JP7514830B2 - In vivo indwelling - Google Patents

Description

The present invention relates to an in vivo implant containing a cell fiber formed by structuring a plurality of cells into a fiber-like shape.

Conventionally, in the treatment of stroke, etc., a drug has been administered after taking an image of the target site of treatment by computed tomography (CT), magnetic resonance angiography (MRA), magnetic resonance imaging (MRI), angiography, etc., or cell tissue has been transplanted by injection. In addition, when performing sensing to obtain information on the target site in treatment, a guide wire may be used to measure fractional flow reserve (FFR) to measure the blood pressure at the stenotic part of the blood vessel, or intravascular ultrasound (IVUS) may be performed to image the vascular lumen using intravascular ultrasound. For example, Patent Documents 1 to 3 disclose methods for transplanting cell tissue in the treatment of lesions such as stroke.

JP 2009-514950 A JP 2004-533277 A International Publication No. 2011/046105

In the treatment of lesions such as stroke, it is necessary to understand the state of cells before and after placement of cellular tissue at the target site, and the environment of the target site after placement of the cellular tissue. The methods disclosed in Patent Documents 1 to 3 were unable to fully understand the state of cells before and after placement of cellular tissue at the target site, or the environment of the target site after placement of the cellular tissue, leaving room for improvement.

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

The in-vivo implant that can solve the above problem is characterized by having a cell fiber composed of multiple cells arranged in a fibrous form, and a functional material.

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

In the in-vivo indwelling device of the present invention, the functional material is preferably a luminescent substance that emits light when irradiated with light. In other words, the in-vivo indwelling device preferably has a cell fiber in which a plurality of cells are arranged in a fibrous form, and a luminescent substance that emits light when irradiated with light.

In the in vivo indwelling device of the present invention, it is preferable that the luminescent substance is present on the surface of the cell fiber.

In the in vivo indwelling device of the present invention, it is preferable that the luminescent substance is a substance that emits fluorescence when irradiated with excitation light in the presence of oxygen.

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

In the in-vivo indwelling device of the present invention, it is also preferable that the functional material is an oxygen sensor that measures the concentration of oxygen. In other words, it is also preferable that the in-vivo indwelling device has a cell fiber in which a plurality of cells are configured in a fibrous form, and an oxygen sensor that measures the concentration of oxygen.

In the in vivo indwelling device of the present invention, it is preferable that the oxygen sensor is fixed to the cell fiber.

In the in vivo indwelling device of the present invention, it is preferable that the oxygen sensor is positioned at the distal end of the cell fiber.

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

It is preferable that the in-vivo indwelling device of the present invention has a transmitter that transmits information detected by the oxygen sensor.

In the in-vivo indwelling device of the present invention, it is also preferable that the functional material is the ion channel protein TRPA1. In other words, it is also preferable that the in-vivo indwelling device has a cell fiber in which multiple cells are configured into a fiber shape, and the ion channel protein TRPA1.

In the in vivo indwelling device of the present invention, it is preferable that TRPA1 is present on the surface of the cell fiber.

It is preferable that the in-vivo indwelling device of the present invention further has an electrode.

In the in vivo indwelling device of the present invention, the electrode is composed of at least a first electrode and a second electrode, and it is preferable that the first electrode is arranged on the outer surface of the proximal end of the cell fiber and the second electrode is arranged inside the distal end of the cell fiber, or that the first 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.

It is preferable that the in-vivo indwelling device of the present invention further contains a luminescent substance that emits light when exposed to light.

In the in-vivo indwelling device of the present invention, it is preferable that the cell fiber is a fiber-shaped configuration of multiple cells, including cells that will differentiate into biological tissue after placement in the body.

According to the in-vivo indwelling device of the present invention, by having a cell fiber in which a plurality of cells are configured in a fiber shape and a functional material, it is possible to grasp the state of cells before and after placement of the in-vivo indwelling device, and the environment of the target site of treatment in which the in-vivo indwelling device is placed. Specifically, according to the in-vivo indwelling device of the present invention, by having a cell fiber in which a plurality of cells are configured in a fiber shape and a luminous substance that emits light when irradiated with light, it is possible to grasp the state of cells before and after placement of the in-vivo indwelling device, and the environment of the target site of treatment in which the in-vivo indwelling device is placed, by irradiating light before and after placement of the in-vivo indwelling device and measuring the luminescence intensity of the in-vivo indwelling device. In addition, according to the in-vivo indwelling device of the present invention, by having a cell fiber in which a plurality of cells are configured in a fiber shape and an oxygen sensor that measures the concentration of oxygen, it is possible to measure the oxygen concentration in the in-vivo indwelling device before placement, and the oxygen concentration in the in-vivo indwelling device and the target site of treatment after placement of the in-vivo indwelling device. Furthermore, according to the in-vivo implant of the present invention, since it comprises a cell fiber in which a plurality of cells are arranged in a fiber shape and the ion channel protein TRPA1, it is possible to confirm the oxygen concentration inside the in-vivo implant before placement, and the oxygen concentration inside the in-vivo implant and at the treatment target site after placement of the in-vivo implant, by measuring the ion current generated by TRPA1 before and after placement of the in-vivo implant.

1 is a schematic diagram of a first in-vivo indwelling device according to an embodiment of the present invention. FIG. 2 shows a cross-sectional view of the in-vivo indwelling device shown in FIG. 1 along line II-II. FIG. 2 is a schematic diagram of a second in-vivo indwelling device according to an embodiment of the present invention. FIG. 2 is a schematic diagram of a third in-vivo indwelling device according to an embodiment of the present invention. 5 shows a cross-sectional view of the in-vivo indwelling device shown in FIG. 4 along VV line. 6 shows a cross-sectional view of the in-vivo indwelling device shown in FIG. 4 taken along the line VI-VI.

The present invention will be described in more detail below based on the following embodiments, but the present invention is not limited to the following embodiments and can of course be modified appropriately within the scope of the above and below, all of which are included in the technical scope of the present invention. In addition, hatching and component symbols may be omitted in each drawing for convenience, but in such cases, reference should be made to the specification or other drawings. Furthermore, the dimensions of various components in the drawings may differ from the actual dimensions, as priority is given to contributing to an understanding of the features of the present invention.

The in-vivo implant of the present invention is used for delivering and placing cellular tissue at a target site in treatment. The in-vivo implant has a cell fiber. The cell fiber includes a cell mass made up of multiple cells arranged in a fibrous shape.

In the present invention, the proximal side refers to the direction toward the user's (surgeon's) hand, and the distal side refers to the direction toward the treatment area, i.e., the opposite direction to the proximal side.

First, the first in-vivo indwelling device 1 of the present invention will be described below. Fig. 1 shows a schematic diagram of the in-vivo indwelling device 1, and Fig. 2 shows a cross-sectional view of the in-vivo indwelling device 1 taken along line II-II. As shown in Figs. 1 and 2, the first in-vivo indwelling device 1 has a cell fiber 10 in which a plurality of cells are arranged in a fibrous form, and a functional material, and the functional material is a luminescent substance 20 that emits light when irradiated with light.

The in-vivo device 1 may have one or more long cellular fibers 10 in the near-far direction, or may have an aggregate of short cellular fibers 10. When the in-vivo device 1 has an aggregate of short cellular fibers 10, the in-vivo device 1 may include an intermediate member that fixes the multiple cellular fibers 10 to each other. In addition to the material used for the cellular fibers 10, the intermediate member may be, for example, a protein such as gelatin.

The cell type constituting the cell fiber 10 is not particularly limited and can be appropriately selected according to 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 cardiac muscle cells, fibroblasts, epithelial cells, hepatocytes, pancreatic islet cells, photoreceptor cells, blood monocytes, and the like. The cell fiber 10 is preferably composed of stem cells having unipotency (muscle stem cells, germline stem cells, hepatic stem cells, etc.), and more preferably composed of various stem cells having pluripotency (neural stem cells, hematopoietic stem cells, mesenchymal stem cells, muse cells, etc.), embryonic stem cells (ES cells) having differentiation potential, induced pluripotent stem cells (iPS cells), somatic cell-derived ES cells (ntES cells), and stem cells having pluripotency (hematopoietic stem cells, neural stem cells, mesenchymal stem cells, etc.). The cell fiber 10 may use only one of these cell types, or may use two or more of them in combination. In addition, the cell fiber 10 may use autologous cells or allogeneic cells. In this application, cells other than neural cells are referred to as non-neuronal cells.

In treating brain damage sites, the cell fiber 10 preferably contains neural stem cell differentiation-inducing fibers in which neural stem cells have differentiated into neurons and glial cells. By containing neural stem cell differentiation-inducing fibers in which neural stem cells have differentiated into neurons and glial cells, it becomes possible to accelerate nerve regeneration at the target site of treatment. Note that in treating other sites, cell fibers 10 containing non-neuronal cells can be used.

The cell fiber 10 may be composed of cells that have been introduced with physiologically active substances such as cell growth factors and cytokines, such as BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial growth factor), EGF (epidermal growth factor), FGF (fibroblast growth factor), insulin-like growth factor (IGF), PDGF (platelet-derived growth factor), and NGF (nerve growth factor), as well as gene plasmids, antibodies, or drug-containing capsules.

The method for producing the cell fiber 10 is not particularly limited, but preferably includes the steps of preparing a tubular body having an inner layer having extracellular matrix and cells and an outer layer, cultivating cells in the inner layer, and dissolving the outer layer. The step of dissolving the outer layer is performed after cultivating cells in the inner layer. In addition, it is preferable that the tubular body has a structure in which the inner layer is disposed inside the outer layer. Furthermore, a portion 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. Of these, 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 layer structure including at least an outer layer and an inner layer. The outer layer is preferably stronger than the inner layer in order to maintain the strength of the cell fiber 10 during production or implantation of the cell fiber 10, and is preferably made of a material that decomposes in the body. The inner layer is preferably made of an extracellular matrix, with a cell layer present inside. The functional material, such as a luminescent substance or an ion channel protein, is preferably contained in the cell layer located inside the inner layer. By containing the functional material in the cell layer, the functional material can be reliably introduced into the body when the indwelling device 1 is implanted in the body. When the indwelling device 1 has an electrode 60 described later, the electrode 60 is preferably contained in the outer layer. Note that other layers may be present between the outer layer and the inner layer. In addition, the outer layer components and the inner layer components may be mixed between the outer layer and the inner layer. This is also true between the inner layer and the cell layer.

The cell fiber 10 may be provided with a support for cells. Examples of the material of the support include bioabsorbable polymers, natural polymers, decellularized biological tissues and cells, or combinations of these. Examples of bioabsorbable polymers that can be used include poly-L-lactic acid (PLLA), polyglycolic acid (PGA), copolymers of lactic acid and glycolic acid (PLGA), and polycaprolactone (PCL). Examples of natural polymers include collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptides.

1 and 2, the in-vivo device 1 has a luminescent substance 20. The luminescent substance 20 refers to a substance that emits light when irradiated with light. Since the in-vivo device 1 has the luminescent substance 20, the in-vivo device 1 can be irradiated with light and the luminescence intensity measured before and after placement of the in-vivo device 1, thereby making it possible to confirm and manage the state of the cells contained in the cell fiber 10 before and after placement of the in-vivo device 1. Furthermore, even after the in-vivo device 1 is placed in the target site for treatment, the state of the cells contained in the in-vivo device 1 can be grasped by measuring the luminescence intensity of the in-vivo device 1.

In order to configure the in-vivo indwelling device 1 to have the cell fiber 10 and the luminescent substance 20, for example, the cell fiber 10 may be co-cultured with a gel containing the luminescent substance 20 during cultivation. When a gel containing the luminescent substance 20 is used for the in-vivo indwelling device 1, the gel may be a porous gel.

The diameter of the in-vivo device 1 can be selected according to the delivery performance and the shape and size of the target site, but is preferably, for example, 100 nm or more and 1000 μm or less. The in-vivo device 1 preferably contains cells over the entire length in the longitudinal direction of the in-vivo device 1. The in-vivo device 1 may also contain substances other than cells or drugs as necessary. Examples of substances other than cells include substances that promote cell growth and substances that promote cell adhesion at the target site of treatment.

The structure of the in-vivo indwelling device 1 is preferably a cylindrical structure, but is not particularly limited, and may be, for example, a spiral shape, a double spiral structure, a nonwoven fabric structure, a sheet shape, a cylindrical bundle shape in which a plurality of string-shaped cell fibers 10 are bundled, a cylindrical stack shape in which a further cell fiber 10 is arranged inside a cylindrical cell fiber 10, a coil shape, or other three-dimensional structure. A hollow cell fiber 10 can be formed and used to configure the in-vivo indwelling device 1. The cell fiber 10 can also be formed into a sheet shape, and the sheet-shaped cell fiber 10 can be rolled into a cylindrical shape or folded for use. The shape of the in-vivo indwelling device 1 can be selected according to the delivery performance, the shape and size of the target site, etc. In particular, when the shape of the in-vivo indwelling device 1 is a spiral shape, a nonwoven fabric structure, or a three-dimensional structure, the rate of attachment and compatibility with the tissue of the target site of treatment can be increased, and the therapeutic effect can be enhanced. In addition, by making the shape of the in-vivo indwelling device 1 into a shape suitable for the tissue of the target site of treatment, the treatment time can be shortened.

Although not shown, the distal end of the in-vivo device 1 is preferably formed in a hemispherical or semi-elliptical shape. By forming the distal end of the in-vivo device 1 in a hemispherical or semi-elliptical shape, friction between the tip of the in-vivo device 1 and the inner wall of the blood vessel is reduced, which contributes to improving the delivery performance of the in-vivo device 1 and suppressing the generation of debris at the distal end of the in-vivo device 1. Note that debris refers to unnecessary material that breaks down and separates from the in-vivo device 1, which is generated when the distal end of the in-vivo device 1 comes into contact with the blood vessel wall or the like.

The luminescent substance 20 may be enclosed within the cell fiber 10, or may be partially exposed on the surface of the cell fiber 10. As shown in Figures 1 and 2, the luminescent substance 20 is preferably present on the surface of the cell fiber 10. By disposing the luminescent substance 20 on the surface of the cell fiber 10, it becomes easier for the light irradiated to the in-vivo indwelling device 1 to hit the luminescent substance 20, and the luminescence intensity of the in-vivo indwelling device 1 can be increased.

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

It is preferable that the luminescent substance 20 is a substance that emits fluorescence when irradiated with excitation light in the presence of oxygen. Since the luminescent substance 20 is a substance that emits fluorescence when irradiated with excitation light in the presence of oxygen, the oxygen concentration can be determined by measuring the intensity of the fluorescence emitted from the in-vivo indwelling device 1. Therefore, the state of the cells that make up the cell fiber 10 and the state of the cells of the cell fiber 10 after the in-vivo indwelling device 1 is placed in the target site of treatment can be easily confirmed, making it possible to perform treatment efficiently.

The luminescent substance 20 includes an oxygen sensor protein having the property of binding and dissociating oxygen molecules, and a fluorescent protein that emits fluorescence when irradiated with excitation light, and the oxygen sensor protein and the fluorescent protein are preferably linked by a polypeptide linker. The oxygen sensor protein is a heme-containing protein, like hemoglobin, a protein that transports oxygen in blood, and has the property of binding and dissociating oxygen molecules according to the oxygen concentration in the environment. By binding the heme-binding region of the oxygen sensor protein and the fluorescent protein with a polypeptide linker, the absorption change caused by the oxygen sensor protein when it binds oxygen molecules can be converted into the degree of quenching of the fluorescence of the fluorescent protein. Since the luminescent substance 20 is a compound in which the oxygen sensor protein and the fluorescent protein are linked by a polypeptide linker, when the in-vivo indwelling device 1 is in the presence of oxygen, the oxygen sensor protein binds oxygen molecules, weakening the quenching of the fluorescence of the fluorescent protein, and the intensity of the fluorescence emitted when the in-vivo indwelling device 1 is irradiated with light increases, so that the oxygen concentration can be easily measured by measuring the fluorescence intensity.

The second in-vivo indwelling device 1 of the present invention will be described below. Figure 3 shows a schematic diagram of the in-vivo indwelling device 1. In Figure 3, the right side of the figure is the distal side, and the left side of the figure is the proximal side. Note that a description of the components having the same configuration as the first in-vivo indwelling device 1 of the present invention will be omitted.

As shown in FIG. 3, the second in-vivo indwelling device 1 has a cell fiber 10 in which multiple cells are arranged in a fiber shape, and a functional material, and the functional material is an oxygen sensor 30 that measures the concentration of oxygen. Since the in-vivo indwelling device 1 has the oxygen sensor 30, the concentration of oxygen inside and around the in-vivo indwelling device 1 can be measured. Therefore, it is possible to grasp the state of the cells that make up the cell fiber 10 before placing the in-vivo indwelling device 1 in the target site of treatment, the state of the cells that make up the cell fiber 10 after placing the in-vivo indwelling device 1 in the target site of treatment, and the state of the target site of treatment, and treatment can be performed efficiently.

The oxygen sensor 30 is preferably fixed to the cell fiber 10. By fixing the oxygen sensor 30 to the cell fiber 10, the oxygen sensor 30 and the cell fiber 10 are integrated. Therefore, the oxygen sensor 30 is less likely to detach from the cell fiber 10 when the in-vivo indwelling device 1 is delivered to the target site of treatment or after placement, making it possible to adequately measure the oxygen concentration at the target site of treatment. The oxygen sensor 30 may be enclosed within the cell fiber 10 or may be exposed on the surface.

The oxygen sensor 30 can be fixed to the cell fiber 10 by, for example, adhesion using an adhesive, engagement, connection, binding, ligation, or a combination thereof. Alternatively, the oxygen sensor 30 can be configured to include a scaffold material for cells, and the oxygen sensor 30 can be co-cultured with the cell fiber 10 during the culture of the cell fiber 10, thereby fixing the oxygen sensor 30 to the cell fiber 10. Among these, it is preferable to fix the oxygen sensor 30 and the cell fiber 10 using a tissue adhesive. As the tissue adhesive, for example, fibrin and fibrin polymers formed by mixing fibrinogen and thrombin, which are a type of blood preparation, dextran, dextrin, polylysine, etc. can be used. Since the oxygen sensor 30 is fixed to the cell fiber 10 by adhesion, the fixation between the oxygen sensor 30 and the cell fiber 10 can be easily and firmly established.

As shown in Figure 3, the oxygen sensor 30 is preferably disposed at the distal end of the cell fiber 10. By disposing the oxygen sensor 30 at the distal end of the cell fiber 10, when the in-vivo indwelling device 1 is delivered to the target site of treatment, the distance between the target site of treatment and the oxygen sensor 30 becomes closer, and the oxygen concentration in the vicinity of the target site of treatment can be accurately measured. Furthermore, when the in-vivo indwelling device 1 is delivered, the distal end of the cell fiber 10 is less likely to come into contact with the inner wall of a blood vessel, etc., and it is also possible to prevent the distal end of the cell fiber 10 from being damaged.

As shown in Fig. 3, the oxygen sensor 30 preferably has a light-emitting unit 31 that emits light and a light-receiving unit 32 that receives the light emitted from the light-emitting unit 31. By having the light-emitting unit 31 and the light-receiving unit 32, the oxygen sensor 30 becomes a so-called pulse oximeter. In other words, by emitting light from the light-emitting unit 31 and receiving this light from the light-receiving unit 32, it is possible to easily measure the hemoglobin that is bound to oxygen among the hemoglobin contained in red blood cells in the blood. This makes it easier to perform treatment while checking the oxygen concentration in the treatment target area.

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

Examples of transmitters 40 include those that communicate using radio waves. Among them, transmitters 40 equipped with Bluetooth (registered trademark) functionality are preferable. By having transmitter 40 equipped with Bluetooth (registered trademark) functionality, after placing intravital indwelling device 1 in the target site of treatment, information obtained by intravital indwelling device 1, such as the oxygen concentration sensed by oxygen sensor 30, can be immediately received, making it possible to immediately check the condition of the target site of treatment.

Although not shown, it is preferable that the oxygen sensor 30 and the transmitter 40 have a power source. Examples of the power source for the oxygen sensor 30 and the transmitter 40 include batteries used in pacemakers and the like. In addition, if 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) using wireless power supply. Examples of wireless power supply include non-radiative types such as electromagnetic induction and magnetic resonance types, and radiative types such as microwave types. Among these, the non-radiative type is preferable for the wireless power supply.

Although not shown, the in-vivo device 1 may have a sensor of a different type from the oxygen sensor 30. Examples of sensors of a different type from the oxygen sensor 30 include a temperature sensor, a pressure sensor, and a distance sensor. By having the in-vivo device 1 have multiple types of sensors, it is possible to obtain various information related to the state of the cells contained in the in-vivo device 1 before and after placement of the in-vivo device 1, and the state of the surrounding area of the treatment target site after placement of the in-vivo device 1. As a result, it is possible to improve the efficiency of treatment and shorten the treatment time.

The third in-vivo indwelling device 1 of the present invention will be described below. Figure 4 shows a schematic diagram of the in-vivo indwelling device 1, Figure 5 shows a V-V cross-sectional view of the in-vivo indwelling device 1, and Figure 6 shows a VI-VI cross-sectional view of the in-vivo indwelling device 1. In Figure 4, the right side of the figure is the distal side, and the left side of the figure is the proximal side. Note that descriptions of devices having the same configuration as the first in-vivo indwelling device 1 and the second in-vivo indwelling device 1 of the present invention will be omitted.

As shown in Figures 4 to 6, the third in-vivo indwelling device 1 has a cell fiber 10 in which multiple cells are arranged in a fiber shape, and a functional material, and the functional material is the ion channel protein TRPA1 (50). TRPA1 (50) is activated and opens in high and low oxygen concentrations, generating an ionic current. By measuring this ionic current, it is possible to determine whether the oxygen concentration in or around the in-vivo indwelling device 1 is high or low, that is, whether the oxygen concentration is different from normal. Therefore, it is possible to confirm the state of the cells that make up the cell fiber 10 before placing the in-vivo indwelling device 1 in the target site of treatment, and the state of the cells that make up the cell fiber 10 and the state of the target site of treatment after placement.

It is preferable that TRPA1 (50) is present on the surface of the cell fiber 10. By disposing TRPA1 (50) on the surface of the cell fiber 10, TRPA1 (50) becomes more likely to react with oxygen surrounding the in-vivo indwelling device 1, making it possible to accurately grasp the state of the oxygen concentration around the in-vivo indwelling device 1.

It is preferable that the in-vivo indwelling device 1 further has an electrode 60. By having the electrode 60, the in-vivo indwelling device 1 can easily measure the ionic current generated by the TRPA1 (50).

4 to 6, the electrode 60 is composed of at least a first electrode 61 and a second electrode 62, and it is preferable that the first electrode 61 is disposed on the outer surface of the proximal end of the cell fiber 10 and the second electrode 62 is disposed inside the distal end of the cell fiber 10, or that the first electrode 61 is disposed inside the proximal end of the cell fiber 10 and the second electrode 62 is disposed on the outer surface of the distal end of the cell fiber 10. In other words, it is preferable that either the first electrode 61 located at the proximal end of the cell fiber 10 or the second electrode 62 located at the distal end of the cell fiber 10 is disposed inside the cell fiber 10, and the other is disposed 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 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. By measuring the potential difference between the first electrode 61 and the second electrode 62 arranged at the distal and proximal ends of the in-vivo implant 1, the ionic current generated from the TRPA1 (50) possessed by the in-vivo implant 1 can be measured and the oxygen concentration can be confirmed.

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

In the first to third in-vivo indwelling devices 1, the cell fiber 10 is preferably a fiber-shaped configuration of multiple cells, including cells that will differentiate into biological tissue after placement in a living body. Since the cell fiber 10 is a fiber-shaped configuration of multiple cells, including cells that will differentiate into biological tissue after placement in a living body, the in-vivo indwelling device 1 becomes integrated with the target site for treatment after placement. Therefore, the in-vivo indwelling device 1 is less likely to shift position, and treatment can be carried out efficiently.

As described above, the first in-vivo placement has a cell fiber in which a plurality of cells are arranged in a fiber shape and a luminous substance that emits light when irradiated with light, the second in-vivo placement has a cell fiber in which a plurality of cells are arranged in a fiber shape and an oxygen sensor that measures the concentration of oxygen, and the third in-vivo placement has a cell fiber in which a plurality of cells are arranged in a fiber shape and a TRPA1. Since the first in-vivo placement has a luminous substance, the state of the cells before and after placement of the in-vivo placement and the environment of the target site of treatment in which the in-vivo placement is placed can be grasped by irradiating light before and after placement of the in-vivo placement and measuring the luminescence intensity of the in-vivo placement. Since the second in-vivo placement has an oxygen sensor, it is possible to measure the oxygen concentration in the in-vivo placement before placement of the in-vivo placement, and the oxygen concentration in the in-vivo placement and the target site of treatment after placement of the in-vivo placement. Since the third in-vivo indwelling device has TRPA1, the oxygen concentration inside the in-vivo indwelling device before placement, and the oxygen concentration inside the in-vivo indwelling device and at the treatment target site after placement of the in-vivo indwelling device can be confirmed by measuring the ionic current generated from TRPA1 before and after placement of the in-vivo indwelling device.

This application claims the benefit of priority based on Japanese Patent Application No. 2019-119549, 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 by reference into this application.

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

Claims (17)

A cell fiber formed by structuring multiple cells into a fiber shape;
and a functional material ,
The distal end of the in-vivo indwelling device is formed in a hemispherical or semi-elliptical spherical shape . The in-vivo indwelling device according to claim 1, wherein the cell fiber has a layered structure including an outer layer and an inner layer, and the functional material is disposed inside the inner layer. The in-vivo indwelling device according to claim 1 or 2, wherein the functional material is a luminescent material that emits light when irradiated with light. The in-vivo indwelling device according to claim 3, wherein the luminescent substance is present on the surface of the cell fiber. The in-vivo indwelling device according to claim 3 or 4, wherein the luminescent substance is a substance that emits fluorescence when irradiated with excitation light in the presence of oxygen. the luminescent substance includes an oxygen sensor protein having a property of binding and dissociating oxygen molecules, and a fluorescent protein that emits fluorescence when irradiated with excitation light;
6. The in-vivo indwelling device according to claim 3, wherein the oxygen sensor protein and the fluorescent protein are linked together via a polypeptide linker. The in-vivo indwelling device according to claim 1 or 2, wherein the functional material is an oxygen sensor that measures the concentration of oxygen. The in-vivo indwelling device according to claim 7, wherein the oxygen sensor is fixed to the cell fiber. The in-vivo indwelling device according to claim 7 or 8, wherein the oxygen sensor is disposed at the distal end of the cell fiber. The in-vivo indwelling device according to any one of claims 7 to 9, wherein the oxygen sensor has a light-emitting part that emits light and a light-receiving part that receives the light emitted from the light-emitting part. The in-vivo indwelling device 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 device according to claim 1 or 2, wherein the functional material is an ion channel protein, TRPA1. The in vivo indwelling device according to claim 12, wherein the TRPA1 is present on the surface of the cell fiber. The in-vivo indwelling device according to claim 12 or 13, further comprising an electrode. The electrode includes at least a first electrode and a second electrode,
The in vivo indwelling device described in claim 14, wherein the first electrode is disposed on the outer surface of the proximal end of the cell fiber and the second electrode is disposed inside the distal end of the cell fiber, or the first electrode is disposed inside the proximal end of the cell fiber and the second electrode is disposed on the outer surface of the distal end of the cell fiber. The in-vivo indwelling device according to any one of claims 12 to 15, further comprising a luminescent substance that emits light when irradiated with light. The in-vivo device according to any one of claims 1 to 16, wherein the cell fiber is a fiber-shaped configuration of multiple cells, including cells that differentiate into biological tissue after placement in the body.

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