Biobattery, electronic device, and stent for intrabody implantation

Abstract

The present disclosure pertains to a battery and a stent comprising an electronic device. The present disclosure also pertains to a stent capable of generating a current in response to glucose. The present disclosure can provide a stent which has a hydrogel and a negative electrode, and in which the hydrogel is bonded to the surface of the stent and carries a sugar-oxidizing enzyme, the hydrogel and the negative electrode are linked together so as to be capable of receiving electrons generated by the enzyme in the hydrogel, and electrons are supplied from the negative electrode when glucose makes contact with the sugar-oxidizing enzyme.

Description

Biobatteries, electronic devices, and stents for placement in the body

[0001] The present disclosure relates to biobatteries, electronic devices, and stents for intracorporeal placement.

[0002] A known biobattery is a power generation device that uses the reaction of decomposing sugars into carbon dioxide to generate electricity. It is expected that the use of biobatteries will enable power to be supplied to implantable medical devices and other devices within the body without external charging or energy supply. Patent Document 1 and Non-Patent Document 1 propose biobatteries with improved biocompatibility.

[0003] JP7359998 No.

[0004] ACS Appl. Polym. Mater. 2021, 3, 2, 631-639

[0005] The present disclosure provides a stent equipped with a battery, a biobattery, an electronic device powered by the biobattery, and a stent equipped with the biobattery or the electronic device. The biobattery, the electronic device, and the stent are preferably placed in a blood vessel. In the stent equipped with a battery, the stent is folded compactly before placement, and the battery can deform in accordance with the expansion of the stent.

[0006] According to the present disclosure, the following inventions are provided, as examples: (1) A stent having a battery (for example, a battery having electrodes with a plate-like or wire-like shape, and the battery itself may have a plate-like or wire-like shape), which has an electronic device or an electronic device connection part, and preferably, the battery can expand in accordance with the expansion of the stent (for example, the battery has a plate-like shape with a hinge and is compactly stored by bending at the hinge, or the battery has a wire-like shape and is compactly stored by bending, and can expand in accordance with the expansion of the stent), and the battery can supply current to the electronic device or the electronic device connection part. (2) The stent according to (1) above, in which the battery is (i) folded or (ii) has a slit so that it can expand in accordance with the expansion of the stent when the stent is expanded. (3) The stent according to (1) above, in which the battery includes a wire-like negative electrode and a wire-like positive electrode. (4) The stent according to (2) above, comprising a first wire, a second wire, and a separator, the separator being interposed between the first wire and the second wire. (5) The stent according to (4) above, in which the first wire, the second wire, and the separator together form a single wire. (6) The stent according to (3) above, in which the first wire and the second wire are folded so as to be able to expand in accordance with the expansion of the stent when the stent is expanded. (7) The stent according to (4) above, in which the first wire, the second wire, and the separator are folded in order to be able to expand in accordance with the expansion of the stent when the stent is expanded. (8) The stent according to (5) above, in which the first wire, the second wire, and the separator are folded in order to be able to expand in accordance with the expansion of the stent when the stent is expanded.

[0007] According to the present disclosure, the following invention is provided as an example: (21) A stent having a battery including a hydrogel, a negative electrode, and a positive electrode, wherein the negative electrode and the positive electrode are electrically connectable by a conductive wire via an electronic device or an electronic device connection part, and the electronic device connection part is equipped with an electronic device, the negative electrode and the positive electrode are arranged so as not to be in direct contact with each other, and when the negative electrode and the positive electrode are close to each other (particularly when insulation is required), a separator may be provided between the negative electrode and the positive electrode, the hydrogel is bonded to the stent and carries an oxidase (e.g., a sugar oxidase such as sugar oxidase or sugar dehydrogenase), and the hydrogel and the negative electrode are connected so as to be able to accept electrons generated by the enzyme in the hydrogel, and when sugar (e.g., glucose) comes into contact with the oxidase (e.g., sugar oxidase), electrons are supplied to the negative electrode, and the battery can supply current to the electronic device or the electronic device connection part. (22) The stent according to (21), wherein the battery is (i) folded or (ii) has a slit so that it can expand in accordance with the expansion of the stent when the stent is expanded. (23) The stent according to (21), comprising a first wire including the hydrogel and the negative electrode and a second wire including the positive electrode. (24) The stent according to (22), comprising a first wire, a second wire, and a separator, the separator being interposed between the first wire and the second wire. (25) The stent according to (24), wherein the first wire, the second wire, and the separator together form a single wire. (26) The stent according to (23), wherein the first wire and the second wire are folded in order to expand in accordance with the expansion of the stent when the stent is expanded. (27) The stent according to (24) above, wherein the first wire, the second wire, and the separator are folded so that they can expand in accordance with the expansion of the stent when the stent is expanded. (28) The stent according to (25) above, wherein the first wire, the second wire, and the separator are folded in accordance with the expansion of the stent when the stent is expanded.(29) The stent according to any one of (21) to (28) above, wherein the negative electrode and the positive electrode are each arranged so as to contact the blood flow. (30) The stent according to any one of (21) to (29) above, wherein the battery is installed on the luminal side of the stent. (31) The stent according to any one of (21) to (29) above, wherein the battery is installed on the luminal wall side of the stent. (32) The stent according to (30) above, wherein the battery comprises, from the luminal side, a positive electrode, a separator, and a negative electrode. (33) The stent according to (30) above, wherein the battery comprises, from the luminal side, a negative electrode, a separator, and a positive electrode, in this order. (34) The stent according to (30) above, which is a vascular stent, does not block blood flow, and further has a gap that allows blood flow to pass through in the vicinity of the stent and the battery (e.g., the contact portion). (35) The stent according to (31) above, which is a vascular stent, does not block blood flow, and further has gaps that allow blood flow to pass through in the vicinity of the stent and the battery (for example, contact areas). (36) The stent according to (32) above, which is a vascular stent, which does not block blood flow, and further has gaps that allow blood flow to pass through in the vicinity of the stent and the battery (for example, contact areas). (37) The stent according to (33) above, which is a vascular stent, which does not block blood flow, and further has gaps that allow blood flow to pass through in the vicinity of the stent and the battery (for example, contact areas). (38) The stent according to any of (30) to (37) above, which is a vascular stent, which does not block blood flow, and the gaps are formed at least by depressions formed on the surface of the stent. (39) The stent according to any one of (30) to (37) above, which is a vascular stent, does not block blood flow, and the gaps are formed at least by depressions formed on the surface of the battery. (40) The stent according to any one of (30) to (37) above, which is a vascular stent, does not block blood flow, and the gaps are formed at least by depressions formed on the surface of the stent and depressions formed on the surface of the battery.

[0008] (51) The stent according to any one of the above, wherein the positive electrode is formed on one part of the stent and the negative electrode is formed on another part. (52) The stent according to any one of the above, wherein the positive electrode is formed on one end side of the stent and the negative electrode is formed on the other end side of the stent. (53) The stent according to any one of the above, wherein the positive electrode and the negative electrode do not contact each other and are formed on the stent in a double spiral shape. (54) The stent according to any one of the above, wherein the positive electrode and the negative electrode do not contact each other directly or indirectly. (55) The stent according to any one of the above, wherein the area ratio of the positive electrode to the negative electrode is about 2:about 1 to about 1:about 2, preferably about 1:about 1.

[0009] (61) The stent according to (25) above, wherein the wire forms a nonwoven fabric. (62) The stent according to (61) above, wherein the nonwoven fabric is (i) folded or (ii) has slits so that it can expand in accordance with the expansion of the stent when the stent is expanded.

[0010] (101) The stent according to any one of (21) to (62), wherein the hydrogel is permeable to water and sugar (e.g., glucose). (102) The stent according to (101), wherein the hydrogel is permeable to water and glucose but (i) is impermeable to immune cells, or (ii) has a barrier impermeable to immune cells, thereby preventing immune cells from accessing the interior of the hydrogel or oxidase (e.g., glucose oxidase). (103) The stent according to (101) or (102), wherein the hydrogel comprises a polymer including a first monomer unit and a second monomer unit, wherein the first monomer unit comprises a zwitterionic group and the second monomer unit comprises a group modified by the oxidase (e.g., glucose oxidase). (104) The stent according to (103), wherein the zwitterionic group comprises 2-methacryloyloxyethyl phosphorylcholine. (105) The stent according to any one of (101) to (104) above, wherein the negative electrode is a carbon electrode. (106) A material for use in producing the stent according to any one of (101) to (105) above, comprising a stent having a hydrogel and a negative electrode, wherein the hydrogel is bound to the stent and has one or more reactive groups selected from the group consisting of an active ester group, a maleimide group, and an azide group, and the hydrogel and the negative electrode are linked so as to be able to accept electrons generated by an enzyme in the hydrogel. (107) The material according to (106) above, having a barrier impermeable to immune cells, preventing immune cells from accessing the interior of the hydrogel or oxidative enzymes (e.g., glycoxidase). (108) The material according to (106) or (107) above, wherein the reactive group comprises an N-hydroxysuccinimide group.(109) A biobattery including a hydrogel, a negative electrode, and a positive electrode, the biobattery being introduced into blood, the hydrogel carrying an oxidase (e.g., glucose oxidase) and an electron transfer mediator compound, and (i) being impermeable to immune cells, or (ii) having a barrier impermeable to immune cells, thereby preventing immune cells from accessing the interior of the hydrogel or the oxidase (e.g., glucose oxidase) or the electron transfer mediator compound, the hydrogel and the negative electrode being linked to be able to accept electrons generated by the enzyme in the hydrogel, and configured so that electrons are supplied to the negative electrode (and preferably so that a voltage is generated between the negative electrode and the positive electrode) when glucose in blood comes into contact with the oxidase (e.g., glucose oxidase). (1010) An electronic device comprising the biobattery according to (109), the electronic device being electrically connected to the negative electrode and the positive electrode of the biobattery and being able to receive power from the biobattery. (1011) A stent equipped with the biobattery described in (109) above or the electronic device described in claim 10, wherein the biobattery or electronic device can be placed within a tubular structure.

[0011] A conceptual diagram showing an example of a negative electrode for a biobattery. The hydrogel stably supports a glycoxidase enzyme, oxidizing glucose to generate electrons (e -) and transfer it to the negative electrode. Electrons can be supplied to an electronic device connected to the negative electrode to drive the electronic device. This is an electrical wiring diagram of a system including the battery and electronic device shown in FIG. 1. In the present disclosure, the entire system can be present in body fluid. A cross-sectional view of a stent showing an example of the arrangement of a negative electrode, a positive electrode, and a stent in a stent of the present disclosure. Side A and Side B are the lumen side and the vessel wall side, or the vessel wall side and the lumen side, respectively, and this also applies to FIGS. 4 to 6 below. A cross-sectional view of a stent showing an example of the arrangement of a negative electrode, a positive electrode, and a stent in a stent of the present disclosure ... FIG. 1 is a cross-sectional view of a stent showing an example of the arrangement of negative electrodes, positive electrodes, and the stent in a stent of the present disclosure. FIG. 2 is a cross-sectional view of a stent showing an example of the arrangement of negative electrodes, positive electrodes, and the stent in a stent of the present disclosure. FIG. 3 is a cross-sectional view of a stent showing an example of the arrangement of negative electrodes, positive electrodes, and the stent in a stent of the present disclosure. FIG. 4 shows an example of the arrangement of negative electrodes and positive electrodes in a stent of the present disclosure. The figure is drawn to illustrate the relative positional relationship between the stent and the electrodes, and the stent is drawn as a cylindrical shape in the figure, with the mesh structure of the stent's skeleton being partially illustrated but omitted in other parts. FIG. 5 shows an example of the arrangement of negative electrodes and positive electrodes in a stent of the present disclosure. The figure is drawn to illustrate the relative positional relationship between the stent and the electrodes, and the stent is drawn as a cylindrical shape in the figure, with the mesh structure of the stent's skeleton being partially illustrated but omitted in other parts. FIG. 6 shows an example of the arrangement of negative electrodes and positive electrodes in a stent of the present disclosure. The figure is drawn to illustrate the relative positional relationship between the stent and the electrodes, and the stent is drawn as a cylindrical shape in the figure, and the mesh structure of the stent's framework is partially illustrated but omitted in other parts. An example of the structure of an expandable battery in a stent of the present disclosure is shown.1 shows an example of a structure of an expandable battery in a stent of the present disclosure. The figure is drawn to illustrate the relative positional relationship between the stent and the electrodes, with the stent drawn as a cylinder, and the mesh structure of the stent's skeleton is partially illustrated but omitted in other parts. 1 shows an example of a structure of an expandable battery in a stent of the present disclosure. The figure is drawn to illustrate the relative positional relationship between the stent and the electrodes, with the stent drawn as a cylinder, and the mesh structure of the stent's skeleton is partially illustrated but omitted in other parts. 1 shows an example of a folding method for a battery in a stent of the present disclosure. The surfaces may be rigid parts of the battery, and the locations of the mountain fold lines and valley fold lines may be plastic hinges. 1 shows an example of a folding method for a battery in a stent of the present disclosure. The surfaces may be rigid parts of the battery, and the locations of the mountain fold lines and valley fold lines may be plastic hinges. 1 shows an example of a folding method for a battery in a stent of the present disclosure. The surfaces may be rigid parts of the battery, and the locations of the mountain fold lines and valley fold lines may be plastic hinges.

[0012] <Definition of Terms> As used herein, a "stent" refers to a medical device used to expand the lumen of tubular tissues in the body (mainly blood vessels, lymphatic vessels, and other vessels; digestive tracts such as the esophagus, duodenum, small intestine, and large intestine; pancreatic duct, bile duct, ureter, and other vessels) to alleviate strictures or blockages. A stent is typically a metallic tube with a mesh-like structure that can be expanded within the lumen. The sidewall does not necessarily have to be mesh-like and is not particularly limited as long as it can expand the lumen. For example, it may be spiral-shaped or coil-shaped. In either case, stents often have a structure with many gaps formed by a thin framework (especially a metallic framework) for the purposes of reducing the contact area with fluid flowing through the tubular tissue, providing the stent with flexibility and expandability, and preventing adhesion to tissue. Expansion can be achieved by inflating a balloon within the stent lumen, expanding the tubular wall from the lumen side toward the outside. The expanded stent is placed in the lumen and maintains the lumen in an expanded state. This ensures the flow of fluid through the tubular tissue. In this specification, the inside of a stent is referred to as the lumen side, and the outside is referred to as the vessel wall side. A stent that is implanted in a blood vessel is called a vascular stent, and can be preferably fabricated according to the present disclosure. The stent may be coated to impart biocompatibility, and the stent can be biocompatible. The vascular stent may be coated to prevent thrombus formation and / or restenosis. The vascular stent may also be coated to promote endothelialization while preventing thrombus formation. Such coatings are well known to those skilled in the art and can be implemented as appropriate. The stent of the present disclosure may be implanted in a normal portion of a blood vessel or in a stenotic portion. The stent may be equipped with a mechanism to prevent restenosis or endothelialization.

[0013] As used herein, a "hydrogel" refers to a polymer aggregate having a network structure and containing water. Hydrogels are considered to be biocompatible. Hydrogels are composed of highly hydrophilic polymers, and form a network structure by forming interactions between polymer molecules through interactions such as hydrogen bonds or ionic bonds. Hydrophilicity can be achieved by charged groups modifying the polymer backbone or polymer side chains. Polymers may also be crosslinked. As used herein, the term "hydrogel" refers to a substance that absorbs water and becomes a hydrogel when placed in the body, even if it does not contain water, and a substance that absorbs water when placed in the body. For example, a dried product obtained by drying a hydrogel is also referred to as a hydrogel.

[0014] As used herein, a "polymer" refers to a polymer of one or more monomer units. A polymer consisting of one monomer unit is called a homopolymer. A polymer containing two or more monomer units is called a copolymer. Copolymers include block copolymers, graft copolymers, regular copolymers, alternating copolymers, crosslinked copolymers, and statistical copolymers. A block copolymer contains multiple blocks, each consisting of a single monomer unit. A graft copolymer has a structure in which one polymer branches off from another. A regular copolymer has a regular sequence of two or more monomer units. An alternating copolymer has a structure in which two monomer units are arranged alternately. A statistical copolymer is a copolymer without any particular sequence regularity, for example, formed by polymerizing a mixture of two or more monomer units. A polymer typically consists of a backbone and side chains that impart chemical properties to the backbone.

[0015] As used herein, "sugar oxidase" refers to an enzyme that oxidizes sugars that it comes into contact with in vivo, and releases electrons (e -). Sugar oxidases include sugar oxidases and sugar dehydrogenases. Sugar oxidases include, for example, glucose oxidase (EC 1.1.3.4). Sugar dehydrogenases include, for example, glucose dehydrogenase (EC 1.1.99.10), glucose dehydrogenase (EC 1.1.5.9), and glucose-1-dehydrogenase (EC 1.1.1.47). Sugar oxidases are used, for example, as biosensors for detecting glucose. Among oxidases, sugar oxidases are particularly preferably used.

[0016] As used herein, "contact" means that two different things come into contact, directly or indirectly. Direct contact means that there is no intervening element between them, while indirect contact means that there is an intervening element between them. Electrical contact, whether direct or indirect, means that two different things are arranged so that electrons flow bidirectionally or unidirectionally between the two different things in an in vivo environment. Note that contact between an enzyme and its substrate means that the substrate comes into contact so that it reacts with the enzyme. For example, contact between glucose and a glycosidase means that glucose comes into contact so that it reacts with the glycosidase.

[0017] As used herein, "bonding" means that two or more different objects are fixed to one another. The fixing can be achieved by adhesion. The bonding can be achieved by contacting two or more members that are in direct contact with each other, with or without an adhesive layer. Alternatively, the bonding can be achieved by fixing two or more members so that they are compressed from the outside (for example, by using a cable tie). The two or more members that are pressed together may or may not be in direct contact with each other in the fixed state (for example, they may be fixed with another member interposed between them). As used herein, "fixing" includes fixing two objects so that they do not substantially move relative to each other.

[0018] <Stent of the Present Disclosure> According to the present disclosure, there is provided a stent having a battery including a negative electrode and a positive electrode. The battery may be of any type and structure as long as it can be operated in a living body.

[0019] In one embodiment, the battery is a biobattery, and the negative electrode may include a hydrogel carrying a sugar oxidase. That is, the present disclosure provides a stent having a hydrogel, a negative electrode, and a positive electrode. By carrying a sugar oxidase or the like, such a stent decomposes sugars in vivo, extracts electrons, and supplies the electrons to the negative electrode. The electrons can be provided in a usable form from the negative electrode. The oxidase may be carried by binding (particularly covalently) to the gel, or by being trapped in the pores of the network structure of the gel without being bound to the gel (physical encapsulation). Covalent binding to the gel can be achieved, for example, by a crosslinker (e.g., 1,4-butanediol diglycidyl ether (BDDE)). Physical encapsulation can be achieved, for example, by contacting a gel before swelling (e.g., a dry gel) with an enzyme-containing aqueous solution. These methods allow the enzyme to be carried within the gel. The amount of the supported enzyme can be quantified, for example, by a protein quantification assay (eg, the bicinchoninic acid method (BCA method)).

[0020] Stents are typically used to dilate stenotic areas (lesions), but in the present disclosure, they can also be used to place batteries not only in lesions but also in tubes other than lesions, such as blood vessels (e.g., normal blood vessels). The stent is placed in the blood vessel to maintain blood flow. The biobattery has a negative electrode and a positive electrode so that both electrodes are in contact with the blood flow. For this purpose, the electrodes may be provided on the lumen side, or if not on the lumen side, a space or flow path through which blood can pass may be provided so that the blood flow comes into contact with the electrodes.

[0021] In some embodiments of the stent of the present disclosure, the hydrogel is bonded to an electrode, and may be bonded to the stent with or without an electrode. The bond between the hydrogel and the electrode allows the enzyme in the hydrogel to transfer electrons extracted therefrom to the electrode, and the bond between the hydrogel and the stent allows the hydrogel to remain in place after the stent is implanted. The hydrogel is preferably bonded to the surface of the stent. For example, to impart biocompatibility to the stent, the entire stent may be covered with the hydrogel. However, only a portion of the stent may be covered with the hydrogel. In some preferred embodiments, the hydrogel may be resistant to biomolecular adhesion (biofouling).

[0022] The hydrogel does not necessarily need to be adhered to the stent; the bonding method is not critical as long as it is placed in the same location as the stent. For example, it may cover the stent or a portion thereof without bonding. Here, "coating" refers to covering the entire stent or a portion thereof. The coating preferably forms a physical barrier. Alternatively, the hydrogel may be bonded to the stent via an adhesive layer. The adhesive layer may include, but is not limited to, a biocompatible adhesive such as cyanoacrylate, epoxy resin, urethane, acrylic, silicone, gelatin, thermoplastic fluoropolymer, or bioadhesive (e.g., one derived from a natural product, e.g., fibrin glue). When placed in a blood vessel, the biobattery preferably remains bonded to the stent for at least one week, at least two weeks, at least three weeks, at least four weeks, at least two months, at least three months, or at least four months (e.g., one month to one year, or one month to six months).

[0023] The hydrogel may be, for example, a cross-linked water-soluble polymer, and examples thereof include extracellular matrix-based hydrogels (e.g., gels containing hyaluronic acid (e.g., HyStem (registered trademark) hydrogel), gels containing laminin or collagen, and gels containing ECM (e.g., ECM gel)), gels containing alginic acid, gels containing polyacrylamide, gels containing polyalkylene glycol (e.g., gels containing polyethylene glycol (PEG gel)), gels containing silicone, gels containing polysaccharides such as gels containing dextran, and gels containing polyvinyl alcohol, as well as any of the above gels having chemical modifications. An example of a hydrogel containing polyvinyl alcohol and dextran is TrueGel3D (registered trademark) polymer. An example of a gel containing polysaccharides is Hydrogel For example, in order to enhance its biocompatibility, the hydrogel may contain a polymer having a hydrophilic group (e.g., an uncharged hydrophilic polymer block, such as a polyalkylene glycol, particularly polyethylene glycol (PEG)), preferably a group containing a zwitterionic group, as a side chain. Examples of the zwitterionic group include, but are not limited to, a phosphorylcholine group, a carboxybetaine group, a sulfobetaine group, a dimethylamine oxide group, and a dimethylsulfoniopropionate group. Examples of the polymer backbone include, but are not limited to, chitosan and Examples of suitable zwitterionic groups include polymers of amino sugars such as chitin, polymers of amino acids such as polylysine, polyglutamic acid, polyarginine, and polyornithine, polysaccharides such as dextran and cellulose, polyvinyls, polyacetylenes, polyesters, polyamides, polyethers, polyethylenes, polypropylenes, polyethylene terephthalates, polydimethylsiloxanes, polyolefins, polyurethanes, polycarbonates, polyacrylates, and polymethacrylates. In a preferred embodiment, the group containing the zwitterionic group comprises an oxy-lower alkylphosphorylcholine group. The lower alkyl is selected from the group consisting of C 1-6 alkyl, for example, C 2-3The lower alkyl may be an alkyl (e.g., a C2 alkyl or a C3 alkyl). The lower alkyl may be a linear alkyl. The hydrophilic group is not particularly limited, but may be, for example, a polyalkylene glycol, preferably polyethylene glycol. In one embodiment, the polymer may be a polymer (MPC polymer) containing 2-methacryloyloxyethyl phosphorylcholine (MPC) as a monomer unit. MPC polymers are biocompatible and blood compatible, making them a material with excellent compatibility for the stents of the present disclosure. Hydrogels are formed by crosslinked polymers and typically include polymers with chemical crosslinks. However, MPC polymers can form physical crosslinks to form hydrogels without chemical crosslinks (however, this does not exclude MPC polymers with chemical crosslinks).

[0024] In a preferred embodiment, the hydrogel supports an enzyme (e.g., an oxidase), preferably a sugar oxidase. This allows electrons to be transferred from sugars in the body to the negative electrode. Hydrogels are rich in water, which is advantageous for maintaining enzyme activity. Examples of sugar oxidases include, but are not limited to, glucose oxidase, hexose oxidase, pentose oxidase, fructose oxidase, galactose oxidase, and glucose dehydrogenase. The sugar oxidase may be contained in a side chain in the polymer. The linkage site between the polymer backbone and the sugar oxidase can be determined appropriately by those skilled in the art. The sugar oxidase may be, but is not limited to, any glucose oxidase prepared from Penicillium spp., Rhizopus punctatum, Saccharomyces cerevisiae, Aspergillus oryzae, or filamentous fungi. Examples of glucose oxidases include, but are not limited to, GOD-A, GOD-N, GOD-P, and GOD-S.

[0025] The permeability of a hydrogel can be adjusted by the degree of cross-linking, the type of monomer, the type of polymer, the molecular weight of the polymer, and the concentration and type of cross-linker. The hydrogel can preferably be permeable to water, oxygen, and sugars (especially glucose). This ensures access of glucose in body fluids to the glycoxidase contained within the hydrogel, increasing the amount of glycoxidase that can be added to the hydrogel and increasing the electron supply. If the hydrogel is impermeable to water or glucose, the hydrogel can have glycoxidase on its surface, accessible to water and glucose. In a preferred embodiment, the hydrogel is impermeable to cells, thereby preventing cell entry. When the glycoxidase is derived from a heterologous source, such as a bacterium, the hydrogel can be designed to be impermeable to immune cells in order to avoid an immune response against the glycoxidase and other components in the gel (e.g., electron transfer mediator compounds). In other words, in one embodiment, the hydrogel is impermeable to immune cells and can encapsulate glycoxidase and other immunogenic substances. Alternatively, a barrier (e.g., a homogeneous or heterogeneous hydrogel) that is permeable to water and glucose but impermeable to immune cells may be provided around the hydrogel. In one embodiment, the hydrogel does not include cell-adhesive functional groups (e.g., peptides). In one embodiment, the hydrogel has stealth properties. Stealth properties mean that the hydrogel is substantially resistant to recognition or binding by biological components such as cells and proteins. Immune cells range in size from approximately 7 μm to 25 μm, and methods for adjusting the mesh size of hydrogels to smaller sizes (e.g., 1 nm to several μm, 1 nm to 1 μm, 1 nm to 2 μm, 1 nm to 3 μm, 1 nm to 4 μm, 1 nm to 5 μm, or 1 nm to 6 μm) are well known. Therefore, one skilled in the art can construct a barrier for immune cells using conventional methods. When placing a biobattery in a blood vessel through which immune cells flow, it is preferable that the hydrogel or its surface be impermeable to immune cells for greater safety.For example, the biobattery may be attached to a stent and placed in the same location as the stent placed in a blood vessel. In this case, it is preferable that the hydrogel of the biobattery or its surface is not permeable to immune cells.

[0026] The polymer may contain a zwitterionic group. In this case, the polymer may have a group other than the zwitterionic group (e.g., an active ester group). In this case, the molar ratio of the zwitterionic group to the other group may preferably be 40:60 to 60:40, for example, 45:55 to 55:45. Examples of the active ester group include, but are not limited to, N-hydroxysuccinimide ester and methacrylic acid N-hydroxysuccinimide ester (MNHS). This group can be used to link functional molecules, such as electron transfer mediator compounds having amino groups. As a result, the polymer may have both a zwitterionic group and an electron transfer mediator compound.

[0027] Examples of groups other than zwitterionic groups on the polymer include hydrophobic groups. Introducing hydrophobic groups into the side chains of the polymer can reduce the water content of the hydrogel depending on the amount of hydrophobic groups introduced, thereby improving the gel strength.

[0028] The hydrogel may further have a hydrophobic group for the purpose of adsorbing the hydrogel to the surface of a material. Examples of the hydrophobic group include an alkylsilyloxysilyl group (e.g., -R 1 -Si(OSiR 2 3) 3) or alkylsilyl groups (e.g., -R 1 -Si(OR 3 ) 3) where each R 1 is independently C 1-5 It can be a straight chain or branched alkylene. 3 is C 1-4 It can be a straight chain or branched alkyl. 2 is C 1-5 It may be a straight chain or branched alkyl.

[0029] The hydrogel may further support an electron transfer mediator compound. The electron transfer mediator compound is a compound that promotes electron transfer within the hydrogel. The electron transfer mediator compound functions as a mediator for the glucose oxidation reaction catalyzed by a sugar oxidase. Examples of the electron transfer mediator compound include, but are not limited to, metal complexes containing at least one element selected from the group consisting of Os, Fe, Ru, Co, Cu, Ni, V, Mo, Cr, Mn, Pt, Rh, Pd, Mg, Ca, Sr, Ba, Ti, Ir, Zn, Cd, Hg, and W as a central metal, and pyrrole, pyrazole, imidazole, 1,2,3- or 1,2,4-triazole, tetrazole, 2,2'-biimidazole, or pyridine as a ligand to the central metal. , 2,2'-bithiophene, 2,2'-bipyridine, 2,2':6',2'-terpyridine, ethylenediamine, porphyrin, phthalocyanine, acetylacetone, quinolinol, ammonia, cyanide ion, triphenylphosphine oxide, metal complexes having a cyclopentadienyl ring and their derivatives, metallocenes (e.g., ferrocene, 1,1'-dimethylferrocene, ferrocene carboxylic acid, ferrocene derivatives such as ferrocene carboxaldehyde), osmium, ruthenium Bipyridine complexes formed from bipyridine and metals such as ammonium, cobalt, and nickel; metal complex ions such as ferricyanide ion, octacyanotungstate ion, and octacyanomolybdate ion; phenazine methosulfate, 1-methoxy-phenazine methosulfate; quinones (e.g., quinone, benzoquinone, naphthoquinone, anthraquinone, pyrroloquinoline quinone, 1,2-naphthoquinone-4-sulfonic acid, 2-hydroxy-1,4-naphthoquinone, dimethylbenzoquinone, hydroquinone, tetracyanoquinodimethane, etc.) and their derivatives, phenazine, phenothiazine, viologen, benzyl viologen, 2,6-dichlorophenol indophenol (DCIP), methylene blue, Meldola blue, toluidine blue, gallocyanine, thionine, dimethyldisulfonated thionine, new methylene blue, brilliant cresyl blue, resorufin, alizarin brilliant blue, safranine, and their derivatives.Similar to glycoxidase, the electron transfer mediator compound can be linked to the polymer in the hydrogel. Linkage can be achieved using methods well known to those skilled in the art. For example, linkage can be achieved by forming a covalent bond by reacting an amine-containing mediator compound in the side chain of the polymer with an active ester group. In one embodiment, the storage modulus of the hydrogel is greater than the loss modulus, i.e., the hydrogel exhibits solid-like properties.

[0030] A hydrogel may contain various groups as described above. These groups may be contained on the side chains of a single polymer, but they do not necessarily have to be contained on the side chains of a single polymer; they may be contained on the side chains of multiple polymers. For example, a hydrogel containing a set of multiple polymers, each containing a unique group, may contain multiple of the various groups described above. In some embodiments, all of the groups contained in the hydrogel are contained on the side chains of a single polymer. The effects of the invention can be expected in either case.

[0031] The negative electrode is connected to the hydrogel (e.g., the negative electrode is in direct contact with the hydrogel) so as to be able to accept electrons from the enzyme in the hydrogel and can receive electrons from the sugar oxidase. Examples of negative electrodes include, but are not limited to, carbon electrodes, gold electrodes, and titanium electrodes, as well as other biocompatible electrodes. Examples of carbon electrode materials include graphite, carbon fiber, carbon whiskers, carbon nanotubes, graphene, graphene nanoribbons, porous carbon, carbon pellets, carbon paper, carbon cloth, carbon felt, and activated carbon. In a preferred embodiment, the carbon electrode is a carbon nanotube electrode.

[0032] An example of the positional relationship between a battery (hereinafter referred to as a "biobattery") including a hydrogel, a negative electrode (hereinafter referred to as the "negative electrode of the biobattery"), and a positive electrode is described below. The hydrogel contains a sugar oxidase enzyme and must be able to contact sugars present in or flowing through the bloodstream on the luminal side. The positive electrode must also be in contact with the bloodstream.

[0033] In one embodiment, the invention can be configured so that side A in Figures 3 to 6 is the luminal side and side B is the vessel wall side. That is, in one embodiment of the stent 20, the negative electrode 11 of the biobattery is preferably located on the luminal side of the stent 12, and it is particularly preferable that it can come into contact with body fluids on the luminal side. For this reason, it is preferable that the hydrogel be located on the luminal side of the stent. If any layer is present on the luminal side of the hydrogel, the layer will be required to be permeable to water, oxygen, and sugars (especially glucose) or to have a structure (e.g., pores, gaps, etc.) that allows water, oxygen, and glucose to contact the hydrogel. As long as the hydrogel can come into contact with water and glucose primarily on the luminal side, it does not have to be present on the vessel wall side, but it can also be present on the luminal side. Because hydrogels are biocompatible, it is believed that there are advantages to having them on the luminal side as a stent coating or to covering the entire stent. The positive electrode 13 may be located on the vessel wall side of the stent 12 (see FIG. 3 ) or may be sandwiched between the negative electrode 11 of the biobattery and the stent 12 (see FIG. 4 ). The negative electrode 11 and positive electrode 13 of the biobattery can be physically separated to prevent an electrical short circuit. However, if the negative electrode 11 and positive electrode 13 of the biobattery are close to each other as shown in FIG. 4 , a separator 14 can be interposed between the negative electrode 11 and positive electrode 13 to prevent an electrical short circuit. Alternatively, the entire structure may be wrapped in hydrogel (see FIGS. 5 and 6 ). In this case, the negative electrode may be located on either the vessel wall side of the stent (see FIG. 5 ) or the lumen side (see FIG. 6 ). In FIGS. 3 to 6 , the hydrogel 1 is arranged to cover the entire stent 12, but this is not necessarily required; it may only cover a portion of the stent 12.

[0034] Furthermore, while the above examples in Figures 3 to 6 show the A side as the luminal side and the B side as the luminal side, the A side may be the luminal side and the B side as the luminal side. In this case, the positive electrode can be in contact with a large amount of blood flow, which can promote oxygen consumption at the positive electrode. In this case, it is desirable to ensure a blood flow path so that a certain amount of blood also contacts the hydrogel on the negative electrode. In one embodiment of the stent 20, the positive electrode 13 of the biobattery is preferably located on the luminal side of the stent 12, and it is particularly preferable that it can come into contact with body fluids on the luminal side. For this reason, it is preferable that the positive electrode be located on the luminal side of the stent. If any layer is present further luminally than the positive electrode 13, the layer will be required to be water- and oxygen-permeable or have a structure (e.g., pores, gaps, etc.) that allows water and oxygen to contact the positive electrode 13. The positive electrode 13 does not need to be located on the luminal side, or it may be located on the luminal side, as long as it can contact water and oxygen mainly on the luminal side. The negative electrode 11 may be located on the lumen wall side of the stent 12 (see FIG. 3 ), or may be sandwiched between the positive electrode 13 of the biobattery and the stent 12. When the negative electrode 11 and the positive electrode 13 of the biobattery are close to each other, a separator 14 may be interposed between the negative electrode 11 and the positive electrode 13 to prevent an electrical short circuit. Alternatively, the entire stent 12 may be wrapped in hydrogel (see FIGS. 5 and 6 ). In FIGS. 3 to 6 , the hydrogel 1 is arranged so as to cover the entire stent 12, but this is not necessarily required; it may only cover a portion of the stent 12. In FIGS. 3 to 6 , whether side A is the lumen side or the lumen wall side can be determined appropriately by a person skilled in the art depending on the output characteristics of the battery.

[0035] The separator 14 is used to prevent electrical short-circuiting between the negative electrode 11 and the positive electrode 13 of the biobattery. The separator 14 is typically a proton-permeable membrane, such as a semipermeable membrane (e.g., a dialysis membrane or separator membrane). The semipermeable membrane may be, for example, a microporous resin membrane, which separates the positive and negative electrodes while ensuring ionic conductivity. The resin may be, for example, a polyolefin resin such as polyethylene or polypropylene. A dialysis membrane may also be used as the semipermeable membrane; Nafion and cellulose membranes are known and preferably used. Nafion is a perfluorocarbon with a hydrophobic Teflon® skeleton composed of carbon and fluorine and perfluoroalkyl groups with sulfonic acid groups extending from the skeleton. If the negative electrode 11 and positive electrode 13 of the biobattery are insulated from each other, the separator 14 is not necessary. Separator 14 is also not required when there is no need to insulate negative electrode 11 and positive electrode 13 of the biobattery (for example, when negative electrode 11 and positive electrode 13 are located sufficiently far apart).

[0036] The attachment of the hydrogel, negative electrode, and stent can be direct or via an adhesive layer, which can be as defined above.

[0037] The stent further includes a positive electrode. Examples of the positive electrode include, but are not limited to, a platinum electrode, a gold electrode, and a carbon electrode. Examples of carbon electrode materials include, but are not limited to, carbon electrode materials capable of reducing oxygen to water, such as nitrogen-containing carbon electrode materials (see, for example, Surface and Vacuum, Vol. 66, No. 1, pp. 10-15, 2023). When an enzyme is used in the positive electrode, the enzyme can be supported on a hydrogel. In this case, the hydrogel, like the negative electrode, contains an electron transfer mediator compound, which can promote the transfer of electrons from the positive electrode to the enzyme. In the stent, the positive electrode can preferably be electrically connected to the negative electrode via an electronic device. Examples of electronic devices include, but are not limited to, stimulating electrodes (e.g., unipolar, bipolar, and multipolar electrodes capable of outputting current), light-emitting elements (e.g., LEDs), wireless communication elements (elements that perform wireless communication in accordance with wireless standards such as wireless LAN (e.g., Wi-Fi) or Bluetooth), blood glucose sensors, blood pressure sensors, vibration elements, and capacitors. Examples of electronic devices that can be used in vivo include, but are not limited to, pressure sensors, intraocular pressure sensors, hormone sensors, blood flow sensors, temperature sensors, artificial organs, neuro-neural interfaces, cardiac pacemakers, artificial joints, drug release devices, and electroencephalogram (EEG) sensors. Examples of electronic devices that can be used in vivo include, but are not limited to, barometric pressure sensors, water pressure meters, pH sensors, temperature sensors, magnetic sensors, wearable devices, and blood glucose meters. Stimulating electrodes can be connected to biofuel cells outside the body. Stimulating electrodes are typically made of, but are not limited to, tungsten, stainless steel, platinum, silver, etc. The area of ​​a stimulating electrode other than the stimulating portion is typically covered with an insulator (e.g., enamel, parylene, vinyl, etc.). Electrical connection can be achieved by wiring, such as platinum wire, gold wire, carbon-based materials, silver, conductive polymers, and other biocompatible conductive materials. Thus, the stents of the present disclosure can include platinum wire for electrical connection. The electronic device can include one or more electronic devices, for example, a combination of electronic devices.

[0038] Blood glucose levels fluctuate throughout the day. That is, blood glucose levels decrease during fasting and increase after meals. Therefore, blood glucose monitoring can be beneficial. Therefore, the electronic device can include a blood glucose sensor and be configured to monitor blood glucose. When blood glucose levels become low, the output from the biobattery can decrease. To stabilize the output from the biobattery or to compensate for a decrease in output from the biobattery, the electronic device can include a capacitor. The capacitor can store electricity, and the stored electricity can be extracted from the capacitor. For example, the stored electricity can be extracted depending on the glucose concentration (if a blood glucose sensor is included). Alternatively, the electronic device may not include a blood glucose sensor. For example, the electronic device may have an output measuring device that measures the output from the biobattery, and the stored electricity can be extracted from the capacitor depending on the output measured by the output measuring device. The electronic device can include a further electronic device, and the power supply to the further electronic device can be stabilized using the mechanism described above.

[0039] The electronic device may also include one or more sensors, which may monitor changes in the body, and the values ​​measured by the one or more sensors may be stored in data storage, particularly non-volatile memory.

[0040] The stent may also include an integrated circuit (IC) for controlling each of the electronic devices contained therein.

[0041] The electronic device may further include a transmitting device, a receiving device, or a transceiver device (e.g., a transmitting coil, a receiving coil, or a transceiver coil). The transmitting device can transmit data stored in the data storage to the outside. The transmitting device converts data to be transmitted into an electric current and passes the electric current through, for example, a coil. When the electric current flows through the coil, an electric field is generated, which induces an electric current in another coil placed nearby, and data can be extracted from the induced electric current. For example, but not limited to, the other coil can be provided on a catheter, and data transmission and reception can be performed between another coil on the catheter introduced near the stent and the coil on the stent. Data transmission and reception technologies that can be used include, but are not limited to, radio frequency identification (RFID), near field communication (NFC), magnetic induction, and the like.

[0042] The electronic device, the biobattery, or the connection portion of the electronic device may be coated to impart biocompatibility, may have biocompatibility, may be coated to prevent thrombus formation and / or restenosis, or may be coated to promote endothelialization while preventing thrombus formation. Such coatings are well known to those skilled in the art and can be implemented as appropriate (see, for example, JP6407513B2 and JP6560560B).

[0043] The relative positions of the positive and negative electrodes of the biobattery and the electronic device on the stent can be freely determined. For example, and not by way of limitation, FIG. 12 shows a stent 100a equipped with a spirally configured positive electrode 105a and a spirally configured negative electrode 104a. The hydrogel may be disposed on the negative electrode 104a, or the hydrogel itself may be configured to cover the entire stent, as shown in FIGS. 3 and 4. In one embodiment, the negative electrode 104a may be disposed on the luminal side of the stent so as to present the hydrogel on the luminal side, while the positive electrode 105a may be disposed so as not to contact them. For example, both the negative electrode and the hydrogel may be spirally disposed on the luminal side of the stent, and the positive electrode may be spirally disposed on the luminal side of the stent so as not to contact them. In one preferred embodiment, the negative electrode and the positive electrode are each spirally configured, but they may be combined to form a double spiral. These electrodes may be formed along (or on) the stent framework, or in portions of the stent where the framework is not present. This maximizes the contact area of ​​the negative and / or positive electrodes with the body fluid flowing through the lumen. The electronic device 101 is connected to the negative electrode 104a and the positive electrode 105a via wires 102 and 103, respectively, and is electrically powered by a biobattery. The electronic device 101 may be connected to either the negative electrode 104a or the positive electrode 105a at either the terminal or non-terminal (central) locations. When the electrodes are configured in a spiral shape, a magnetic field is generated within the stent, which can be utilized appropriately.

[0044] The shape and positional relationship of the positive and negative electrodes of the biobattery and the electronic device can be freely determined. For example, without limitation, FIG. 13 shows a stent 100b having a positive electrode 105b on one end and a negative electrode 104b on the other end. In FIG. 13, the respective electrodes are provided in sheet form on the right and left halves of the tubular structure. Also, for example, FIG. 14 shows a stent 100c having a positive electrode 105c on one portion of the stent and a negative electrode 104c on the other portion. The positive electrode 105c and the negative electrode 104c are provided in positions where they do not overlap each other. In FIG. 14, the respective electrodes are provided in sheet form on the upper and lower halves of the tubular structure. In either case, the negative and positive electrodes can be exposed to the bloodstream, which is considered to be a suitable arrangement for a biobattery. The positive and negative electrodes may each be in the form of a thin layer or a wire. That is, the battery may include a wire-shaped positive electrode (also referred to as a positive electrode wire) and a wire-shaped negative electrode (also referred to as a negative electrode wire). Each of the wire-shaped positive and negative electrodes may include at least a wire-shaped portion, for example, consisting of a wire-shaped portion. Part or all of the wire may be flexible (plastic) to bending. In general, increasing the surface area of ​​the electrode improves power generation. Layering the electrode can increase the contact area with blood flow, for example. Providing an uneven surface on the electrode surface can further increase the surface area. Examples of such uneven shapes include, but are not limited to, a pin-frog shape. An electrode with a pin-frog shape has numerous needle-shaped electrodes on its surface. When the electrode is wire-shaped, increasing the electrode length can increase the contact area with blood flow. When the electrode is wire-shaped, the electrodes may be formed into a sheet shape by intertwining them, like a nonwoven fabric. When the electrode is wire-shaped, the positive electrode wire and negative electrode wire may be bundled together in a wire-like shape via a separator. When the electrodes are wire-shaped, the electrode assembly may further include a layer that encases the bundled electrodes and separator. Such a layer that encases the bundle prevents electrical shorts between the wire bundles and is permeable to water, sugars, ions, etc.Examples of such layers include semipermeable membranes (separator membranes and dialysis membranes), etc. When a positive electrode and a negative electrode are close to each other, a separator is interposed between the electrodes to prevent the positive electrode and the negative electrode from coming into direct contact with each other. However, when the positive electrode and the negative electrode are placed apart so as not to come into direct contact with each other or to conduct electricity directly, a separator is not necessary.

[0045] The positive and negative electrodes of a biobattery typically have the same area. The ratio of the positive and negative electrodes of a biobattery is typically about 1:1, but can be adjusted appropriately by those skilled in the art. The term "about" may include a range of ±25% of the specified numerical value.

[0046] The stent may be separate from the negative or positive electrode, or the negative and / or positive electrode may function as a stent. That is, in some embodiments, the stent may be composed of a negative and / or positive electrode. For example, the stent of the present disclosure may comprise (a) (i) a negative electrode that functions as a stent and (ii) a hydrogel, or (b) (iii) a positive electrode that functions as a stent, (iv) a hydrogel, and (v) a negative electrode. Thus, a stent having a negative electrode includes an embodiment having a negative electrode separate from the stent and a stent that itself functions as a negative electrode. Similarly, a stent having a positive electrode includes an embodiment having a positive electrode separate from the stent and a stent that itself functions as a positive electrode. Such embodiments are also encompassed by a stent equipped with a battery including a positive electrode and a negative electrode. For example, a stent whose surface functions as an electrode may be made of a material with excellent conductivity (e.g., a conductive metal material or a conductive carbon material), or the stent surface may be coated with a material with excellent conductivity (e.g., a conductive metal material). The conductive metal coating is not particularly limited, but may be achieved by, for example, electroplating. A conductive metal coating is advantageous in that the stent itself does not need to be conductive. A stent made of a carbon material is preferred in terms of the mechanical strength and conductivity of the stent.

[0047] A hydrogel can be obtained by polymerizing a mixture containing each of the monomer units. A person skilled in the art can appropriately carry out the polymerization method using conventional methods. Well-known methods for synthesizing copolymers include radical polymerization, solution polymerization, emulsion polymerization, and suspension polymerization. Radical polymerization uses a polymerization initiator. Any substance that generates radicals at the reaction temperature can serve as a polymerization initiator. Examples of such polymerization initiators include 2,2-azobis(2-amidinopropyl)dihydrochloride, 4,4-azobis(4-cyanovaleric acid), 2,2-azobis(2-(5-methyl-2-imidazolin-2-yl)propane)dihydrochloride, 2,2-azobisisobutylamide dihydrate, 2,2-azobisisobutyronitrile, ammonium persulfate, potassium persulfate, benzoyl peroxide, succinic acid peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butylperoxypivalate, t-butylperoxydiisobutyrate, lauroyl peroxide, azobisisobutyronitrile, 2,2-azobis(2,4-dimethylvaleronitrile), t-butylperoxyneodecanoate, benzoin methyl ether, and benzophenone. Preferably, 2,2-azobisisobutyronitrile (AIBN) is used.

[0048] For example, polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) and methacrylic acid N-hydroxysuccinimide ester (MNHS) as monomer units results in a polymethacrylate copolymer (e.g., a statistical copolymer) having phosphorylcholine and NHS groups in its side chains. The molar ratio of the monomers can be, for example, 1:1. AIBN can be used as the polymerization initiator. The reaction time can be, for example, 24 hours, and the reaction temperature can be, for example, 59°C. Chloroform can be used as the solvent. Various compounds can be linked to the NHS group of the resulting polymer to functionalize the polymer. For example, an electron transfer mediator compound (e.g., aminoferrocene) can be linked. Triethylamine can be used as a catalyst. The reaction can be carried out at room temperature overnight. Glycoxidase can be linked to the resulting polymer or to another polymethacrylate copolymer having phosphorylcholine and NHS groups in its side chains. When glycoxidase is linked to another copolymer, it can be mixed with a copolymer linked to an electron transfer mediator compound to obtain a hydrogel containing glycoxidase and an electron transfer mediator compound. The glycoxidase and polymer may be linked in the presence of a crosslinking agent. 1,4-butanediol diglycidyl ether (BDDE) can be used as the crosslinking agent.

[0049] Linking of the polymer backbone to groups such as glycoxidase can be performed using bioorthogonal chemistry, if necessary. Bioorthogonal chemistry is a chemical reaction that can occur in the internal environment of a biological system (e.g., under physiological conditions) and minimizes the impact on biomolecules. Examples of bioorthogonal chemistry include the reaction between an azide group and an alkyne group (click chemistry). Reactions between an amino group and a succinimidyl group and between a thiol group and a maleimide group can also be used for the above linkage. For example, in the reaction between an amino group and a succinimidyl group, an N-hydroxyester (NHS ester) can react with the amino group at pH 7-9 to link two different compounds via a peptide bond. A polymer having an activated ester, such as an NHS ester, in its side chain can be linked to the side chain or terminal amino group of a glycoxidase. In the reaction between a thiol group and a maleimide group (Michael addition reaction), for example, a maleimide can react with a cysteine ​​group at approximately pH 7 to link two different compounds. In the reaction between an azide group and an alkyne group, a polymer having a maleimide group in its side chain can be linked to the thiol group in the side chain of cysteine ​​in a glycoxidase via 1,2,3-triazole. Therefore, the linking site after synthesis can have a linking structure resulting from these reactions. Alternatively, the glycoxidase may be linked to the hydrogel via a crosslinking agent. For example, the crosslinking agents listed above can be used, and preferably, 1,4-butanediol diglycidyl ether (BDDE) may be used to link the glycoxidase to the hydrogel.

[0050] The resulting hydrogel can be attached to electrodes and can be attached to a stent with or without electrodes.

[0051] The negative and positive electrodes can each be bonded to the stent using an adhesive, including, but not limited to, cyanoacrylate, epoxy, urethane, acrylic, silicone, gelatin, thermoplastic fluoropolymer, and bioadhesives (e.g., those derived from natural sources, such as fibrin glue).

[0052] The stent may be packaged in a dry state. In this form of stent, water may be absorbed to form a hydrogel before or after placement. The stent may expand by the force of the hydrogel that absorbs water and swells in the lumen, or it may expand spontaneously, or it may be expanded with a balloon. The stent may be packaged in a state where the hydrogel is saturated with water. The stent is sterilized in the package.

[0053] The stent is contracted before placement and expands when placed in a blood vessel. The battery or biobattery attached to the stent preferably expands in accordance with this expansion. Therefore, each component of the battery and biobattery may be made of a flexible material, or may be made of a rigid portion and a plastic hinge portion. Alternatively, when each component of the battery and biobattery is formed on the framework of the stent, the entire battery and biobattery may be made of a rigid portion, or part or all of the battery and biobattery may be made of a flexible material.

[0054] The connection between the battery and biobattery and the stent can be carried out as appropriate. The battery and biobattery are fixed to the stent so as not to interfere with the process of deploying the stent in the lumen by expanding the stent and maintaining the deployed state. The battery and biobattery are placed on the stent so as not to significantly impede flow within the lumen of the stent. Significant interference means interference to the extent that placing the stent in the lumen for a long period of time (e.g., one week or more, two weeks or more, three weeks or more, or one month or more) would have unacceptable adverse effects on the living body. Furthermore, the battery and biobattery are fixed to the stent so as not to detach unintentionally from the stent.

[0055] For example, the biobattery may have a shape formed by connecting multiple strips, and the strip-shaped batteries may be connected at one end or the other end. The strip-shaped batteries may be connected alternately at one end and the other end, as shown in FIG. 15 . This structure can also be considered a structure with notches. The strips may be electrically connected to each other, either by wire or by direct connection between the batteries (e.g., FIG. 15 ). While FIG. 15 illustrates a case in which the biobattery is installed on the luminal side of the stent, the biobattery may also be installed on the vascular wall side of the stent. In another example, the biobattery may be formed to fit the size of the expanded stent and, when the stent is contracted, may be folded to fit the shape of the contracted stent, as shown in FIG. 16 . While FIG. 16 illustrates a case in which the biobattery is installed on the vascular wall side of the stent, the biobattery may also be folded when installed on the luminal side of the stent. It is desirable that this or a similar mechanism allows the biobattery to flexibly contract and expand in response to the contraction and expansion of the stent. If the biobattery is wire-type, it may be beneficial to fold it. Similarly, if the biobattery is nonwoven fabric-type, it may be beneficial to fold it or have slits. It may also be beneficial for the folded portion to be wire-type or a flexible electrode made of a flexible material. Here, "folded" means to be bent and stored compactly, regardless of whether there is a crease or not. While the positive and negative electrodes are not depicted in Figures 15 and 16, the electrodes can be positioned as appropriate.

[0056] The folding method is not particularly limited. Examples of folding methods include accordion folding, which alternates between one or more mountain folds and one or more valley folds. Figure 17 shows a structure in accordion folding, in which one mountain fold and one valley fold are alternately repeated. The mountain fold and the valley fold are parallel. An accordion fold can be constructed, for example, using rectangular rigid surfaces (e.g., biobatteries) and plastic hinges (e.g., plastic materials such as wire) connecting the rectangular surfaces. Another known folding method is the Miura folding (see Figure 18). As shown in Patent No. 5,152,624, for example, the Miura folding method involves arranging parallelogram-shaped rigid surfaces in a matrix, with each rigid surface connected by a plastic hinge. A Miura-folded object can be unfolded by pulling two vertices on a specific diagonal line apart, forming a single large surface. By utilizing this folding method and fixing the two vertices to the expanding framework of the stent, it is possible to form a surface that unfolds and expands as the stent expands. For example, by connecting multiple expanding surfaces to the stent surface, it is possible to accommodate the expansion of a cylindrical stent. For example, a torsional folding method can be used (see Figure 19). Although the positive and negative electrodes are not depicted in Figures 17 to 19, the electrodes can be positioned as appropriate.

[0057] When the biobattery is mounted on or along the framework of the stent, the biobattery will be able to flexibly contract and expand in response to the contraction and expansion of the stent, which may be beneficial if the battery has poor elasticity.

[0058] <Biobattery for Implantation in the Body> The present disclosure provides a biobattery for implantation in the body, particularly in a blood vessel. The biobattery includes a hydrogel, a negative electrode, and a positive electrode. The hydrogel supports a glucose oxidase. The hydrogel and the negative electrode are connected to each other so as to accept electrons generated by the enzyme in the hydrogel. The negative electrode and the positive electrode are electrically connected, and electrons are supplied to the negative electrode upon contact between glucose in the blood and the glucose oxidase. The hydrogel may further support an electron transfer mediator compound. The biobattery may have an electronic device between the positive electrode and the negative electrode. In one embodiment, the hydrogel, the glucose oxidase, the negative electrode, the electron transfer mediator compound, the positive electrode, and the electronic device may each be as defined above. The biobattery may be bonded to a stent, but the hydrogel does not necessarily need to be adhered to the stent. The bonding method is not important as long as the biobattery is implanted in the same location as the stent. The bonding may be performed, for example, using an adhesive. The biobattery can be attached to the stent, for example, via an adhesive layer. The hydrogel can be permeable to water and glucose but impermeable to immune cells. A barrier (e.g., a homogeneous or heterogeneous hydrogel) that is permeable to water and glucose but impermeable to immune cells may be provided around the hydrogel. The biobattery may be provided in a dry state. The biobattery may be provided in a sterile state. Electrical connection may be achieved, but is not limited to, with platinum wire.

[0059] In a preferred embodiment, the sugar-oxidase is glucose oxidase, the negative electrode is a carbon nanotube electrode, the positive electrode is a platinum electrode, and the electrical connection can be made with a platinum wire. In a preferred embodiment, the hydrogel further carries an electron transfer mediator compound (e.g., ferrocene, preferably aminoferrocene). In a preferred embodiment, the hydrogel comprises an MPC polymer, and the sugar-oxidase and the electron transfer mediator compound are covalently linked to the MPC polymer. This linking can be achieved, for example, by the method described in ACS Appl. Polym. Mater. 2021, 3, 2, 631-639.

[0060] The biobatteries of the present disclosure may generate voltages in blood of, for example, 10 mV to 1000 mV, e.g., 50 mV to 800 mV, 100 mV to 700 mV, or 200 mV to 600 mV. If higher voltages are required, multiple biobatteries could be connected in series.

[0061] Implantable biobatteries may require a continuous supply of energy for power generation. In such cases, placing a biobattery in the bloodstream is beneficial. Specifically, when placed in a blood vessel, glucose contained in the blood is constantly supplied to the electrodes of the biobattery by the bloodstream. The constant supply of sugar from the blood to the negative electrode generates electrons, while the constant supply of oxygen from the bloodstream to the positive electrode accepts electrons and produces water. This is expected to facilitate the reactions at both the positive and negative electrodes. Therefore, placing a biobattery in the bloodstream is considered preferable for achieving stable battery effects. Furthermore, once glucose consumption and supply reach equilibrium, the hydrogel can supply current at a constant voltage. To supply current at a constant voltage, it is desirable for the hydrogel to be placed in the bloodstream.

[0062] The present disclosure provides a stent having a connector for connecting a battery of the present disclosure. This stent can be used to connect a battery of the present disclosure to obtain a stent equipped with the battery of the present disclosure. The present disclosure provides a battery (e.g., a biobattery) having a connector for connecting to a stent having the connector. The present disclosure provides a combination including the battery and the stent. This combination can be used to manufacture a stent equipped with the battery of the present disclosure. The present disclosure also provides a stent equipped with a connector for connecting an electronic device and the battery of the present disclosure. A cassette containing a desired electronic device can be connected to the connector for connecting an electronic device as appropriate. By separately preparing cassettes containing various electronic devices or a combination thereof, the desired electronic device or combination thereof can be connected to the stent, thereby enhancing the functionality of the stent. The present disclosure provides an electronic device having a counterpart connector for connecting to the connector for this purpose.

[0063] 1: Negative electrode 2: Hydrogel carrying sugar oxidase 3: Positive electrode 4: Electronic device 5: Wiring 10: Biobattery 11: Negative electrode of biobattery 12: Stent 13: Positive electrode of biobattery 20: Embodiment 1 30: Embodiment 2 40: Embodiment 3 50: Embodiment 4 60: Embodiment 5 61: Composite of negative electrode and hydrogel 62: Positive electrode 63: Substrate 60a: Embodiment 5a 61a: Composite of negative electrode and hydrogel 61aa: Hydrogel 61ab: Negative electrode 62a: Positive electrode 63a: Substrate 60b: Embodiment 5b 61b: Composite of negative electrode and hydrogel 61ba: Hydrogel 61bb: Negative electrode 62b: Positive electrode 63b: Substrate 64b: Separator 60c: Embodiment 5c 61c: Composite of negative electrode and hydrogel 61ca: Hydrogel 61cb: Negative electrode 62c: Positive electrode 63c: Substrate 60d: Embodiment 5d 61d: Composite of negative electrode and hydrogel 61da: Hydrogel 61db: Negative electrode 62d: Positive electrode 63d: Substrate 100a: Example of a stent provided with an electronic device and a biobattery 100b: Example of a stent provided with an electronic device and a biobattery 100c: Example of a stent provided with an electronic device and a biobattery 101: Electronic device 102: Wiring connecting a negative electrode and an electronic device 103: Wiring connecting a positive electrode and an electronic device 104a: Example of a spirally configured negative electrode and a hydrogel bonded to the electrode 104b: Example of a spirally configured negative electrode and a hydrogel bonded to the electrode 104c: Example of a spirally configured negative electrode and a hydrogel bonded to the electrode 105a: Example of a positive electrode configured in a spiral shape 105b: Example of a positive electrode configured in a spiral shape 105c: Example of a positive electrode configured in a spiral shape 201: Mountain fold 202: Valley fold

Claims

1. A stent having a battery, the stent having an electronic device or an electronic device connection, the battery being expandable in accordance with the expansion of the stent, and the battery being capable of supplying current to the electronic device or the electronic device connection.

2. The stent of claim 1, wherein the battery is (i) folded or (ii) has slits so that it can expand in line with the expansion of the stent when the stent is expanded.

3. The stent of claim 1, wherein said battery comprises a wire-shaped negative electrode and a wire-shaped positive electrode.

4. A stent having a battery including a hydrogel, a negative electrode, and a positive electrode, wherein the negative electrode and the positive electrode are electrically connectable by a conductive wire via an electronic device or an electronic device connection part, and the electronic device connection part is equipped with an electronic device, wherein the negative electrode and the positive electrode are arranged so as not to be in direct contact with each other, and when the negative electrode and the positive electrode are close to each other, a separator may be provided between the negative electrode and the positive electrode, wherein the hydrogel is bonded to the stent and carries a glycoxidase, and the hydrogel and the negative electrode are connected so as to be able to accept electrons generated by the enzyme in the hydrogel, and when sugar (e.g., glucose) comes into contact with the glycoxidase, electrons are supplied to the negative electrode, and the battery can supply current to the electronic device or the electronic device connection part.

5. The stent of claim 4, wherein the battery is (i) folded or (ii) has slits so that it can expand in line with the expansion of the stent when the stent is expanded.

6. The stent of claim 4, comprising a first wire containing said hydrogel and said negative electrode and a second wire containing said positive electrode.

7. A stent according to any one of claims 4 to 6, wherein the negative electrode and the positive electrode are each positioned so as to be in contact with the blood flow.

8. The stent of any one of claims 4 to 7, wherein the hydrogel is permeable to water and glucose, but (i) is impermeable to immune cells, or (ii) has a barrier that is impermeable to immune cells, thereby preventing immune cells from accessing the interior of the hydrogel or glycoxidase.

9. The stent of any one of claims 4 to 8, wherein the hydrogel comprises a polymer comprising a first monomer unit and a second monomer unit, wherein the first monomer unit comprises a zwitterionic group and the second monomer unit comprises a group modified by the glycoxidase.

10. The stent of claim 9, wherein the zwitterionic group comprises 2-methacryloyloxyalkylphosphorylcholine.

11. The stent according to any one of claims 1 to 10, wherein at least one of the battery, the electronic device, and the electronic device connection portion is coated to impart biocompatibility.

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