Structural body

Abstract

This structural body (100) has a structure that allows for self-assembly, and comprises: a base plate (101); a sacrificial layer (102) formed on one principal surface (101a) of the base plate; and a layered body (103) formed by layering a first conductor layer (104), a dielectric layer (105), and a second conductor layer (106) in that order on the sacrificial layer (102). The first conductor layer (104) is a conductive two-dimensional atomic layer; and the second conductor layer (106) is a dispersion in which a conductive material has been dispersed.

Description

structure

[0001] The present invention relates to a structure comprising a self-assembling laminate.

[0002] Technologies that measure and control the brain and nerves using electrical devices, including brain-machine interfaces, are attracting attention. Electronic devices that enable measurement and control at various scales, from the level of nerve cells to various nerve tissues throughout the body and the entire brain, are being fabricated. However, a problem remains in that while devices have a planar nature based on semiconductor processes, biological tissues have a three-dimensional curved surface, resulting in poor electrical contact between the devices and biological tissues. Solving this problem remains a common challenge.

[0003] In recent years, methods using self-assembling thin films that self-organize into three-dimensional shapes such as cylinders (self-assembling thin films) have attracted attention as a method for fabricating devices with curved surfaces. While many self-assembling thin films and self-assembly methods are known, the number of self-assembly methods for thin films suitable for cell culture and biological tissues is limited. First, it is essential that both the thin film material and the self-assembly method for thin films are harmless to living organisms. Furthermore, it is necessary that a process method capable of processing thin films into arbitrary patterns be established, and that at least one conductive thin film that can be connected to external devices be employed. Graphene and parylene are examples of thin film materials that meet these conditions and are inexpensive and commercially advantageous.

[0004] Graphene is used as a material for implantable and wearable devices, and parylene has high biocompatibility, having received approval from the U.S. Food and Drug Administration for medical applications. Thin films made of graphene and parylene are characterized by their high biocompatibility and ease of self-assembly into three-dimensional shapes. A typical example is a process in which a layer of calcium alginate (sacrificial layer) is formed on a substrate, graphene and parylene are deposited on top of it, and the sacrificial layer is dissolved with ethylenediaminetetraacetic acid (EDTA) to obtain the three-dimensional shape. This method is characterized by low toxicity to biological tissue, not only in the thin film material but also in the self-assembly method itself (Non-Patent Literature 1). In this method, since the parylene surface, which is an insulator, is on the inside of the cylinder, it is necessary to add a conductive layer to the surface that comes into contact with biological tissue (Non-Patent Literature 2). In prior examples, graphene is used as the conductive layer, and to counteract the mechanical effects of the conductive layer, graphene is further laminated below the parylene (i.e., a layered structure of two graphene layers / parylene / graphene).

[0005] The methods described in previous examples have a limited range of choices for thin film materials to serve as the conductive layer, other than graphene. Since the mechanical properties of graphene and parylene are key to self-assembly, thin films that have mechanical effects cannot be selected. For example, metal thin films have high rigidity, which hinders self-assembly. Furthermore, graphene is obtained by wet etching a copper thin film and transferring it to a substrate, but the methods described in previous examples require three or more transfer steps. Therefore, the transfer process is time-consuming, hindering cost reduction.

[0006] K. Sakai et al., Nanoscale, 13249 (2019)K. Sakai et al., Advanced Functional Materials 2301836 (2023)

[0007] This invention has been made in view of the above circumstances, and aims to provide a structure that has a wide range of material options, a biocompatible conductive layer, a self-assembling laminate, and can be manufactured with fewer processes.

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

[0009] A structure according to one aspect of the present invention is a self-assembling structure comprising a substrate, a sacrificial layer formed on one main surface of the substrate, and a laminate in which a first conductive layer, a dielectric layer, and a second conductive layer are sequentially laminated on the sacrificial layer, wherein the first conductive layer is a conductive two-dimensional atomic layer, and the second conductive layer is a dispersion in which a conductive material is dispersed.

[0010] According to the present invention, it is possible to provide a structure that has a wide range of material options, a biocompatible conductive layer, a self-assembling laminate, and can be manufactured with fewer processes.

[0011] This is a perspective view of a structure according to one embodiment of the present invention. This is a top view of the laminate constituting the structure of the same embodiment. This is a perspective view of the structure of the same embodiment during the manufacturing process. This is a top view of the structure before self-assembly with electrodes and nerve bundles mounted in the same embodiment. This is a side view of the structure before self-assembly with electrodes and nerve bundles mounted in the same embodiment. This is a side view of the structure after self-assembly with electrodes and nerve bundles mounted in the same embodiment. This is a top view of the structure before self-assembly with electrodes and cells mounted in the same embodiment. This is a side view of the structure before self-assembly with electrodes and cells mounted in the same embodiment. This is a perspective view of the structure after self-assembly with electrodes and cells mounted in the same embodiment. This is an image of the laminate before self-assembly in the structure of Example 1. This is an image of the laminate after self-assembly in the structure of Example 1. This is an image of the laminate after self-assembly in the structure of Example 1. This is an image of the laminate before self-assembly in the structure of Example 2. This is an image of the laminate after self-assembly in the structure of Example 2. This is an image of the laminate after self-assembly in the structure of Example 2. This is an image of the state in which nerve cells are cultured on the basement membrane as in Example 3.

[0012] The following describes in detail, with reference to the drawings, a structure according to an embodiment to which the present invention is applied. Note that, for convenience, the drawings used in the following description may show enlarged versions of characteristic parts to make the features easier to understand, and the dimensional ratios of each component may not be the same as in reality. Furthermore, the materials, dimensions, etc., exemplified in the following description are merely examples, and the present invention is not limited to these; it can be implemented with appropriate modifications without altering its essence.

[0013] [Structure] Figure 1 is a perspective view of a structure 100 according to one embodiment of the present invention. The structure 100 is a structure having a self-assembly structure, and mainly comprises a substrate 101, a sacrificial layer 102 formed on one main surface 101a of the substrate, and a self-assembly laminate 103.

[0014] The substrate 101 is a plate-shaped member having a flat surface 101. The constituent material of the substrate 101 can be any material that can be used in a normal semiconductor process, such as glass, silicon, or plastic. The constituent material of the substrate 101 may also be a flexible material such as polyethylene terephthalate (PET).

[0015] The sacrificial layer 102 is formed on one main surface 101a of the substrate. The sacrificial layer 102 is made of a material that can be removed by a predetermined method without damaging each layer of the laminate 103 and the biological tissue to be measured. The constituent material of the sacrificial layer 102 is not particularly limited, but in this embodiment, the use of calcium alginate is exemplified.

[0016] A sodium alginate aqueous solution is spin-coated onto a substrate 101, and this is then immersed in a calcium chloride aqueous solution to obtain a gelled calcium alginate thin film. By adding EDTA (ethylenediaminetetraacetic acid) to the calcium alginate thin film, the calcium ions in the calcium alginate are chelated with EDTA, and the calcium alginate thin film is removed.

[0017] The laminate 103 is a thin film formed by sequentially stacking a first conductive layer 104, a dielectric layer 105, and a second conductive layer 106 on a sacrificial layer 102. The laminate 103 can be processed into any pattern by known processes such as semiconductor processes. In Figure 1, multiple laminates processed into a rectangular pattern are shown as examples in a plan view from the stacking direction L.

[0018] The laminate 103 has a self-assembly configuration, that is, a configuration in which all layers are curved in the same direction. Such a configuration can be obtained, for example, by adjusting the material, thickness, etc., of each layer so that the Young's modulus decreases with increasing size of the upper layers, which are further from the substrate 101.

[0019] The first conductive layer 104 is made of graphene, MoS ２ Preferably, it is a two-dimensional atomic layer composed of atoms arranged along one surface. The material of the first conductive layer 104 is not particularly limited as long as it is self-assembling, but graphene is most preferred considering processability and cost.

[0020] As the material for the dielectric layer 105, a polymer that can be self-assembled together with the two-dimensional atomic layer can be used. Parylene, which can adhere closely to the material of the first conductive layer (graphene) and is biocompatible, is most preferred.

[0021] The second conductive layer 106 is a dispersion of a conductive material, and the material used is one that is conductive, harmless to biological tissue, and has little effect on the self-assembly shape of the laminate 103. Here, we illustrate the case in which a dispersion of graphene flakes is used as the conductive material. Graphene flakes are flake-shaped graphene foils with an average diameter of about 1 to 10 μm, and are dispersed in the solvent of the dispersion.

[0022] Many types of dispersions with different solvents and concentrations are commercially available. Those skilled in the art can use their own synthesized dispersions, or those that have been modified from commercially available products, depending on the purpose. However, since the manufacturing process of the structure 100 involves patterning of the laminate 103, the dispersion must be insoluble in common organic solvents used in the process, such as acetone and ethanol, and water, and must not hinder the formation of the laminate 103.

[0023] The conductive material to be dispersed only needs to maintain biocompatibility and be self-assembling. Examples of dispersions other than graphene flakes include PEDOT:PSS (Poly3,4-EthyleneDiOxyThiophene / Poly4-StyreneSulfonate) or MXene. MXene is a general term for composite atomic layer compounds composed of pre-periodic transition metals (titanium or vanadium) and light elements (carbon or nitrogen). PEDOT:PSS and MXene are colloids dispersed in aqueous solutions or organic solvents and exhibit excellent biocompatibility.

[0024] By dissolving part or all of the sacrificial layer 102, the open portion of the laminate 103 self-assembles by curving in a predetermined direction. The direction of curvature is determined by the Young's modulus of each layer of the laminate 103. If the layers further from the substrate 101 have smaller Young's moduli, the laminate becomes cylindrical with the second conductive layer 106 on the inside.

[0025] Figure 2 is a plan view of the laminate 103 from the stacking direction L. The outer periphery of the laminate 103 curves as the laminate 103 self-assembles, forming a curved region R. １ And the non-curved region R ２ It has a curved region R. １ This is the region where the sacrificial layer 102 dissolves relatively quickly during self-assembly, causing it to curve. (Non-curved region R) ２ In this case, the dissolution of the sacrificial layer 102 proceeds relatively slowly, and the curved region R curves first. １ This is the region where curvature is suppressed.

[0026] Non-curved region R ２For example, it has a plurality of through holes (hole patterns) 107 that penetrate the laminate 103 in the lamination direction L. The plurality of through holes 107 are formed in a line along the outer circumference of the laminate 103. Non-curved region R having through holes 107 ２ Therefore, the sacrificial layer melts faster compared to other regions. As a result, cylindrical self-assembly can preferentially occur with the direction in which the through holes 107 of the laminate 103 are aligned as the axial direction.

[0027] [Method for manufacturing the structure] The structure 100 can be manufactured by the following procedure.

[0028] (Substrate Cleaning) The substrate 101 is cleaned with a piranha, oxygen plasma, etc. If cleaning with a strong acid such as a piranha is not possible, cleaning may be done with an organic solvent such as ethanol, acetone, or IPA.

[0029] (Formation of Sacrificial Layer) A sacrificial layer 102 is formed on one of the main surfaces 101a of the cleaned substrate. At this time, the sacrificial layer 102 may be formed over the entire main surface 101a, or it may be formed only in a predetermined area of ​​the main surface 101a by using a combination of photolithography patterning or the like. If the sacrificial layer 102 is composed of metal or calcium alginate, it can be used as a sacrificial layer even after the photoresist pattern has been removed with acetone. In this embodiment, calcium alginate, which has low toxicity to biological tissue, is assumed to be the material for the sacrificial layer 102.

[0030] (Formation of the first conductive layer) A two-dimensional atomic layer, for example, is transferred onto the sacrificial layer 102 as the first conductive layer 104. The two-dimensional atomic layer to be transferred may be an atomic layer exfoliated from a two-dimensional crystal, or an atomic layer grown by the CVD method. The two-dimensional atomic layer is preferably approximately 1 atomic layer (single atomic layer) to 100 atomic layers, with a thickness of about 0.1 nm to 50 nm.

[0031] (Dielectric Layer Formation) A dielectric layer (dielectric thin film) 105 is formed (deposited) on the first conductive layer 104. When parylene is used as the material for the dielectric layer 105, a parylene polymer grown from a dimer by CVD is deposited. Parylene can be easily deposited by vapor deposition and bonds strongly to π-conjugated two-dimensional thin films such as graphene by π-π conjugation. Therefore, it is possible to prevent the formed dielectric layer 105 from easily peeling off from the π-conjugated two-dimensional thin film. When parylene is used, the thickness of the dielectric layer 105 is preferably 100 nm to 3000 nm.

[0032] (Formation of the second conductive layer) A second conductive layer 106 made of a dispersion is formed (film-deposited) on the dielectric layer 105. The thickness of the second conductive layer 106 formed by coating the material onto the substrate by bar coating or printing is several μm or more, which is a concern as it may hinder the self-assembly of the laminate. Furthermore, even if patterning is performed on the thick second conductive layer 106, it may not be possible to completely remove the second conductive layer 106 outside the pattern, so it is not preferable to form the second conductive layer 106 by bar coating or printing.

[0033] The formation of the second conductive layer 106 is preferably carried out by spin coating. When graphene flakes are spin coated at 2000 rpm, the thickness of the second conductive layer 106 is generally between 40 nm and 100 nm, which is within the range of thickness applicable to self-assembled thin films. In particular, since graphene flakes have a loose π-π conjugation bond with the parylene layer, the influence on the self-assembled shape can be minimized. The structure 100 with the second conductive layer 106 formed is heated to 60°C or higher using a hot plate or bake oven to evaporate the solvent of the dispersion. However, if the two-dimensional atomic layer is graphene, heating above 350°C will reduce conductivity, so it is preferable to avoid heating above this temperature.

[0034] When the dispersion is PEDOT:PSS or maxine, either an aqueous solution system or an organic solvent system may be used. In order to make the laminate 103 a thin film that can self-assemble, the thickness of the second conductor layer 106 is usually 100 nm or less, but it may be increased according to the size (thickness) of the pattern of the laminate 103. For example, when the laminate 103 has a large pattern of mm size, the thickness of the second conductor layer 106 may be 100 nm or more. The second conductor layer 106 formed by spin coating is heated to 60 °C or higher to remove the solvent.

[0035] (Patterning) The formed laminate 103 is patterned by lithography. For example, a resist 108 is spin-coated on the laminate 103. FIG. 3 is a perspective view of the structure coated with the resist 108. The resist may be either positive or negative, but the resist after development should be formed at the location where the pattern is to be left. The film thickness of the resist for forming the pattern is preferably such that it remains without being removed even after the subsequent dry etching process. Here, although the pattern of the laminate 103 is a rectangular parallelepiped, any pattern according to the purpose may be used.

[0036] After forming the pattern of the laminate 103, the thin film layer outside the pattern is removed by dry etching. With the configuration of the laminate 103 of the present embodiment, the thin film layer outside the pattern can be removed by oxygen plasma treatment. Other conditions can also be adjusted by those skilled in the art. When a thin film material that cannot be removed by oxygen plasma treatment is used for the laminate 103, it may be removed by physical etching such as an ion beam. Those skilled in the art can also set optimal conditions for the removal process of the thin film layer. Through the above dry etching, a structure 100 having the pattern of the laminate 103 as shown in FIG. 1 is obtained.

[0037] A method of encapsulating biological tissue in the thin film composed of the laminate 103 (sacrificial layer / first conductor layer / dielectric layer / second conductor layer) of the present embodiment will be described.

[0038] FIGS. 4A, 4B, and 4C show a nerve bundle T such as a peripheral nerve １This figure shows the state in which the electrode 109 and nerve bundle T are enclosed in a thin film of the laminate 103. Figures 4A and 4B show the electrode 109 and nerve bundle T, respectively. １ Figure 4C shows a top view and a side view of the thin film before self-assembly. Figure 4C is a side view of the thin film after self-assembly. Here, an electrode 109 is placed at one end of a rectangular thin film pattern. The material of the electrode 109 can be selected according to the intended use by those skilled in the art. For example, a metal such as gold or chromium may be selected, or a conductive polymer such as PEDOT:PSS may be selected.

[0039] In this embodiment, a hole array 107 may be placed at the edge of the thin film so as to self-assemble in the short axis direction. The hole array 107 is a plurality of through holes that penetrate the thin film of the laminate 103 in the lamination direction L. By placing the hole array 107, the area in contact with the dissolving solution of the sacrificial layer is widened, and self-assembly in the short axis direction (self-assembly by bending the long side of the rectangle) becomes dominant. Through this self-assembly, nerve bundle T １ It is enclosed so as to be in contact with the second conductive layer 106 located on the inner surface of the cylindrical thin film, and nerve bundle T １ In contrast, the nerve bundle T is transmitted from electrode 109 through the second conductive layer 106. １ Electrical stimulation and electrical measurement can be performed. The structure 100 of this embodiment can be applied, for example, to implantable nerve stimulation electrodes.

[0040] Figures 5A, 5B, and 5C show cell T ２ This figure shows the state in which the electrode 109 and cell T are enclosed in a thin film of the laminate 103. Figures 5A and 5B show the electrode 109 and cell T, respectively. ２ Figure 5C shows a top view and a side view of the thin film before self-assembly. Figure 5C is a perspective view of the same thin film after self-assembly. Here, the thin film self-assembles in the direction of the long axis (self-assembly by bending the short side of the rectangle) and becomes cylindrical. In this case, since self-assembly is performed in the direction of the long axis, a hole array as shown in Figure 4A is not necessary, but if self-assembly is performed in the direction of the short axis, a hole array is formed at the end of the thin film.

[0041] The surface of the second conductive layer 106 is modified with cell adhesion proteins such as laminin or cationic polymers such as PEI (polyethyleneimine). After seeding cells on this layer, the sacrificial layer is dissolved to allow self-assembly. Because a thin film and sacrificial layer lysis solution that are harmless to cells are used, it is possible to grow the cells even after self-assembly. Although not shown here, by providing electrodes as in Figure 4A, it becomes possible to stimulate cultured cells and perform electrical measurements.

[0042] As described above, the structure 100 of this embodiment includes a thin film of a laminate 103 that self-assembles (bends) into a cylindrical shape by dissolving the sacrificial layer 102, with a first conductive layer 104, a dielectric layer 105, and a second conductive layer 106 stacked in that order on the sacrificial layer 102. After self-assembly, biological tissue is placed inside the cylindrical laminate 103, and the properties of the biological tissue can be electrically measured by bringing the biological tissue into contact with the second conductive layer 106, which is the outermost layer on the inside.

[0043] The second conductive layer 106 is a dispersion of conductive material, and therefore has the advantage of being conductive and not mechanically inhibiting self-assembly. By selecting a highly biocompatible dispersion as the second conductive layer 106, it is possible to maintain good contact with living tissue. By having a thin film of such a laminate 103, the structure 100 can be applied to devices for measuring nerve tissue at different scales, such as cells and nerve tissue.

[0044] A thin film consisting of a parylene-based π-electron polymer sandwiched between transferred graphene and a conductive dispersion self-assembles into a three-dimensional shape with the dispersion on the inside and the inside shrinking. Since typical conductive dispersions have a sheet resistance value (1-3 kΩ / □) that is sufficient for use as a bioelectrode, biological tissue can be enclosed inside the self-assembled tubular dispersion thin film, and sufficient electrical contact is achieved between the biological tissue and the dispersion. Furthermore, since the minimum number of transfers required for the two-dimensional atomic layer (graphene) is only one, the number of transfers can be reduced compared to the conventional process for obtaining graphene / parylene / graphene thin films, resulting in lower costs. Therefore, the structure 100 of this embodiment can be expected to have various industrial applications, from research to medical applications, as a three-dimensional electrode that encapsulates biological tissue within its three-dimensional shape.

[0045] The effects of the present invention will be made clearer by the following examples. However, the present invention is not limited to the following examples and can be modified as appropriate without altering its essence.

[0046] (Example 1) A structure was manufactured according to the above embodiment. A rectangular thin film pattern (calcium alginate / graphene / parylene / graphene flakes) measuring 300 μm × 600 μm was formed on a substrate. The sacrificial layer was made of calcium alginate. The laminate was made up of a first conductive layer (two-dimensional atomic layer (graphene)), a dielectric layer (parylene / 70 nm thick), and a second conductive layer (graphene flakes) stacked in that order.

[0047] EDTA was dropped into the sacrificial layer and dissolved, and the laminate was bent into a cylindrical shape within 30 seconds for self-assembly. Figures 6A and 6B are images of the laminate before and after self-assembly. Figure 6C is an image of the laminate after self-assembly. The laminate was self-assembled with the first conductive layer on the outside. The radius of curvature of the self-assembled laminate in Example 1 was the same as the radius of curvature of the self-assembled laminate (calcium alginate / graphene / parylene) produced under the same conditions as Example 1, except for the absence of the second conductive layer.

[0048] (Example 2) A rectangular thin film pattern was formed on the substrate in the same manner as in Example 1, except that the parylene film thickness was 170 nm. Figures 7A and 7B are images of the laminate before and after self-assembly. Figure 7C is an image of the laminate after self-assembly. The radius of curvature of the self-assembled laminate in Example 2 was larger than that of Example 1, but it was equal to the radius of curvature of a laminate (calcium alginate / graphene / parylene) made under the same conditions as Example 2, except that there was no second conductive layer, when it was self-assembled.

[0049] The results from Examples 1 and 2 show that, in the structure of the present invention, the graphene flakes constituting the second conductive layer do not affect the self-assembly shape.

[0050] (Example 3) Nerve cells were cultured on a graphene flake thin film coated with laminin (basement membrane). Figure 8 shows an image of the cultured nerve cells. The fact that nerve cells are growing across the entire surface of the graphene flake thin film clearly demonstrates the excellent adhesion of graphene flakes to nerve cells.

[0051] 100 Structure 101 Substrate 101a One main surface of the substrate 102 Sacrificial layer 103 Laminate 104 First conductive layer 105 Dielectric layer 106 Second conductive layer 107 Through hole 108 Resist 109 Electrode D １ , D ２ Self-assembly direction L, Stacking direction R １ Curved region R ２ Non-curved area T １ Nerve bundle T ２ cell

Claims

1. A structure having a self-assembly capability, comprising: a substrate; a sacrificial layer formed on one main surface of the substrate; and a laminate in which a first conductive layer, a dielectric layer, and a second conductive layer are sequentially laminated on the sacrificial layer, wherein the first conductive layer is a conductive two-dimensional atomic layer, and the second conductive layer is a dispersion in which a conductive material is dispersed.

2. The structure according to claim 1, characterized in that the conductive material is one of graphene flakes, PEDOT:PSS, or Maxine.

3. The structure according to either claim 1 or 2, characterized in that the thickness of the second conductive layer is 40 nm or more and 100 nm or less.

4. The structure according to either 1 or 2, characterized in that the outer periphery of the laminate, viewed in plan from the stacking direction, has a curved region that curves during self-assembly and a non-curved region, and the laminate has a plurality of through holes that are aligned along the non-curved region of the outer periphery and penetrate in the stacking direction.

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