectional view of the in-vivo indwelling object 1. In FIG. 4, the right side of the figure is the distal side and the left side of the figure is the proximal side. The description of the first in-vivo indwelling object 1 and the second in-vivo indwelling object 1 of the present invention having the same configuration will be omitted.

As shown in FIGS. 4 to 6, the third in-vivo indwelling object 1 has a cell fiber 10 in which a plurality of cells are formed into a fiber shape, and a functional material. TRPA1 (50), an ion channel protein. TRPA1 (50) is activated and opened in high and low oxygen concentrations to generate an ionic current. By measuring this ionic current, it is possible to determine whether or not the oxygen concentration in or around the in-vivo indwelling object 1 is high or low, that is, whether or not the oxygen concentration is different from the normal one. Therefore, the state of the cells constituting the cell fiber 10 before the in vivo indwelling substance 1 is placed at the target site of the treatment, the state of the cells constituting the cell fiber 10 after the placement, and the state of the target site of the treatment are confirmed. can do.

TRPA1 (50) is preferably present on the surface of the cell fiber 10. By arranging TRPA1 (50) on the surface of the cell fiber 10, TRPA1 (50) becomes more responsive to oxygen around the in-vivo indwelling object 1, and the state of oxygen concentration around the in-vivo indwelling object 1 is described. It becomes possible to grasp accurately.

The in-vivo indwelling object 1 preferably further has an electrode 60. Since the in-vivo indwelling object 1 has the electrode 60, the ion current generated by TRPA1 (50) can be easily measured.

As shown in FIGS. 4 to 6, the electrode 60 is composed of at least a first electrode 61 and a second electrode 62, and the first electrode 61 is arranged on the outer surface of the proximal end of the cell fiber 10. And the second electrode 62 is located inside the distal end of the cell fiber 10, or the first electrode 61 is located inside the proximal end of the cell fiber 10. , The second electrode 62 is preferably located on the outer surface of the distal end of the cell fiber 10. That is, either one of the first electrode 61 located at the proximal end of the cell fiber 10 and the second electrode 62 located at the distal end of the cell fiber 10 is arranged inside the cell fiber 10. The other is preferably located on the outer surface of the cell fiber 10. The first electrode 61 is arranged on the outer surface of the proximal end of the cell fiber 10, and the second electrode 62 is arranged inside the distal end of the cell fiber 10, or the first electrode. Since 61 is arranged inside the proximal end of the cell fiber 10 and the second electrode 62 is arranged on the outer surface of the distal end of the cell fiber 10, the in vivo indwelling object 1 By measuring the potential difference between the first electrode 61 and the second electrode 62 arranged at the distal end and the proximal end, the ion current generated from TRPA1 (50) of the in-vivo indwelling object 1 is measured. , The oxygen concentration can be confirmed.

It is preferable that the in-vivo indwelling object 1 further contains a luminescent substance 20 that emits light when irradiated with light. The change in the potential of the ionic current generated from TRPA1 (50) possessed by the in-vivo indwelling object 1 is proportional to the change in the intensity of light emitted by the luminescent substance 20. Therefore, since the in-vivo indwelling object 1 has both TRPA1 (50) and the luminescent substance 20, the in-vivo indwelling object 1 is irradiated with light to reduce the intensity of the light emitted from the in-vivo indwelling object 1. By confirming, it becomes possible to grasp the state of the oxygen concentration around the in-vivo indwelling object 1 and the in-vivo indwelling object 1.

In the first to third in-vivo indwelling objects 1, the cell fiber 10 is preferably composed of a plurality of cells including cells that differentiate into living tissues after being placed in the living body in the form of fibers. Since the cell fiber 10 is composed of a plurality of cells including cells that differentiate into living tissue after being placed in the living body in a fiber shape, the in-vivo indwelling object 1 is the therapeutic target after the in-vivo indwelling object 1 is placed. Integrate with the part. Therefore, the position of the in-vivo indwelling object 1 is less likely to shift, and the treatment can be performed efficiently.

As described above, the first in-vivo indwelling substance has a cell fiber in which a plurality of cells are formed into a fiber shape and a luminescent substance that emits light when irradiated with light, and is a second in-vivo indwelling substance. Has a cell fiber in which a plurality of cells are formed into a fiber shape and an oxygen sensor for measuring the oxygen concentration, and the third in vivo indwelling is a cell in which a plurality of cells are formed into a fiber shape. It has a fiber and TRPA1. Since the first in-vivo indwelling substance has a luminescent substance, the in-vivo indwelling is placed in vivo by irradiating light before or after indwelling and measuring the luminescence intensity of the in-vivo indwelling. It is possible to grasp the state of cells before and after the placement of the substance and the environment of the target site of the treatment in which the in-vivo placement is placed. Since the second in-vivo indwelling has an oxygen sensor, the oxygen concentration in the in-vivo in-vivo before the in-vivo indwelling and the in-vivo in-vivo after the in-vivo indwelling is placed. It is possible to measure the oxygen concentration at the target site of treatment. Since the third in-vivo indwelling object has TRPA1, the in-vivo indwelling object before the in-vivo indwelling is placed by measuring the ionic current generated from the TRPA1 before and after the in-vivo indwelling. It is possible to confirm the oxygen concentration in the living body and the oxygen concentration in the in-vivo in-vivo object and the target site for treatment after the in-vivo indwelling object is placed.

This application claims the benefit of priority based on Japanese Patent Application No. 2019-19549 filed on June 27, 2019. The entire contents of the specification of Japanese Patent Application No. 2019-119549 filed on June 27, 2019 are incorporated herein by reference.

1: In-vivo indwelling 10: Cell fiber 20: Luminescent substance 30: Oxygen sensor 31: Luminous part 32: Light receiving part 40: Transmitter 50: TRPA1
60: Electrode 61: First electrode 62: Second electrode

Claims (17)

Cell fibers that are composed of multiple cells in the form of fibers,
An in vivo indwelling having a functional material. The in-vivo indwelling product according to claim 1, wherein the cell fiber has a layer structure including an outer layer and an inner layer, and the functional material is arranged inside the inner layer. The in-vivo indwelling product according to claim 1 or 2, wherein the functional material is a luminescent substance that emits light when irradiated with light. The in-vivo indwelling product according to claim 3, wherein the luminescent substance is present on the surface of the cell fiber. The in-vivo indwelling substance according to claim 3 or 4, wherein the luminescent substance is a substance that fluoresces when irradiated with excitation light in the presence of oxygen. The luminescent substance contains an oxygen sensor protein having a property of binding and dissociating oxygen molecules, and a fluorescent protein that fluoresces when irradiated with excitation light.
The in-vivo indwelling product according to any one of claims 3 to 5, wherein the oxygen sensor protein and the fluorescent protein are bound by a polypeptide linker. The in-vivo indwelling product according to claim 1 or 2, wherein the functional material is an oxygen sensor that measures the concentration of oxygen. The in-vivo indwelling product according to claim 7, wherein the oxygen sensor is fixed to the cell fiber. The in-vivo indwelling according to claim 7 or 8, wherein the oxygen sensor is arranged at the distal end of the cell fiber. The in-vivo indwelling object according to any one of claims 7 to 9, wherein the oxygen sensor has a light emitting unit that emits light and a light receiving unit that receives light emitted from the light emitting unit. The in-vivo indwelling object according to any one of claims 7 to 10, which has a transmitter that transmits information detected by the oxygen sensor. The in-vivo indwelling product according to claim 1 or 2, wherein the functional material is TRPA1, which is an ion channel protein. The in-vivo indwelling product according to claim 12, wherein the TRPA1 is present on the surface of the cell fiber. The in-vivo indwelling product according to claim 12 or 13, further comprising an electrode. The electrode is composed of at least a first electrode and a second electrode.
The first electrode is located on the outer surface of the proximal end of the cell fiber, and the second electrode is located inside the distal end of the cell fiber, or the first. The in-vivo indwelling according to claim 14, wherein the electrode is arranged inside the proximal end of the cell fiber and the second electrode is arranged on the outer surface of the distal end of the cell fiber. Stuff. The in-vivo indwelling product according to any one of claims 12 to 15, further comprising a luminescent substance that emits light when irradiated with light. The in-vivo indwelling product according to any one of claims 1 to 16, wherein the cell fiber is formed in the form of a plurality of cells including cells that differentiate into living tissue after being placed in the living body.

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