Structure, structure manufacturing method, and structure fixing method

Abstract

This structure comprises: a flat plate-shaped laminate having a first xerogel layer and a second xerogel layer laminated on the first xerogel layer. The swelling / shrinkage stress is greater on the surface side on which the first xerogel layer is formed, compared to the surface side on which the second xerogel layer is formed.

Description

Structure, method for manufacturing the structure, and method for fixing the structure

[0001] The present invention relates to a structure, a method for manufacturing a structure, and a method for fixing a structure.

[0002] Cylindrical cuff electrodes are electrical stimulation electrodes designed to wrap around nerve bundles or muscle bundles. They are particularly widely used for vagus nerve stimulation and have been shown to alleviate symptoms of conditions such as Parkinson's disease, epileptic seizures, depression, and intractable pain. More recently, their regulatory effects on immunity and multi-organ interactions have attracted attention. As shown in Figure 1, the market for vagus nerve stimulation electrodes is projected to expand significantly to $1.6 billion by 2030. Currently used cuff electrodes consist of a metal electrode attached to a rolled-up silicone rubber, secured to the nerve with a string (Figure 2). There is considerable room for improvement in reducing the risk of nerve damage; an organic cuff electrode that gently wraps around and secures to the nerve is ideal, and research reports are continuing toward its realization.

[0003] For example, Lee et al. developed an electrode that wraps around a hollow silicone sheet substrate by adjusting the pressure within it (Non-Patent Literature 1). Horn et al. and Zhou et al. aimed for soft wrapping around nerves by using hydrogel instead of silicone rubber as the substrate (Non-Patent Literature 2, Non-Patent Literature 3). Hiendlmeier et al. proposed a mechanism in which hydrogel is used in the bent portion of the electrode to clamp the nerve through swelling deformation (Non-Patent Literature 4).

[0004] The present inventors previously fabricated the structure shown in Figure 3 by combining a curled hydrogel with electrodes made of the conductive polymer PEDOT (Non-Patent Documents 5 and 6). As described in Non-Patent Documents 5 and 6, this structure can be stably fixed to nerve bundles with a diameter of 2 mm or more. The hydrogel and electrode structure described in Non-Patent Documents 5 and 6 has a tubular structure in its initial state before being brought close to the nerve bundle, as shown in Figure 3(a). Therefore, the procedure for fixing this structure to a nerve bundle will be explained. First, the tubular structure is unfolded to an extended state (Figure 3(b)), the structure is brought close to the nerve bundle so that one end in the direction of extension of the structure is on the underside of the nerve bundle (Figure 3(c)), and the force that stretches the structure is removed so that the structure wraps around the nerve bundle (Figure 3(d)). Through this procedure, Non-Patent Documents 5 and 6 show that the structure can be fixed so that it wraps around the nerve bundle.

[0005] G. Lee et al., “Nature-inspired rollable electronics”, NPG Asia Mater, 11, 67 (2019).CC Horn et al., “Hydrogel-based electrodes for selective cervical vagus nerve stimulation”, J. Neural Eng. 18, 055008 (2021).Tao Zhou et al., “3D printable high-performance conducting polymer hydrogel for all-hydrogel bioelectronic Mater. 35, 2210206 (2023).D. Terutsuki et al., “Totally Organic Hydrogel-Based Self-Closing Cuff Elect rode for Vagus Nerve "Stimulation", Adv. Healthc. Mater., 11, 2201627 (2022). Tohoku University Press Release, October 6, 2022, "All-organic gel electrode that softly wraps around nerves - Realization of an MRI-compatible electrode useful for vagus nerve stimulation."

[0006] Thus, Non-Patent Documents 1 to 6 disclose electrodes having a curled structure, such as a cylindrical shape, in their initial state. Conventional structures require the curled electrode to be straightened before insertion under the nerve bundle, which has been pointed out by clinical experts as a serious problem that complicates surgical procedures. Furthermore, the environment in which the curled electrode is fixed is often surrounded by nerve bundles. In such an environment, in order to straighten the curled electrode without adversely affecting the surroundings, precise manipulation using a component inserted separately from the electrode is necessary.

[0007] This invention was made in view of the above circumstances, and aims to provide a structure that is initially in an extended state and can be deformed into a curled shape or the like by swelling, a method for manufacturing the structure, and a method for fixing the structure by deforming the extended state structure and wrapping it around biological tissue.

[0008] To solve the above problems, the present invention provides the following means.

[0009] [1] A structure according to one aspect of the present invention comprises a plate-shaped laminate having a first xerogel layer and a second xerogel layer laminated with the first xerogel layer, wherein the swelling and shrinkage stress is greater on the side where the first xerogel layer is formed than on the side where the second xerogel layer is formed.

[0010] [2] In the structure described in [1] above, the plate-shaped laminate may further include a conductive layer between the first xerogel layer and the second xerogel layer.

[0011] [3] In the structure described in [1] and [2] above, the first xerogel layer and the second xerogel layer may be in contact directly or via an adhesive layer in the plate-shaped laminate.

[0012] [4] The structures described in [1] to [3] above may have a conductive layer made of carbonized bamboo fiber having a weft-woven structure, with a thickness of 0.50 mm or less.

[0013] [5] In the structures described in [1] to [4] above, the shrinkage stress of the first xerogel layer upon contact with moisture may be 5 kPa or more and 20 kPa or less.

[0014] [6] The structures described in [1] to [5] above may include at least one polymer selected from the group consisting of polyvinyl alcohol, alginic acid, hyaluronic acid, chitosan, and gelatin in the first xerogel layer and the second xerogel layer.

[0015] [7] In the structures described in [1] to [6] above, the first xerogel layer is 5.0 × 10 -5 mol / cm 3 The above is 1.0 × 10 -3mol / cm 3 The following soluble components may be included.

[0016] [8] The structures described in [1] to [7] further comprise a drug, the drug being contained in the first xerogel layer or between the first xerogel layer and the second xerogel layer.

[0017] [9] A method for manufacturing a structure according to one aspect of the present invention comprises: a first xerogel layer formation step of drying a first gel in an extended state to form a first xerogel layer; a second xerogel layer preparation step of preparing a second xerogel layer having a smaller swelling and shrinkage stress than the first xerogel layer; and an integration step of integrating the first xerogel layer and the second xerogel layer in a laminated state.

[0018]

[10] The method for manufacturing the structure described in [9] further comprises an electrode preparation step of preparing electrodes containing conductive fibers, wherein in the integration step, the first xerogel layer and the second xerogel layer are integrated by a freeze-thaw method, with the laminate being formed by laminating the conductive fibers in between.

[0019]

[11] The manufacturing method of the structures described in [9] and

[10] above may include an integration step in which the first xerogel layer and the second xerogel layer are laminated directly or via an adhesive layer, and the laminate is integrated by a freeze-thaw method.

[0020]

[12] In the method for manufacturing the structures described in [9] to

[11] above, the first gel may be dried in the first xerogel layer formation step with an elongation ratio λ of 1.5 or more and 3.0 or less.

[0021]

[13] A method for fixing a structure according to one aspect of the present invention comprises a proximity step of bringing any of the structures described in [1] to [8] above close to a tubular biological tissue, and a wrapping step of swelling the structure and wrapping it around the biological tissue.

[0022]

[14] The method for fixing the structure in

[13] above may involve inserting the structure under the biological tissue in the proximity step, bringing the liquid medium into contact with the structure in the wrapping step, and completing the wrapping around the biological tissue within 30 seconds.

[0023] According to the present invention, it is possible to provide a structure that is initially in an extended state and can be deformed into a curled shape or the like by swelling, a method for manufacturing the structure, and a method for fixing the structure by deforming the extended structure and wrapping it around biological tissue.

[0024] This is a graph showing the market size of vagus nerve stimulating electrodes. This is a diagram showing the structure of a conventional cuff electrode. This is a diagram showing the procedure for fixing the cuff electrode to a nerve bundle as described in Non-Patent Documents 5 and 6. This is a cross-sectional view showing an example of the configuration of a structure according to one embodiment of the present invention. This is a diagram showing the configuration of a structure according to one embodiment of the present invention, where Figure 5(a) is a partially exploded perspective view of the structure, Figure 5(b) is a perspective view of the structure in its initial state, Figure 5(c) is a cross-sectional view of the structure deformed by swelling, and Figure 5(d) is a diagram showing the deformation process of the structure due to swelling. This is a diagram illustrating a conductive fiber membrane applicable to a structure according to one embodiment of the present invention, where Figure 6(a) shows a conductive carbon fiber membrane with a weft knit structure, and Figure 6(b) is a graph showing the electrical double-layer capacitance of the conductive carbon fiber membrane in Figure 6(a). This is a plan view showing the structure of a conductive fiber membrane with a plain weave structure. This is a flowchart illustrating a method for manufacturing a structure according to one embodiment of the present invention. Figure 9(a) is a plan view illustrating the first xerogel layer formation step in a method for manufacturing a structure according to one embodiment of the present invention. Figure 9(a) shows the prepared first gel, Figure 9(b) shows the process of applying strain to the first gel and drying it, and Figure 9(c) shows the formed first xerogel layer. Figure 10(a) is a schematic diagram showing an example of the configuration of a structure according to one embodiment of the present invention, and Figure 10(b) is a photograph of the structure. Figure 11(a) is a cross-sectional view illustrating a method for manufacturing and fixing a structure according to one embodiment of the present invention. Figure 11(a) shows the first xerogel layer formation step, Figure 11(b) shows the integration step, Figure 11(c) shows the deformation of the structure due to swelling, Figure 11(d) shows the state of the gel (xerogel) before and after drying, Figure 11(e) shows the state of the swollen second xerogel in Figure 11(c), and Figure 11(f) shows the state of the swollen first xerogel layer in Figure 11(c). Figures 12(a) and 12(b) are cross-sectional views showing an example of the structure configuration according to one embodiment of the present invention. A cross-sectional view showing an example of a DDS structure according to one embodiment of the present invention. A cross-sectional view showing an example of a DDS structure according to one embodiment of the present invention. Figure 15(a) shows how a structure according to one embodiment of the present invention deforms due to swelling, and Figure 15(b) is a graph showing the deformation rate due to swelling of a structure having a xerogel layer to which a soluble component (glucose) has been added and a structure having a xerogel layer without the addition.Fig. 16(a) shows a state of a structure according to an embodiment of the present invention after deformation, Fig. 16(b) is a graph showing the dependence of the inner diameter of the deformed structure on the magnitude of strain applied during the first xerogel layer forming step, Fig. 16(c) is a graph showing the dependence of the inner diameter of the deformed structure on the PVA sol concentration of the first xerogel layer, and Fig. 16(d) is a graph showing the dependence of the inner diameter of the deformed structure on the thickness of the first xerogel layer. Fig. 17(a) is a micrograph of a structure according to an embodiment of the present invention, showing an insulated member in which PDMS is applied and solidified to an electrode support portion, and Fig. 17(b) is a perspective view of an electrode whose electrode support portion is insulated. Figs. 18(a) to 18(d) are diagrams showing a state of a method for fixing a structure according to an embodiment of the present invention, wherein Fig. 18(a) shows an approaching step, Fig. 18(b) shows a wrapping step, Fig. 18(c) shows a state where the structure is fixed to a biological tissue (porcine vagus nerve), and Fig. 18(d) is a graph showing a measured heart rate when electrical stimulation is transmitted to an electrode of the structure. It is a graph showing the time dependence of contraction force for each soluble component added to xerogel.

[0025] Hereinafter, an embodiment of the present invention will be described with reference to the drawings. In the drawings used in the following description, characteristic portions of the present invention may be enlarged for convenience in order to make the features of the present invention easy to understand. Therefore, the dimensional ratio and the like of each component may differ from actual dimensions.

[0026] First, terms used in the present embodiment will be explained. The term "gel" includes "wet gel".

[0027] The term "wet gel" means a gel in which a three-dimensional network is swollen by a swelling agent. It includes hydrogels in which the swelling agent is water, alcogels in which the swelling agent is alcohol, and organogels in which the swelling agent is an organic solvent.

[0028] According to the "Definitions of Terms relating to the Structure and Process of Sols, Gels, Networks, and Inorganic-Organic Composites (IUPAC Recommendation 2007)" of the "Subcommittee on Polymer Terminology of the Inorganic and Polymer Sections of the International Union of Pure and Applied Chemistry (IUPAC)," "xerogel" means "a gel consisting of an open network formed by removing a swelling agent from a gel." There is also a classification method that classifies those obtained by removing the swelling agent by supercritical drying as aerogels, those obtained by removing the swelling agent by normal evaporation drying as xerogels, and those obtained by freeze-drying as cryogels, but in this specification and the claims, these are collectively referred to as xerogels.

[0029] [Structure] Figure 4 is a cross-sectional view showing an example of the configuration of a structure according to one embodiment of the present invention, and Figure 5(a) is an exploded perspective view of the structure of Figure 4. The structure 100A shown in Figure 4 comprises a flat plate-shaped laminate 10A having a first xerogel layer 1 and a second xerogel layer 2 laminated with the first xerogel layer 1. The structure 100A shown in Figure 4 comprises, for example, a flat plate-shaped laminate 10A and a conductor 20 connected to the flat plate-shaped laminate 10A, but it may also be a configuration consisting only of the flat plate-shaped laminate 10A. The conductor 20 may be connected to the structure 100A of the said configuration and used.

[0030] In structure 100A, the swelling and shrinkage stress is greater on the first surface S1 where the first xerogel layer 1 is formed than on the second surface S2 where the second xerogel layer 2 is formed. This configuration, where the swelling and shrinkage stress is greater on the first surface S1 where the first xerogel layer 1 is formed than on the second surface S2 where the second xerogel layer 2 is formed, can be confirmed by observing that when the plate-shaped laminate 10A is swollen, it deforms so that the first surface S1 becomes the inner surface. Structure 100A, as shown in Figure 5(b), deforms upon swelling into a structure as shown in Figure 5(c) as an example. Figure 5(d) shows the process of deformation of the plate-shaped laminate 10A due to swelling. Due to this deformation in which the first surface S1 of the plate-shaped laminate 10A becomes the inner surface, structure 100A has a configuration in which the radius of curvature on the first surface S1 is smaller than the radius of curvature on the second surface S2. Furthermore, swelling-shrinkage stress is the shrinkage stress applied when swelling occurs. Swelling of structure 100A is performed by immersing it in a swelling material.

[0031] Hereinafter, for convenience of explanation, in FIG. 4, in the structure 100A, the lamination direction in which the first xerogel layer 1 overlaps the second xerogel layer 2 is indicated as the Z direction, and two directions on a plane orthogonal to the Z direction are indicated as the X direction and the Y direction. For example, the X direction is the transverse direction of the structure 100A, and the Y direction is the stretching direction in which strain is applied to the first xerogel layer 1 of the structure 100A during production. For example, the X direction and the Y direction are orthogonal to each other.

[0032] For example, the structure 100A further includes a conductive layer 3 between the first xerogel layer 1 and the second xerogel layer 2. The conductive layer 3 includes, for example, an electrode portion 31 provided at the innermost position of the conductive layer 3 after deformation, and an electrode support portion 32 aligned with the electrode portion 31 in the Y direction. The structure 100A may further include one or both of a first insulating portion 4 between the conductive layer 3 and the first xerogel layer 1, and a second insulating portion 5 between the conductive layer 3 and the second xerogel layer 2.

[0033] <First Xerogel Layer> The first xerogel layer 1 is a layer containing xerogel. Xerogel is a porous monolith. As described in detail in the manufacturing method mentioned later, the first xerogel layer 1 is formed by applying strain to a gel and drying the gel. Therefore, when the first xerogel layer 1 is swollen, shrinkage stress is applied thereto so that it shrinks in the Y direction. The swelling shrinkage stress of the first xerogel layer 1 refers to the shrinkage stress generated when the first xerogel layer 1 installed on a strain gauge is immersed in a swelling agent. Physiological saline is typically used as the swelling agent.

[0034] The thickness of the first xerogel layer 1 is, for example, 0.2 mm or more and 2.0 mm or less, preferably 0.3 mm or more and 1.0 mm or less from the viewpoint of fabricating a cuff-type electrode, and preferably 0.4 mm or more and 0.6 mm or less. The thickness of the first xerogel layer 1 is calculated, for example, by observing the cross-section of the flat laminate 10A with an electron microscope and taking the average value of the thickness (Z-direction dimension) measured at each measurement position that divides the Y-direction dimension into 10 equal parts. Hereinafter in this embodiment, unless otherwise specified, the thickness of each layer and each component is calculated as the average value of the thickness measured at each measurement position that divides the Y-direction dimension into 10 equal parts by observing with an electron microscope, similar to the means described above.

[0035] The xerogel contained in the first xerogel layer 1 is, for example, a carbon xerogel or an organic / polymer xerogel. The first xerogel layer 1 is made from a ductile gel. The first xerogel layer 1 is formed by applying a strain of more than 0.2 to the gel and drying it. The gel that can be used for xerogel production is a ductile gel that deforms without breaking when such strain is applied and shrinks due to swelling.

[0036] In a plate-shaped laminate 10A used for fixation to biological tissue, the xerogel contained in the first xerogel layer 1 is an organic polymer xerogel. Such a xerogel is, for example, a xerogel obtained by removing a swelling agent from a hydrogel having a network structure of one or more polymers selected from the group consisting of natural polymers, synthetic polymers, and semi-synthetic polymers.

[0037] Examples of natural polymers include alginic acid, hyaluronic acid, chitosan, cellulose, dextran, pullulan, collagen, and gelatin. Examples of synthetic polymers include polyvinyl alcohol, polyethylene glycol, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyHEMA, and polyurethane. Examples of semi-synthetic polymers include gelatin methacryloyl, methacrylated hyaluronic acid, and carboxymethylcellulose.

[0038] The above hydrogel may be a hybrid gel comprising any one of the network of one or more of the above polymers, or one or more interpenetrating networks, double networks, and nanocomposites of the above polymers.

[0039] The xerogel contained in the first xerogel layer 1 is preferably a biodegradable xerogel in a structure used for fixing biological tissue in a living body. The biodegradable xerogel is a xerogel obtained by removing a swelling agent from a biodegradable gel containing the swelling agent. Examples of the biodegradable xerogel include gelatin methacryloyl, hyaluronic acid and derivatives thereof, alginic acid and oxides thereof, and chitosan; copolymers of polyethylene glycol with polylactic acid, polyglycolic acid, polylactic acid-co-glycolic acid or polycaprolactone; and xerogels obtained by removing a swelling agent from interpenetrating networks, double networks and composite gels thereof.

[0040] The first xerogel layer 1 may be configured to further include a soluble component added to the xerogel. As the soluble component, for example, one or more selected from the group consisting of sugars such as glucose, sucrose, and trehalose, sugar alcohols such as mannitol, sorbitol, and xylitol, polyols such as glycerol and propylene glycol, amino acids such as glycine and alanine, and inorganic salts such as NaCl, phosphate, and citrate can be used.

[0041] The concentration of the soluble component in the first xerogel layer 1 is, for example, 5×10 -5 mol / cm 3 or more and 2×10 -3 mol / cm 3 or less, and preferably 0.1×10 -3 mol / cm 3 or more and 1×10 -3 mol / cm 3 or less.

[0042] The first xerogel layer 1 has a shrinkage stress upon contact with moisture that is, for example, 2 kPa or more and 30 kPa or less, preferably 5 kPa or more and 20 kPa or less, and more preferably 7 kPa or more and 10 kPa or less. The shrinkage stress upon contact with moisture is measured when the first xerogel layer 1, placed on a strain gauge, is immersed in a swelling agent.

[0043] <Second Xerogel Layer> The second xerogel layer 2 is a layer containing xerogel. The second xerogel layer 2 has, for example, a swelling-shrinkage stress that is smaller than that of the first xerogel layer 1. The second xerogel layer 2 may be formed by applying strain to the gel and drying it, or it may be formed by drying the gel without applying strain. If the second xerogel layer 2 is formed by applying strain to the gel and drying it, the strain is formed such that the swelling-shrinkage stress is smaller than that of the first xerogel layer 1. For example, it is formed by applying a strain smaller than the strain applied when the first xerogel layer 1 was formed.

[0044] The thickness of the second xerogel layer 2 is, for example, 0.2 mm or more and 2.0 mm or less, preferably 0.3 mm or more and 1.0 mm or less from the viewpoint of fabricating a cuff-type electrode, and preferably 0.4 mm or more and 0.6 mm or less.

[0045] The xerogel contained in the second xerogel layer 2 may be the same as or different from the xerogel contained in the first xerogel layer 1. In structures used for fixing biological tissues in living organisms, the xerogel contained in the second xerogel layer 2 is preferably a biodegradable xerogel. In the plate-shaped laminate 10A, it is preferable that at least one of the first xerogel layer 1 and the second xerogel layer 2 contains at least one polymer selected from the group consisting of polyvinyl alcohol, alginic acid, hyaluronic acid, chitosan, and gelatin.

[0046] The second xerogel layer 2 may further contain soluble components. The concentration of the soluble components in the second xerogel layer 2 can be within the same range as the concentration of the soluble components in the first xerogel layer 1.

[0047] The concentration of soluble components in the second xerogel layer 2 is preferably lower than that of the first xerogel layer 1, and the ratio to the concentration of soluble components in the first xerogel layer 1 may be 50% or less. Since the second xerogel layer 2 does not necessarily contain soluble components, the concentration of soluble components in the second xerogel layer 2 may be 0.0 of the concentration of soluble components in the first xerogel layer 1, and the lower limit of the above ratio is 0.0, while a value of 0.1 or higher is preferable from the viewpoint of deformation speed. As will be described in detail later, in the plate-shaped laminate 10A, the second xerogel layer 2 follows the deformation of the first xerogel layer 1 during swelling, so it is thought that deformation can be accelerated by setting the above ratio so that the concentration of soluble components in the first xerogel layer 1 is higher than that of the second xerogel layer 2. The concentration of soluble components in each layer can be measured by analyzing an extract obtained from a specified volume of xerogel or xerogel fragment using solvent extraction, by high-performance liquid chromatography, inductively coupled plasma emission spectroscopy, ion chromatography, etc.

[0048] The second xerogel layer 2 exhibits less shrinkage stress upon contact with moisture than the first xerogel layer 1.

[0049] <Conductive Layer> The conductive layer 3 is a conductive layer provided between the first xerogel layer 1 and the second xerogel layer 2. The conductive layer 3 has, for example, an electrode portion 31 at one end in the Y direction and an electrode support portion 32 connected to the electrode portion 31 and extending to the other end opposite to the one end in the Y direction. The electrode portion 31 is located on the inside when the flat laminate 10A is deformed into a cylindrical shape.

[0050] The electrode support portion 32 is a member formed integrally with or separately from the electrode portion 31. The electrode support portion 32 is a region of the conductive layer 3 located on the opposite end in the Y direction from the end where the electrode portion 31 is located. The electrode support portion 32 is located outside the electrode portion 31 when the flat plate laminate 10A is deformed into a cylindrical shape. The X-direction dimension of the electrode support portion 32 may be larger, the same size as, or smaller than the X-direction dimension of the electrode portion 31, but it is preferable that it be smaller than the X-direction dimension of the electrode portion 31 in order to increase flexibility and facilitate swelling deformation. The ratio of the width of the electrode support portion 32 to the width (X-direction dimension) of the electrode portion 31 is preferably 10% or more and 100% or less, and more preferably 20% or more and 40% or less. When used for cuff-type electrode applications, the width of the electrode support portion 32 is preferably, for example, 0.5 mm or more and 2.0 mm or less.

[0051] The conductive layer 3 is a flexible member that can deform in accordance with the deformation of the first xerogel layer 1. The thickness of the conductive layer 3 is, for example, 0.1 mm or more and 1.0 mm or less, and is preferably 0.20 mm or more and 0.50 mm or less, and more preferably 0.35 mm or less, from the viewpoint of increasing the deformation speed and ensuring higher strength and high electrical double layer capacitance. Furthermore, from the viewpoint of ensuring higher strength and electrical double layer capacitance, the thickness of the conductive layer 3 may be 0.25 mm or more.

[0052] For example, the conductive layer 3 can be a conductive cloth having conductive fibers, a flexible electrode film containing a conductive material, or the like.

[0053] The conductive fabric is, for example, a woven or nonwoven fabric of conductive fibers, and is preferably a woven fabric of conductive fibers from the viewpoint of exhibiting high flexibility. The woven fabric has a structure in which multiple conductive fibers are arranged in a plain weave (plain wave), weft knit, etc., and is preferably a weft knit. Examples of conductive fibers include carbon fibers. The carbon fibers contain element C as the main component, and it is preferable that the element C composition ratio is 90 at% or more. As a conductive fabric having carbon fibers, it is particularly preferable that it is a conductive fabric made by carbonizing bamboo fiber knit.

[0054] Figure 6(a) shows an example of the fiber structure of a conductive fabric that can be used as a conductive layer 3 on a flat laminate 10A, with multiple conductive fibers F1 to F4 arranged in a weft weave. Figure 6(b) is a graph showing the electrical double layer capacitance of a conductive fabric formed in a weft weave structure of multiple carbon fibers, which is a preferred form of conductive fabric. Figure 7 shows an example of the structure of another conductive fabric and is a diagram illustrating the plain weave fiber structure. In the plain weave fiber structure, there are multiple first conductive fibers F1 to F6 arranged in a first direction and multiple second conductive fibers F7 to F11 arranged in a second direction perpendicular to the first direction, and the structure is woven so that the first conductive fibers and second conductive fibers are alternately located at the top along the first and second directions, respectively. Note that the electrical double layer capacitance shown in Figure 6(b) is for a carbonized bamboo fiber knit with a weft weave structure and a thickness of 0.29 mm.

[0055] <Insulating parts> The structure 100A may further have insulating parts between the first xerogel layer 1 and the conductive layer 3, and between the second xerogel layer 2 and the conductive layer 3, or both. In the example shown in Figure 1, a configuration is shown having a first insulating part 4 provided between the first xerogel layer 1 and the conductive layer 3, and a second insulating part 5 provided between the second xerogel layer 2 and the conductive layer 3. Hereinafter in this embodiment, the first insulating part 4 and the second insulating part 5 will not be particularly distinguished, and when describing a common configuration, they will simply be referred to as insulating parts.

[0056] The insulating portion overlaps, for example, with the electrode support portion 32 of the conductive layer 3. By having an insulating portion, the structure 100A can provide a higher potential while suppressing short circuits in a deformed configuration of the flat laminate 10A. In particular, it is preferable to provide an insulating portion in a flat laminate 10A that has a conductive layer 3 and in which the thickness of the first xerogel layer 1 and the second xerogel layer 2 is thin.

[0057] The thickness of the insulating portion is preferably, for example, 0.005 mm or more and 0.5 mm or less, and preferably 0.01 mm or more and 0.1 mm or less.

[0058] <Conducting Wire> The structure 100A may further have a conductor 20 connected to the electrode support portion 32 of the conductive layer 3. The conductor 20 can have any configuration as long as it is made of a conductive material capable of sending and receiving signals to and from the conductive layer 3.

[0059] [Method for Manufacturing the Structure] Next, a method for manufacturing a structure according to one embodiment of the present invention will be described, using the method for manufacturing the structure shown in Figure 4 as an example. Figure 8 is a flowchart illustrating the method for manufacturing a structure according to one embodiment of the present invention.

[0060] The method for manufacturing the structure according to this embodiment includes the steps of: drying the first gel in an extended state to form a first xerogel layer 1 (first xerogel layer formation step: step S10); preparing a second xerogel layer 2 having a lower swelling and shrinkage stress than the first xerogel layer (second xerogel layer preparation: step S20); and integrating the first xerogel layer 1 and the second xerogel layer 2 in a bonded state (integration step: step S40). As shown in Figure 8, when manufacturing the structure 100A shown in Figure 4, the method for manufacturing the structure according to this embodiment may further include a step of preparing a conductive layer 3 before the integration step (electrode preparation step: step S30).

[0061] <First Xerogel Layer Formation Step> Figure 9 is a plan view illustrating the first xerogel layer formation step in a method for manufacturing a structure according to one embodiment of the present invention, where Figure 9(a) shows the prepared first gel, Figure 9(b) shows the first gel being dried by applying strain, and Figure 9(c) shows the formed first xerogel layer.

[0062] First, a first gel 1Z shown in Figure 9(a) is prepared. The first gel 1Z is a hydrogel having a network structure of one or more polymers selected from the group consisting of natural polymers, synthetic polymers, and semi-synthetic polymers. As these hydrogels, the hydrogels described in the above embodiments can be used. The first gel 1Z can include, for example, a network of one or more polymers described in the above embodiments, or a hybrid gel containing any of the interpenetrating networks, double networks, and nanocomposites of one or more of the above polymers. The first gel 1Z is preferably a biodegradable gel.

[0063] The first gel can be prepared using known methods such as chemical crosslinking and physical crosslinking, and the means are not limited. For example, a raw material solution containing a predetermined polymer selected according to the desired type of xerogel and a swelling agent is prepared, and a sol is prepared by mixing them, and then gelled. The method for gelling the sol is not particularly limited and includes, for example, physical gelling methods such as freeze-thaw, chemical crosslinking using a crosslinking agent, photocrosslinking by light irradiation, thermal gelling by temperature change, gelling by pH change, and ion crosslinking.

[0064] When preparing the first gel 1Z, the sol concentration can be adjusted by the strain applied to the first gel 1Z and the desired inner diameter during swelling deformation of the flat laminate, but it is preferably, for example, 5 wt% to 20 wt%, and 15 wt% to 18 wt%.

[0065] The first gel 1Z may further have the above-mentioned soluble component 11. The concentration of the soluble component 11 in the first gel 1Z is, for example, 5 × 10⁻⁶ -5 mol / cm 3 The above 2 x 10 -3 mol / cm 3 The following is true: 0.1 × 10 -3 mol / cm 3 The above 1 x 10 -3 mol / cm 3The following is preferable. In order to include a soluble component in the first gel 1Z, an immersion step can be performed in which the first gel 1Z is immersed in a solution in which the soluble component is dissolved. The concentration of the soluble component in the solution used in the immersion step and the immersion time can be adjusted according to the desired concentration of the soluble component in the first xerogel layer 1.

[0066] Next, as shown in Figure 9(b), strain is applied to the first gel 1Z. For example, in the standard state, the Y-direction dimension L １Ｚ The first gel 1Z having the Y-direction dimension L １ The deformation occurs in such a way. When the Y-direction dimension of the first gel 1Z is represented by the above letter, the deformation is {(L １ -L １Ｚ ) / L １Ｚ This is expressed as}. The strain to be applied is greater than 0.2 and less than or equal to 2.5, preferably between 0.5 and 2.0, and more preferably between 1.5 and 1.75. The means of applying strain to the first gel 1Z are not particularly limited. For example, it can be done by fixing both ends of the first gel 1Z with fasteners and pulling one or both sides.

[0067] Next, as shown in Figure 9(c), the first gel 1Z, which has been subjected to strain, is dried to form the first xerogel layer 1. That is, the elongation ratio of the length after drying to the original length is λ (= L). １ / L １Ｚ The first gel 1Z, which has been stretched so that the elongation ratio λ is greater than 1.2 and less than or equal to 3.5, is dried. The first gel 1Z to be dried is preferably dried with an elongation ratio λ of 1.5 or more and less than or equal to 3.0, and more preferably dried with an elongation ratio of 2.5 or more and less than or equal to 2.75. The means for drying the first gel 1Z to form the first xerogel layer 1 can be carried out by known gel drying methods, provided that the strain is applied to the first gel 1Z as described above. For example, known drying methods such as drying and evaporation, freeze-drying, and vacuum drying can be used.

[0068] The swelling-shrinkage stress generated when the first xerogel layer 1 is swollen with water using a strain gauge is preferably 80 mN or more and 500 mN or less, more preferably 100 mN or more, more preferably 150 mN or more, and even more preferably 200 mN or more. The swelling-shrinkage stress may be 300 mN or less. Furthermore, the swelling-shrinkage stress of the first xerogel layer 1 upon contact with water is preferably 2 kPa or more and 30 kPa or less, preferably 5 kPa or more and 20 kPa or less, and more preferably 7 kPa or more and 10 kPa or less. The swelling-shrinkage stress is the shrinkage stress measured by a strain gauge at least one minute after the start of swelling of the first xerogel layer 1. The time required for the swelling deformation of the first xerogel layer 1 is, for example, 10 seconds or more and 60 seconds or less, and preferably 40 seconds or less. The time required for swelling deformation is 10 seconds or more to allow for fine adjustment after swelling. From a similar viewpoint, it may be 20 seconds or more. Furthermore, the time required for swelling deformation is more preferably 20 seconds or less, and even more preferably 15 seconds or less. The time required for swelling deformation is the time after the contraction stress has reached its maximum. This time can be said to be the time when the deformation stops.

[0069] <Preparation Step for the Second Xerogel Layer> A second xerogel layer 2 is prepared, which has a lower swelling and shrinkage stress than the first xerogel layer 1. The preparation step for the second xerogel layer is not limited to being performed after the first xerogel layer formation step, but may be performed before or in parallel with it. The second xerogel layer 2 may be dried while strain is applied, similar to the first xerogel layer 1, but it may also typically be dried without strain being applied.

[0070] The second xerogel layer 2 may be a commercially available product or may be fabricated. The method for fabricating the second xerogel layer 2 is the same as the method for fabricating the first xerogel layer 1, or it can be done by drying without applying strain, following the method for fabricating the first xerogel layer 1. When strain is applied to the second gel, or when drying, the strain applied to the second gel is preferably half or less of the strain applied to the first gel 1Z, and preferably one-quarter or less.

[0071] The second gel 2Z can be, for example, a hybrid gel containing a network of one or more types of polymers as described in the above embodiment, or a network of interpenetrating polymers, a double network, or a nanocomposite of one or more types of polymers. The second gel 2Z is ​​preferably a biodegradable gel. Although not shown in the figures, the second gel 2Z may further contain the same soluble components 11 as the first gel 1Z. The type and concentration of the soluble components 11 in the second gel 2Z may be the same as or different from that of the first gel 1Z.

[0072] In a configuration where the second xerogel layer 2 swells and deforms, the swelling and shrinkage stress is preferably 1 / 2 or less of that of the first xerogel layer 1, and preferably 1 / 4 or less.

[0073] <Electrode Preparation Process> Next, the conductive layer 3 is prepared. The electrode preparation process is not limited to being performed after the first xerogel layer formation and the second xerogel layer formation process, but may be performed before or in parallel with the electrode preparation process. In the electrode preparation process, for example, when forming the conductive layer 3 shown in the upper right of Figure 5(a) in the layer structure shown in the cross-sectional view of Figure 4, first a layer of conductive material such as a conductive cloth having conductive fibers or a flexible electrode film is prepared, processed into a predetermined shape, and a conductive layer having an electrode portion 31 and an electrode support portion 32 is formed. The means for processing the conductive material layer into a predetermined shape can be, for example, punching or cutting. The conductive material layer to be prepared may have a conductor 20 connected to one end in the Y direction in advance, or the conductor 20 may be formed to connect to the electrode support portion 32 after processing into a predetermined shape.

[0074] Next, when manufacturing a structure having an insulating portion, an insulating material is formed in the conductive layer 3 at a position overlapping with the electrode support portion 32, and the insulating material is processed into a predetermined shape so that only the region overlapping with the electrode support portion 32 remains, thereby forming the insulating portion. The means for processing the insulating material into a predetermined shape can be punching, cutting, etc. The insulating portion may be formed on the conductive layer 3 by means of an adhesive (not shown), for example, or it may simply be arranged so as to overlap.

[0075] Furthermore, the configuration of the conductive layer and the insulating portion may be any of the four patterns illustrated in the upper right of Figure 5(a). The first and third conductive layers 3A from the top have not been processed in plan view and have the same plan view shape as the first xerogel layer 1 and the second xerogel layer 2. In the first and third patterns from the top, no insulating portion is formed. In the third pattern from the top, the insulating portion is removed only in the area of ​​the plan view shape of the first xerogel layer 1 and the second xerogel layer 2 that overlaps with the electrode portion 31.

[0076] <Integration Process> Next, the member containing the first xerogel layer 1 and the second xerogel layer 2 produced in the above process is laminated and integrated. Figure 11(a) is a schematic diagram showing an example of the structure configuration according to one embodiment of the present invention, and shows the integration process. In the integration process, for example, a conductive layer 3 is formed on the second xerogel layer 2 directly or via an adhesive layer 6, and the first xerogel layer 1 is laminated on the conductive layer 3 directly or via an adhesive layer and integrated. Figure 11(a) shows how insulating portions are formed on both sides in the Z direction and the conductive layer 3 is laminated.

[0077] In the integration process, the first xerogel layer 1 and the second xerogel layer 2 can be integrated in a laminated state by, for example, a freeze-thaw method. For example, an adhesive layer 6 is formed on the second xerogel layer 2, and then the freeze-thaw method is performed. In the cross-sectional view shown in Figure 11(a), the adhesive layer 6 is provided only between the second xerogel layer 2 and the conductive layer 3. However, the planar dimensions of the conductive layer 3 and the insulating portion provided on the conductive layer 3 are smaller than those of the first xerogel layer 1 and the second xerogel layer 2, and the adhesive layer 6 is configured to be in contact with the second xerogel layer 2, the conductive layer 3, and the first xerogel layer 1. The adhesive layer 6 is, for example, an adhesive sol such as polyvinyl alcohol (PVA). The adhesive layer 6 may remain in the finished product, or it may not remain and become part of another layer. For example, if it is made of the same material as the xerogel layer, it can be considered part of the xerogel layer, and if it is made of a different material, it remains as an adhesive layer. Using this method, structures like those shown in Figures 4 and 11(b) can be fabricated.

[0078] Figure 11 is a cross-sectional view illustrating a method for manufacturing and fixing a structure according to one embodiment of the present invention. Figure 11(a) shows the first xerogel layer formation process, Figure 11(b) shows the integration process, Figure 11(c) shows the deformation of the structure due to swelling, Figure 11(d) shows the state of the gel (xerogel) before and after drying, Figure 11(e) shows the state of the swollen second xerogel in Figure 11(c), and Figure 11(f) shows the state of the swollen first xerogel layer in Figure 11(c).

[0079] As shown in Figures 11(a) and 11(d), in the method for manufacturing the structure according to this embodiment, in the first xerogel layer formation step, the first gel 1Z is dried in an extended state, thereby forming H from the polymer network indicated by the symbol CNF. ２ When swelling agents such as O are removed, the elastic force for shrinkage decreases compared to the start of drying. When the first xerogel layer 1 is integrated with the second xerogel layer 2, which has a smaller swelling and shrinkage stress than the first xerogel layer 1, and then swelled, the first xerogel layer 1, which is dried under a large strain, becomes the first gel 1Z, and the second xerogel layer 2 exhibits a higher shrinkage stress than the swollen gel. Therefore, the structure 100C deforms into a cylindrical shape, for example, with the first surface S1 on the inside and the second surface S2 on the outside. The shape of the flat laminate 10A after deformation due to swelling is not necessarily cylindrical, but it becomes a curled structure with the first surface S1 on the inside and the second surface S2 on the outside.

[0080] Xerogel rapidly increases in elasticity upon swelling. For example, deformation is preferably completed in 90 seconds or less, preferably in 60 seconds or less, and more preferably in 40 seconds or less. Therefore, the structure according to the above embodiment can be said to have a fast deformation rate and high reactivity. This rate is based on the time at which the swelling contraction stress, measured by placing the structure 100A on a strain gauge and immersing it in a swelling agent, reaches its maximum. If a soluble component 11 is added to the xerogel layer 1, the deformation rate is further accelerated by osmotic pressure.

[0081] [Method for fixing the structure] The structure according to the above embodiment includes, for example, a proximity step of approaching the tubular biological tissue to be fixed and a wrapping step of swelling the structure and wrapping it around the biological tissue. The tubular biological tissue is, for example, a nerve bundle, muscle fiber, blood vessel, etc.

[0082] In the proximity process, the structure 100A is brought close to the biological tissue such that the distance between the first surface S1 of the structure 100A and the biological tissue is less than or equal to half of the X-direction dimension of the structure 100A. For example, when viewed from a plane perpendicular to the first surface S1, the structure 100A is brought close to the biological tissue such that the biological tissue is located between the two ends of the structure 100A in the X-direction (the elongation direction when the first xerogel layer 1 is fabricated). In this embodiment, this method of bringing the structure close so that the biological tissue is located between the two ends of the structure in the X-direction is sometimes referred to as inserting the structure under the biological tissue.

[0083] Next, in the winding process, the structure 100A is swollen. In the winding process, a liquid medium is dropped onto the structure 100A. The liquid medium is, for example, a swelling agent. The swelling agent is preferably physiological saline. In the winding process, it is preferable to complete the winding within 30 seconds from the dropping of the liquid medium. Here, completion of winding corresponds to completion of swelling deformation. The time required for the swelling deformation of the structure 100A is preferably 10 seconds or more and 60 seconds or less, and more preferably 20 seconds or more and 40 seconds or less. This time can be confirmed by observing with an optical microscope during swelling deformation, when a sufficient amount of liquid medium (the volume of the xerogel provided) for swelling of the xerogel is dropped onto the structure 100A.

[0084] According to this embodiment, a structure can be provided that is initially in an extended state and can be deformed into a curled shape or the like by swelling. Unlike conventional structures, the flat plate-shaped laminate 10A of the structure 100A can be deformed into a cylindrical shape by a simple process called swelling, without going through an expansion operation, and fixed to biological tissue. This deformation is thought to occur because, in the first xerogel layer formation process, the structure is formed by applying strain, resulting in a configuration where the swelling and contraction stress on the surface on the first xerogel layer 1 side is greater than the swelling and contraction stress on the surface on the second xerogel layer 2 side. As a result, the entire structure follows the contraction due to swelling of the first xerogel layer 1. According to the structure of this embodiment, the structure 100A fixed to biological tissue such as muscle fibers and nerve bundles can be used for the treatment and measurement of living organisms by transmitting and receiving signals between the structure 100A fixed to biological tissue and the conductive layer 3 via a conductive wire 20. Furthermore, the reaction rate due to swelling can be further improved by adding soluble components. The dry, flat xerogel electrode provided in this embodiment, after being inserted under the target biological tissue, swells and deforms into a hydrogel upon water absorption, becoming a cuff-type electrode that wraps around the tissue. Furthermore, the large deformation (significant bending) necessary for application to peripheral nerves such as the sciatic nerve (outer diameter approximately 1 mm) and the vagus nerve of small animals such as mice is achieved by using a highly flexible fibrous carbon electrode. Partial insulation of the electrode significantly improves stimulation efficiency. [Main differences from the inventor's prior art (non-patent literature 5, 6)] - It has a dry, flat xerogel shape, and deforms into a cylindrical shape upon swelling and deformation when it absorbs water and becomes a hydrogel. - The rate of swelling and deformation is controlled (accelerated) by osmotic pressure from sugars and electrolytes, and deformation is completed within 60 seconds. - The inner diameter of the cylindrical shape after deformation can be made 2 mm or less. Furthermore, in this embodiment, it has been confirmed that configurations with an inner diameter of 1 mm or less, 600 μm or less, or 500 μm or less after deformation are also achievable, which means that the range of applicable biological tissues has expanded significantly compared to conventional technology. • In the case of flexible carbon fiber cloth used as the electrode material for the conductive layer in the embodiments described later, since it is composed solely of organic matter, it can be used in conjunction with measurements that use strong magnetic fields, such as MRI.PEDOT, used in Non-Patent Documents 5 and 6, raises concerns regarding its chemical stability during long-term use in the body. Therefore, it is important to find a more stable and flexible organic electrode, and the conductive layer made of carbon fiber used in the examples is considered to be a component that satisfies such characteristics.

[0085] [Modifications] Although embodiments of the present invention have been described in detail above, the present invention is not limited to the above embodiments, and various omissions, substitutions, modifications, and changes are possible within the scope of the gist of the present invention as described in the claims. For example, the following configuration is possible.

[0086] The plate-shaped laminate 10B of the structure 100B shown in Figure 12(a) does not have a conductive layer 3 and an insulating portion, and the first xerogel layer 1 and the second xerogel layer 2 are formed directly or via an adhesive layer (not shown). As shown in the structure 100C in Figure 12(b), the plate-shaped laminate 10C may also have a configuration that does not have an insulating portion. Even with such a structure, the same functions as in the above embodiment can be achieved.

[0087] Furthermore, the structure according to this embodiment can be transported to a specific location within biological tissue, and deformation can be initiated and completed rapidly at a specific time and location. In addition, the components contained within the structure can be pre-adjusted. By utilizing these characteristics, it can be used in drug delivery systems (DDS) to deliver the necessary amount of drug to a specific location in the body in a short amount of time. Examples of DDS applications include structures 100D to 100G as shown in Figures 13 and 14.

[0088] (Structures for DDS) Structures 100D to 100G further contain drug D. Structures 100D and 100E have a drug layer 8 containing drug D and xerogel between a first xerogel layer 1 and a second xerogel layer 2. Each layer is a biodegradable xerogel, and the xerogel that can be used for the drug layer 8 is not particularly limited as long as it is a biodegradable xerogel. The biodegradable xerogel exemplified as the material for the first xerogel layer 1 may be used, or it may be a brittle biodegradable gel that cannot withstand the drying process while applying a strain greater than 0.2. The thickness of the drug layer 8 is, for example, 5 μm or more and 500 μm or less. Structures 100F and 100G have drug D contained in the first xerogel layer 1X.

[0089] When manufacturing structures 100D to 100G, for example, the drug layer 8 is formed by impregnating xerogel with drug D, and in the integration process, it is laminated and integrated together with other plate-like laminate components such as the first xerogel layer 1 and the second xerogel layer 2. That is, when manufacturing structures 100D and 100E, there is a drug layer formation step before the integration step in which xerogel is prepared and impregnated with drug to form the drug layer 8. The drug layer 8 is integrated together with other components in the integration step. When forming structures 100E and 100F, in the first xerogel formation step, for example, drug is impregnated into xerogel while strain is applied to disperse the drug, and it is dried while the strain is applied. In this case, the first xerogel formation step can be said to include a drug addition step.

[0090] These embodiments and their variations are included within the scope and essence of the invention, as well as within the scope of the claims and its equivalents.

[0091] The upper and / or lower limits of the numerical ranges described herein can be arbitrarily combined to define a preferred range. For example, the upper and lower limits of the numerical ranges can be arbitrarily combined to define a preferred range, the upper limits of the numerical ranges can be arbitrarily combined to define a preferred range, and the lower limits of the numerical ranges can be arbitrarily combined to define a preferred range.

[0092] Throughout this disclosure, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (for example, "a," "an," and "the" in English) should be understood to include the concept of their plural form unless otherwise specified.

[0093] The following describes embodiments of the present invention. The present invention is not limited to the following embodiments.

[0094] [Example 1] The structure of Example 1 was prepared using the following procedure. First, the materials listed in "1" below were prepared. 1. Reagents and materials: ・Polyvinyl alcohol (PVA solution, 10849-250G; Mowiol 28-99, Sigma-Aldrich) ・Dimethyl sulfoxide (DMSO, 043-07216, Fujifilm Wako Chemical) ・Polydimethylsiloxane (PDMS, SILPOT 184, DuPont-Toray Specialty Materials) ・Phosphate-buffered saline (D-PBS(-)) (Fujifilm Wako Pure Chemical Corporation) ・Carbonized bamboo fiber knit (No. 19, No. 21 and RT-01, Nakatsuyama Heat Treatment)

[0095] Furthermore, the carbonized bamboo fiber knit prepared in section "2" below will be explained. 2. Evaluation of the carbonized bamboo fiber knit electrode The carbon cloth used as the electrode (conductive layer) is a flexible organic electrode material manufactured by Nakatsuyama Heat Treatment Co., Ltd., which is made by carbonizing a bamboo fiber knit at 1200°C. No. 19 is a carbonized bamboo fiber membrane with a weft knit structure, and No. 21 is a carbonized bamboo fiber membrane with a plain weave structure. These can be used as conductive layers. No. 19 with a thickness of approximately 0.33 mm and No. 21 with a thickness of approximately 0.29 mm showed electrical double layer capacitance values ​​that far exceeded those of the platinum cuff electrode (Figure 6(b)). Specifically, the electrical double layer capacitance measured under the same conditions after adjusting to the same shape was approximately 1200 μF / cm for No. 19. ２ No. 21 showed approximately 600 μF / cm². ２ In the RT-01, the capacitance is approximately 400 μF / cm. ２ The result was as follows: A commercially available metal electrode (made of Pt, film thickness approximately 0.5 mm) measured under the same conditions showed a reading of 150-200 μF / cm².２ The electrical double-layer capacitance value was 10 mVs. －１ Measured by cyclic voltammetry (CVs) testing. A higher capacitance makes electrolysis less likely, allowing for safer stimulation. RT-01, with a thickness of approximately 0.22 mm, has a low density that allows for transparency, yet possesses a surface capacitance equivalent to or greater than that of existing platinum cuff electrodes.

[0096] 3. Fabrication of a plate-shaped xerogel electrode structure (plate-shaped laminate) Inner xerogel layer (first xerogel layer) (1) A 15 wt% polyvinyl alcohol (PVA) sol was prepared using a 4:1 mixed solution of DMSO and distilled water. (DMSO is used to improve the elasticity of the hydrogel) (2) The PVA sol solution was poured into a mold (a depression with a depth of 0.5 mm to 1.0 mm) made with a 3D printer, covered with a glass slide, and gelled by repeating the freeze-thaw method (10 minutes at -28°C, 10 minutes at room temperature cycle) three times. (3) DMSO was removed by immersion in distilled water for 12 hours. (4) If swelling acceleration by osmotic pressure was performed, the material was immersed in a 0.3 M glucose aqueous solution for 12 hours. (5) The hydrogel was stretched by applying strains (1, 1.25, 1.5, 1.75, 2), and then left to dry in a 25°C oven for 12 hours to obtain a 0.5 mm thick PVA xerogel sheet (first xerogel layer). Strain {(L １ -L １Ｚ ) / L １Ｚ A sample prepared by setting} to 1 and following the procedure described later will be referred to as Example 1. Similarly, a sample with a strain of 1.25 will be referred to as Example 2, a sample with a strain of 1.5 as Example 3, a sample with a strain of 1.75 as Example 4, and a sample with a strain of 2 as Example 5.

[0097] Outer Xerogel (Second Xerogel Layer) (1) A 15 wt% PVA sol was prepared using distilled water as the solvent. (2) The PVA sol was dropped onto a glass plate and thinned using a spin coater (700 rpm, 30 seconds). (3) The sheet was frozen at -28°C for 10 minutes and left to stand in a 25°C dryer for 12 hours to obtain a dried PVA xerogel sheet (Second Xerogel Layer) (thickness 0.03 mm).

[0098] Formation of Laminated Structure (Platform Structure) (1) A PVA sol solution (15 wt%) was dropped onto the second xerogel layer on a glass plate. Dropping conditions: Spin coat at 1500 rpm for 30 seconds. (2) A carbide nit electrode (No. 19 or RT-01) and the first xerogel layer were laminated on the second xerogel layer and the PVA sol formed thereon, and bonded by freeze-thaw method (-28°C for 10 minutes, room temperature for 10 minutes). (3) The laminated structure was peeled off and recovered from the glass plate with tweezers. The fabricated laminated structure had a width of 40 mm in plan view and a length of 30 mm in the elongation direction. All peeled and recovered laminated structures were confirmed to be flat laminates under standard conditions. The following example numbers may be referred to below. Example 1-1: Strain during the first xerogel layer formation process: 1, Conductive layer: RT-01 Example 1-2: Strain during the first xerogel layer formation process: 1, Conductive layer: No. 19 Example 2-1: Strain during the first xerogel layer formation process: 1.25, Conductive layer: RT-01 Example 2-2: Strain during the first xerogel layer formation process: 1.25, Conductive layer: No. 19 Example 3-1: Strain during the first xerogel layer formation process: 1.50, Conductive layer: RT-01 Example 3-2: Strain during the first xerogel layer formation process: 1.50, Conductive layer: No. 19 Example 4-1: Strain during the first xerogel layer formation process: 1.75, Conductive layer: RT-01 Example 4-2: Strain during the first xerogel layer formation process: 1.75, Conductive layer: No. 19 Example 5-1: Strain during the first xerogel layer formation process: 2.0, conductive layer: RT-01 Example 5-2: Strain during the first xerogel layer formation process: 2.0, conductive layer: No. 19

[0099] 4. Evaluation of Swelling Deformation Function The deformation behavior of the samples prepared in Examples 1-1 to 5-2 was evaluated by immersion in phosphate-buffered saline (PBS). As shown in Figure 15(a), the xerogel layered structures of Examples 1-1 to 5-2 all began to deform when immersed in phosphate-buffered saline (PBS), and deformed into a cylindrical shape with the first xerogel layer facing inward. The inner diameter of the annular region located at the innermost part of the structure, as shown in Figure 15(a) after sufficient time had elapsed since deformation, was measured to be 1 mm or less.

[0100] In the above-mentioned conditions for forming the first xerogel layer, a reference example (PVA xerogel) was prepared by omitting step (4) (immersion of the first gel in an aqueous glucose solution) from the xerogel (PVA xerogel with 0.3M glucose) prepared under conditions where the strain was 1.5.

[0101] Deformation Rate Evaluation The time dependence of the change in inner diameter when the above samples were immersed in PBS was evaluated by image analysis. Figure 15(b) shows the change in inner diameter of the cylindrical shape after swelling deformation over time, gradually decreasing to the final inner diameter (in this case, No. 19 was used, and the final inner diameter was approximately 2 mm). In the reference example without glucose, a deformation time of about 90 seconds was required, whereas the sample immersed in a 0.3 M glucose solution before drying completed the deformation in about 30 seconds. This is thought to be the result of the glucose-containing xerogel, which has a high osmotic pressure, absorbing water at high speed.

[0102] Influence of structural parameters on the inner diameter after deformation (dependence of inner diameter on strain applied during the first xerogel layer formation process) Using highly flexible carbonized bamboo knit RT-01 (thickness 0.22 mm), xerogel structures with small inner diameters (large deformation rate) that can accommodate thin nerves of small animals were fabricated (Examples 1-1 to 5-1). Figure 16(a) shows a side view of these typical cuff-type hydrogel electrodes after deformation. After sufficient deformation, the inner diameter was measured by image analysis using images taken from the side of the inside of the cylindrical structure. Figure 16(b) shows the change in inner diameter after swelling deformation due to the "strain" applied during the fabrication of the inner xerogel layer (first xerogel layer formation process). Up to a strain of 1.5, it was confirmed that the inner diameter decreased as the amount of strain increased, because the contraction force when the hydrogel swelled again increased. At a strain of 1.75, the inner diameter did not become any smaller. This is thought to be because the rigidity of the hydrogel and bamboo knit suppressed further deformation even when a greater contracting force was applied.

[0103] (Dependence of inner diameter on sol concentration used during first gel formation) Figure 16(c), which shows the relationship between the raw material sol concentration and the inner diameter when the swelling of the structure is complete, was produced by changing the raw material sol concentration in operation (1) during the first xerogel layer formation process in Example 3-1 with a strain of 1.5. There was almost no change in the inner diameter at 15% and 17.5%. On the other hand, at 20%, the inner diameter became 600 μm or more. This is thought to be because as the polymer concentration of the hydrogel increases, the Young's modulus increases and flexibility decreases. However, since the force that maintains the cylindrical shape becomes stronger as the Young's modulus increases, it may be an important parameter for increasing the fixing force.

[0104] (Dependence of inner diameter on the thickness of the first xerogel layer) In Example 3-1, the thickness of the first xerogel layer in the structure was adjusted by adjusting the depth of the mold in operation (2) during the first xerogel layer formation process. Figure 16(d) shows the relationship between the thickness of the first xerogel layer and the inner diameter when the swelling of the structure is complete. As the thickness of the inner layer (first xerogel layer) increased, the inner diameter tended to increase. This is thought to be because, similar to when the sol concentration was changed, the thickness of the gel suppresses the deformation of the hydrogel cuff. Figures 16(b) to 16(d) above are box plots summarizing the maximum, minimum, and average values ​​of multiple samples prepared under similar conditions for each condition.

[0105] From these results, it was found that a cuff-type structure with a minimum inner diameter of approximately 400 μm using the RT-01 electrode can be realized by at least "fabricating a 0.5 mm thick inner layer xerogel from 15% PVA sol with a strain of 1.5". The minimum inner diameter of existing cuff-type electrodes for animal experiments is 500 μm, and the inner diameter obtained this time is expected to be suitable for the fine nerves of small animals.

[0106] Deformation Mechanism In addition to the example in which the conditions were adjusted based on Example 3-1 described above, all fabricated xerogel structures (flat structures) deformed into a cylindrical cuff shape due to differences in hydrogel stress when they absorbed water and swelled. This is thought to be the result of the following action: Swollen hydrogel has elasticity, but dried xerogel has reduced elasticity. Therefore, when hydrogel is stretched and dried, it maintains the shape it had when stretched. When it swells again, it becomes hydrogel and regains its original stress state, and stress in the contraction direction is generated only in the stretched inner layer (first xerogel layer), causing it to deform into a cylindrical shape.

[0107] By insulating the insulating wiring around the electrode and the back surface of the electrode, electrical stimulation can be delivered to the nerve more efficiently. Figure 17 shows an example where polydimethylsiloxane (PDMS) is applied and solidified to insulate the electrode support. While insulating the back surface of the electrode support is effective, insufficient flexibility of the insulating layer is thought to affect the deformation behavior of the xerogel structure. On the other hand, a flat plate-shaped structure with an insulating layer is expected to have a larger inner diameter in the deformed cylindrical structure compared to a flat plate-shaped structure without an insulating layer.

[0108] Demonstrating usefulness through animal experiments Figures 18(a) to 18(c) show the process of fixing the electrode structure to the vagus nerve of a pig. Figure 18(a) shows the proximity process, Figure 18(b) shows the wrapping process, and Figure 18(c) shows the state after fixation. After the dry, flat xerogel electrode is inserted under the nerve, phosphate-buffered saline is applied, and wrapping is completed in about 30 seconds. Existing electrodes from LivaNova have a helical structure (Figure 2), requiring a complex procedure when attaching them to nerve bundles. On the other hand, the electrode structure of the present invention has a simple flat structure, yet it has sufficient fixing force, and can be said to have greatly improved operability. Figure 18(d) shows the change in heart rate when a pair of electrode structures are fixed to the vagus nerve of a pig and stimulation is applied. When the pigs were stimulated with a 10mA current and a bipolar square wave with a pulse width of 500μs for 30 seconds (yellow time domain), their heart rate decreased from 78 bpm to 74 bpm, indicating that a sufficient electric field was generated to stimulate the nerves.

[0109] (Dependence of swelling and shrinkage stress on the type of soluble component) In Example 3-1 above, a first xerogel layer was prepared under the same conditions as when the plate-shaped laminate was prepared. In addition, a sample was prepared by changing only the soluble component used in step (4) to NaCl (0.3M) under the conditions of the above example, and by omitting step (4). The three types of first xerogels prepared were placed on strain gauges, and the time dependence of the shrinkage force generated when immersed in physiological saline was measured.

[0110] Figure 19 is a graph showing the time dependence of the shrinkage force for each soluble component added to the xerogel. In Figure 19, NaCl and Glucose represent the measurement results of xerogels prepared using NaCl and glucose as soluble components, respectively, while control is a sample in which step (4) was omitted and no soluble components were added. From the measurement results, it was confirmed that xerogels with glucose and NaCl added showed a higher shrinkage force immediately after the start of swelling and a higher maximum value of swelling-shrinkage stress compared to xerogels without added soluble components. The maximum values ​​of swelling-shrinkage stress were approximately 21 kPa for NaCl, approximately 8 kPa for glucose, and approximately 6.5 kPa for xerogels without added soluble components.

[0111] 1, 1X First xerogel layer 1Z First gel 2 Second xerogel layer 2Z Second gel 3 Conductive layer 4 First insulating part 5 Second insulating part 6 Adhesive layer 8 Drug layer 10A, 10B, 10C Flat laminate 11 Soluble component 20 Conductor wire 31 Electrode part 32 Electrode support part 100A-100G Structure D Drug S1 First surface S2 Second surface λ Elongation ratio

Claims

1. A structure comprising a plate-shaped laminate having a first xerogel layer and a second xerogel layer laminated with the first xerogel layer, wherein the swelling and shrinkage stress is greater on the side where the first xerogel layer is formed than on the side where the second xerogel layer is formed.

2. The structure according to claim 1, wherein the plate-shaped laminate further comprises a conductive layer between the first xerogel layer and the second xerogel layer.

3. The structure according to claim 1, wherein in the plate-shaped laminate, the first xerogel layer and the second xerogel layer are in contact directly or via an adhesive layer.

4. The structure according to claim 2, wherein the conductive layer is made of carbonized bamboo fiber having a weft-woven structure and has a thickness of 0.50 mm or less.

5. The structure according to any one of claims 1 to 4, wherein the shrinkage stress of the first xerogel layer upon contact with moisture is 5 kPa or more and 20 kPa or less.

6. The structure according to any one of claims 1 to 5, wherein the first xerogel layer and the second xerogel layer each contain at least one polymer selected from the group consisting of polyvinyl alcohol, alginic acid, hyaluronic acid, chitosan, and gelatin.

7. The first xerogel layer is 5.0 × 10 -5 mol / cm 3 The above is 1.0 × 10 -3 mol / cm 3 The structure according to any one of claims 1 to 6, comprising the following soluble components.

8. The structure according to any one of claims 1 to 7, further comprising a drug, wherein the drug is contained in the first xerogel layer or contained between the first xerogel layer and the second xerogel layer.

9. A method for manufacturing a structure, comprising: a first xerogel layer formation step of drying a first gel in an extended state to form a first xerogel layer; a second xerogel layer preparation step of preparing a second xerogel layer having a lower swelling and shrinkage stress than the first xerogel layer; and an integration step of integrating the first xerogel layer and the second xerogel layer in a laminated state.

10. An electrode preparation step of preparing an electrode containing conductive fibers, wherein in the integration step, the first xerogel layer and the second xerogel layer are integrated by a freeze-thaw method to form a laminate in which the conductive fibers are laminated.

11. The method for manufacturing a structure according to claim 9, wherein in the integration step, the laminate in which the first xerogel layer and the second xerogel layer are laminated, either directly or via an adhesive layer, is integrated by a freeze-thaw method.

12. A method for producing a structure according to any one of claims 9 to 11, wherein in the first xerogel layer formation step, the first gel is dried with an elongation ratio λ of 1.5 or more and 3.0 or less.

13. A method for fixing a structure, comprising: an access step of bringing a structure according to any one of claims 1 to 8 close to a tubular biological tissue; and a wrapping step of swelling the structure and wrapping it around the biological tissue.

14. The method for fixing a structure according to claim 13, wherein in the proximity step, the structure is inserted under the biological tissue, and in the wrapping step, a liquid medium is brought into contact with the structure and the wrapping around the biological tissue is completed within 30 seconds.

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