Seamless hollow microneedle and method for producing seamless hollow microneedle

Abstract

To provide a seamless hollow microneedle and a method for producing the same.SOLUTION: Provided is a seamless hollow microneedle in which a rod-shaped metal with rotational symmetry at an arbitrary angle, with one hole parallel to a rotation axis of the rotational symmetry, both ends cut off in an arbitrary shape, a ratio of an outer diameter of a tip to an outer diameter of a base being 5% or more and 90% or less, and the maximum outer diameter being 6 mm or less. The seamless hollow microneedle is a hollow shaped in order to transport substances from the outside, has sufficiently different outer diameters at both ends, and is made of a material that is electrically conductive and has excellent strength and toughness. A strain rate sensitivity index (m value) is 0.00001 or more and 0.3 or less at a strain rate range of 0.0001 s-1 or more and 100 s-1 or less at an absolute temperature equal to or higher than half the absolute temperature at which the material is liquefied.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to seamless hollow microneedles and methods for producing seamless hollow microneedles. [Background technology]

[0002] Seamless hollow microneedles are useful not only for applications in the medical and biochemical fields but also as tools for manipulating cells. Recently, an electropuncture method has been proposed in which the needle electrode is treated with a conductive material to further improve its ability to puncture cell membranes (see Non-Patent Document 1).

[0003] The requirements for seamless hollow microneedles for handling such cells are, for example, (a) It has a hollow shape to transport substances from the outside. (b) The base should be thick and the tip should be thin for connection to the outside. That is, the outer diameters of both ends are sufficiently different. (c) Made of a material that is electrically conductive and has excellent strength and toughness. Patent Document 1 proposes a method for producing seamless hollow microneedles as described above by using a dieless drawing process to pull a superplastic metal as far as possible like a glass tube.

[0004] The method for measuring the strain rate sensitivity index (m value) is described in Patent Document 2, for example. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2021-115632 [Patent Document 2] Patent No. 6893354

[0006] [Non-Patent Document 1] Ryo Shirakashi and 7 others, "Changes in the dielectric properties of medaka fish embryos during development, studied by electrorotation", Biochemical and Biophysical Research Communications, Volume 428, Issue 1, November 9, 2012, Pages 127-131 Summary of the Invention [Problem to be solved by the invention]

[0007] The technology disclosed in Patent Document 1 has the problem that stable production is not possible due to the complex control of the pulling speed.

[0008] The present invention has been made to solve the above-mentioned problems, and aims to provide a seamless hollow microneedle made of metal that simultaneously satisfies the following (a), (b), and (c), and a method for stably producing the seamless hollow microneedle. (a) It has a hollow shape to transport substances from the outside. (b) The base should be thick and the tip should be thin for connection to the outside. That is, the outer diameters of both ends are sufficiently different. (c) Made of a material that is electrically conductive and has excellent strength and toughness. [Means for solving the problem]

[0009] The present inventors have conducted extensive research into the above-mentioned problems and have found that it is possible to stably obtain seamless hollow microneedles whose outer diameters at both ends are sufficiently different.

[0010] The present invention includes the following inventions. (1) A rod-shaped metal with rotational symmetry at an arbitrary angle, with one hole parallel to the rotation axis of the rotational symmetry, both ends cut off in an arbitrary shape, the ratio of the outer diameter of the tip to the outer diameter of the base is more than 5% but not more than 90%, the maximum outer diameter is 6 mm or less, and the strain rate sensitivity index (m value) of the metal is 0.0001 s at an absolute temperature equal to or higher than half the absolute temperature at which the metal liquefies. -1 Over 100s -1 A seamless hollow microneedle characterized by having a diameter of 0.00001 or more and 0.3 or less in the following range.

[0011] (2) The seamless hollow microneedle according to (1) above, wherein the metal is a superelastic metal.

[0012] (3) The seamless hollow microneedle according to (1) above, wherein the metal is a TiNi alloy containing 53 to 59 mass % of Ni, with the remainder being Ti and unavoidable impurities.

[0013] (4) The seamless hollow microneedle according to any one of (1) to (3) above, characterized in that the outer diameter of the tip portion is more than 0.02 mm and 0.5 mm or less.

[0014] (5) A rod-shaped metal with rotational symmetry at an arbitrary angle, with one hole parallel to the rotation axis of the rotational symmetry, with both ends cut off in an arbitrary shape, with the ratio of the outer diameter of the tip to the outer diameter of the base being 5% to 90% and the maximum outer diameter being 6 mm or less, and the strain rate sensitivity index (m value) of the metal being such that the strain rate is 0.0001 s at an absolute temperature equal to or higher than half the absolute temperature at which the metal liquefies. -1 Over 100s -1 In the production of seamless hollow microneedles having a diameter of 0.00001 or more and 0.3 or less in the following range: The method for producing the seamless hollow microneedle is characterized in that a series of steps consisting of [Step 1] to [Step 3] below are carried out once or twice or more in sequence on a seamless metal tube having a rod-shaped metal with rotational symmetry at an arbitrary angle, with one hole parallel to the rotation axis of the rotational symmetry, and whose minimum outer diameter is 90% or more of its maximum outer diameter. [Step 1]: A seamless tube in which a rod-shaped metal having rotational symmetry at an arbitrary angle has one hole parallel to the rotation axis of the rotational symmetry, and the minimum outer diameter is 90% or more of the maximum outer diameter. or A seamless hollow needle is provided, which has a rod-shaped metal having rotational symmetry at an arbitrary angle, a hole parallel to the rotation axis of the rotational symmetry, both ends of which are cut off in an arbitrary shape, and the ratio of the outer diameter of the tip to the outer diameter of the base is 5% or more and 90% or less. A dieless drawing process in which local heating is performed and the feeding speed and pulling speed of the seamless tube or the seamless hollow needle are controlled so that the pulling speed is greater than the feeding speed, thereby drawing the seamless tube or the seamless hollow needle to reduce its diameter. [Step 2]: An unloading step in which the diameter reduction is stopped by controlling the feeding speed and the pulling speed to be equal. [Step 3]: A cutting step of cutting the seamless tube or the seamless hollow needle at the portion where the diameter has been reduced by being pulled out and the portion where the diameter has not been reduced by being pulled out.

[0015] (6) The method for producing a seamless hollow microneedle according to (5) above, wherein the metal in step 1 is a superelastic metal.

[0016] (7) The method for producing seamless hollow microneedles according to (5) above, wherein the metal in step 1 is a TiNi alloy containing 53 to 59 mass % Ni, with the remainder being Ti and unavoidable impurities. [Effects of the Invention]

[0017] According to the seamless hollow microneedle and the method for manufacturing the seamless hollow microneedle of the present invention, seamless hollow microneedles made of conductive metal and having sufficiently different outer diameters at both ends can be manufactured stably at relatively low cost from, for example, a superelastic metal that is resistant to bending due to plastic deformation. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is a diagram illustrating the dieless drawing process of a tube. [Figure 2] FIG. 2 is a conceptual diagram illustrating the production of seamless hollow microneedles according to the present invention. [Figure 3] FIG. 3 is a conceptual diagram of the production of seamless hollow microneedles according to the present invention. [Figure 4] FIG. 4 is a schematic diagram of a dieless drawing device. [Figure 5] FIG. 5 is a schematic diagram of a seamless hollow microneedle according to the present invention. [Figure 6] FIG. 6 is a graph showing the outer diameter etc. of the seamless hollow microneedles obtained in Example 1. [Figure 7] FIG. 7 is a graph showing the outer diameter etc. of the seamless hollow microneedles obtained in Example 2. [Figure 8] FIG. 8 is a graph showing the outer diameter etc. of the seamless hollow microneedles obtained in Example 3. [Figure 9] FIG. 9 is a graph showing the results of comparing puncture resistance in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0019] Hereinafter, a seamless hollow microneedle and a method for manufacturing a seamless hollow microneedle according to an embodiment of the present invention will be described with reference to the drawings. <Terminology>

[0020] First, some terms used in this specification will be defined. In this specification, a hollow needle refers to an object that has a thin, gapless rod-like shape parallel to the axis of rotation that does not change shape when rotated at any angle around a straight line as the axis of rotation, has a single hole parallel to the axis of rotation, and has different outer diameters at both ends, with the end with the smaller outer diameter, i.e., the tip, being 90% or less of the outer diameter at the end with the larger outer diameter, i.e., the base, having both ends cut off into an arbitrary shape. Objects with such shapes are defined as hollow needles, and even objects with such shapes that have joints such as welds are considered hollow needles. In this specification, a tube is defined as an object that has a thin, rod-like shape with no voids parallel to the axis of rotation, does not change shape when rotated at any angle around a certain line as the axis of rotation, has one hole parallel to the axis of rotation, and has a minimum outer diameter that is 90% or more of the maximum outer diameter. Objects with such shapes are defined as tubes, and even objects with such shapes that have joints such as welds are also considered tubes. Here, the outer diameter refers to the outside diameter of an object in a cross section perpendicular to the rotation axis. The maximum and minimum values ​​of the outer diameter refer to the maximum and minimum values ​​of the change in the outer diameter when moving on the rotation axis. Also, the inner diameter refers to the diameter of the largest circle that can be drawn inside the object in a cross section perpendicular to the rotation axis. The maximum and minimum values ​​of the inner diameter refer to the maximum and minimum values ​​of the change in the inner diameter when moving on the rotation axis. In this specification, a seamless hollow needle refers to a hollow needle that does not have any joints formed by welding or the like, and a seamless tube refers to a tube that does not have any joints formed by welding or the like. In this specification, a hollow microneedle refers to a hollow needle having a maximum outer diameter of 6 mm or less, and a seamless hollow microneedle refers to a seamless hollow needle having a maximum outer diameter of 6 mm or less. <Ingredients>

[0021] If hollow microneedles with thin tips are made of glass, they may break when punctured because glass has poor toughness. In contrast, the seamless hollow microneedles of the present invention are made of metal, and therefore have excellent toughness, making them less likely to break when punctured, even if the tip is thin. However, for reasons that will be explained later, the strain rate sensitivity index (m value) of the metal is 0.0001 s at an absolute temperature of at least half the absolute temperature at which it liquefies. -1 Over 100s -1 It must be in the following range, between 0.00001 and 0.3. Furthermore, since it is seamless with no joints such as welds, the mechanical properties of the material have the same rotational symmetry as the shape and are not anisotropic, so it is less likely to develop a tendency to bend in a certain direction when punctured. However, even if the seamless hollow microneedle is made of metal, although it is less likely to break, bending due to plastic deformation may occur. If bending due to plastic deformation occurs when the seamless hollow microneedle is punctured, it becomes difficult to further advance or remove the seamless hollow microneedle. This bending due to plastic deformation is particularly likely to occur when the outer diameter of the seamless hollow microneedle is small, and to prevent this, it is preferable to use a superelastic metal as the metal, although this is not particularly limited. Since superelastic metals have a wide elastic range, even if bending occurs when the seamless hollow microneedle is punctured, it becomes an elastic deformation, so it can naturally return to its original shape, and it is almost never difficult to further advance or remove the seamless hollow microneedle. In this way, when the metal is made of superelastic metal, if there is a joint by welding or the like, the significant anisotropy of the mechanical properties causes a tendency to bend when punctured, resulting in a significant deterioration of the puncture characteristics. Therefore, when the metal is made of superelastic metal, it is extremely important to make it seamless and free of joints by welding or the like. In the present invention, a "superelastic metal" refers to a metal whose residual strain after a 6% strain load is 1.0% or less, preferably 0.5% or less, and more preferably 0.3% or less. Here, the residual strain refers to the strain that remains after a specified load strain or load stress is applied and then released, and is determined from the stress-strain curve after stress application and release in a tensile test. From the above, the strain rate sensitivity index (m value) is 0.0001 s at an absolute temperature of more than half the absolute temperature at which the material liquefies. -1 Over 100s -1 A seamless tube made of a metal, preferably a superelastic metal, having a modulus in the range of 0.00001 to 0.3 is prepared as a raw material. Examples of superelastic metals include TiNi alloys, copper-based alloys, iron-based alloys, gold-based alloys, etc. Among these, TiNi alloys are preferred because they are widely used, relatively inexpensive, and readily available.

[0022] The outer diameter of the seamless tube prepared here may be, for example, more than 0.1 mm and not more than 6 mm. By setting the outer diameter within this range, the base of the seamless hollow microneedle can be made to have a certain thickness, allowing the seamless hollow microneedle to be stably held. The lower limit of the outer diameter of the seamless tube may be more than 0.2 mm, more than 0.3 mm, or more than 0.5 mm, and the upper limit may be not more than 5 mm, not more than 4 mm, or not more than 3 mm.

[0023] The inner diameter of the seamless tube may be, for example, more than 0.02 mm and not more than 5 mm. The lower limit of the inner diameter of the seamless tube may be more than 0.05 mm, more than 0.1 mm, or more than 0.2 mm, and the upper limit may be not more than 4.0 mm, not more than 3.0 mm, or not more than 2.0 mm. The length of the seamless tube is not particularly limited, but may be, for example, not less than 10 mm. <Typical and steady dieless drawing>

[0024] Dieless drawing is a process that can reduce the diameter of a tube or hollow needle by drawing it out simply by applying localized heating and tension to the tube or hollow needle, enabling shorter manufacturing times and lower costs. As shown in Figure 1, local heating is performed using a heating device that locally heats the tube or hollow needle, and a cooling device that locally cools the tube or hollow needle downstream of the heating device. The tube or hollow needle is supplied from the heating device side while in a locally heated state, and is pulled from the cooling device side, causing the tube or hollow needle to be drawn out and reduced in diameter. Although it is not necessary to install a cooling device and perform local cooling, the degree of freedom in the shape of the hollow microneedle obtained by locally cooling the tube or hollow needle with a cooling device can be increased. Local cooling with a cooling device can be achieved, for example, by blowing compressed air onto the tube or hollow needle.

[0025] First, we will explain a typical steady dieless drawing process. As shown in Figure 1, the tube is locally heated and the drawing speed is increased. TIFF2025177329000002.tif42. At this time, the locally heated part has a small deformation resistance, so the diameter is reduced by constriction. Furthermore, Feed rate less than TIFF2025177329000003.tif42 As shown on the right side of Figure 1, if the specimen is moving at a constant speed of 1000 sq. m / s, the diameter-reduced portion due to this necking will expand continuously. TIFF2025177329000005.tif42 and supply speed If TIFF2025177329000006.tif43 remains constant and these ratios remain constant, the diameter of the narrowed portion due to the necking will be uniform, and the diameter can be reduced to a uniform diameter by pulling it out.

[0026] The mechanism by which the diameter becomes uniform is as follows. As shown in Figure 1, the cross-sectional area of ​​the tube before the diameter reduction due to necking occurs is TIFF2025177329000007.tif43, the cross-sectional area of ​​the tube at the narrowed part due to the constriction TIFF2025177329000008.tif43. Tensile speed TIFF2025177329000009.tif42 and supply speed If TIFF2025177329000010.tif43 remains unchanged, the following equation (1) holds true due to the condition of constant volume. TIFF2025177329000011.tif412...(1)

[0027] On the other hand, the reduction rate of area is TIFF2025177329000012.tif42, the area reduction rate TIFF2025177329000013.tif42 is expressed as the following formula (2).

number

[0028] From the above formulas (1) and (2), the following formula (3) is obtained.

number

[0029] Tensile speed TIFF2025177329000016.tif42 and supply speed If TIFF2025177329000017.tif43 remains unchanged, the area reduction rate is calculated from the above formula (3). TIFF2025177329000018.tif42 also remains unchanged. In other words, it is possible to draw to a uniform diameter using dieless drawing.

[0030] Hollow microneedles made of glass capillaries are manufactured by heating and pulling, similar to dieless drawing. This suggests that dieless drawing is effective for manufacturing hollow microneedles. However, the typical steady dieless drawing process described above alone cannot produce hollow microneedles with sufficiently different outer diameters at both ends. TIFF2025177329000019.tif42 is changed in a complex manner to make it non-steady, making the outer diameters at both ends different, but stable production was not possible because complex control was required. <Manufacturing method for seamless hollow microneedles using dieless drawing>

[0031] An example of a method for producing a seamless hollow microneedle according to the present invention will be described with reference to FIG. First, a seamless tube made of the above-mentioned metal as shown in FIG. 2(A) is prepared. Next, as shown in Figure 2(B) and (C), a typical steady dieless drawing process is performed. At this time, the start of the dieless drawing process is instantaneous, and the drawing speed is changed to Supply speed in TIFF2025177329000020.tif42 Set it to TIFF2025177329000021.tif42. Here, The file is TIFF2025177329000022.tif47. Next, as shown in Figure 2(D), both the pulling speed and the feeding speed are instantaneously increased. The diameter reduction by pulling is completed as TIFF2025177329000023.tif42. Finally, as shown in Figure 2(E), the seamless tube is cut at the portion of the seamless tube that has been drawn and the portion of the seamless tube that has not been drawn and has not been reduced in diameter. The cutting method is not particularly limited, but laser cutting may be used, for example. In conventional dieless drawing, cutting is performed only at the portion of the seamless tube that has been drawn and is reduced in diameter, as shown on the right side of Figure 2(E). 2(B) to 2(D) can be implemented at relatively low cost by using a dieless drawing device described later. Note that Fig. 2(E) can also be implemented by installing a cutting machine in the dieless drawing device described later.

[0032] This method enables the stable production of seamless hollow microneedles with different outer diameters at both ends, which cannot be achieved by conventional, typical, steady-state dieless drawing methods. Because the start and end of the drawing process are instantaneous, the pulling speed is a simple step function rather than a complex function of time as in the technology of Patent Document 1, making stable production possible. However, since the strain rate changes instantaneously, the strain rate sensitivity index (m value) of the metal being drawn is 0.0001 s at an absolute temperature of 1 / 2 or more of the absolute temperature at which the metal liquefies. -1 Over 100s -1 It is necessary to keep the strain rate sensitivity index (m value) within the range below 0.3. If the strain rate sensitivity index (m value) exceeds 0.3, the dependency on the strain rate is too strong, and if the strain rate changes instantaneously, the stress becomes unstable and uniform diameter reduction is not possible. Also, if the strain rate sensitivity index (m value) of the metal to be drawn is more than 0.0001 s at an absolute temperature of 1 / 2 or more of the absolute temperature at which the metal liquefies, -1 Over 100s -1 If the strain rate sensitivity index (m value) of the metal being drawn is less than 0.00001 in the following range, necking will occur. Therefore, the strain rate sensitivity index (m value) of the metal being drawn should be set to a strain rate of 0.0001 s at an absolute temperature of 1 / 2 or more of the absolute temperature at which the metal liquefies. -1 Over 100s -1 It must be 0.00001 or greater within the following range.

[0033] An example of the present invention in which the difference in outer diameter between both ends is further increased will be described with reference to FIG. First, as shown in FIG. 3(A), a seamless hollow microneedle having different outer diameters at both ends is prepared by the method shown in FIG. At this time, the length of the side with the smaller outer diameter is manufactured to be long enough to allow dieless drawing. Next, as shown in Figure 3(B) and (C), a typical steady dieless drawing process is performed on the side with the smaller outer diameter of the seamless hollow microneedle. At this time, the start of the dieless drawing process is instantaneous, and the pulling speed is increased at a certain time. Supply speed in TIFF2025177329000024.tif42 Set it to TIFF2025177329000025.tif73. Here, The file is TIFF2025177329000026.tif47. Next, as shown in Figure 3(D), both the pulling speed and the feeding speed are instantaneously increased. Finish reducing the diameter by pulling as TIFF2025177329000027.tif42. Finally, as shown in Figure 3(E), the seamless hollow microneedle is cut at the part that has been pulled out and the part that has not been pulled out and has not been reduced in diameter. The cutting method is not particularly limited, but may be, for example, laser cutting. 3(B) to 3(D) can be implemented at relatively low cost by using a dieless drawing apparatus described later. Note that Fig. 3(E) can also be implemented by installing a cutting machine in the dieless drawing apparatus described later.

[0034] In this way, by starting and finishing a typical, steady dieless drawing process and then performing cutting multiple times, it is possible to stably increase the difference in outer diameter between both ends sufficiently. Because the start and end of the drawing process are instantaneous, the pulling speed is a simple step function rather than a complex function of time as in the technology of Patent Document 1, making stable production possible. However, since the strain rate changes instantaneously, the strain rate sensitivity index (m value) of the metal being drawn is 0.0001 s at an absolute temperature of 1 / 2 or more of the absolute temperature at which the metal liquefies. -1 Over 100s -1It is necessary to keep the strain rate sensitivity index (m value) within the range below 0.3. If the strain rate sensitivity index (m value) exceeds 0.3, the dependency on the strain rate is too strong, and if the strain rate changes instantaneously, the stress becomes unstable and uniform diameter reduction is not possible. Also, if the strain rate sensitivity index (m value) of the metal to be drawn is more than 0.0001 s at an absolute temperature of 1 / 2 or more of the absolute temperature at which the metal liquefies, -1 Over 100s -1 If the strain rate sensitivity index (m value) of the metal being drawn is less than 0.00001 in the following range, necking will occur. Therefore, the strain rate sensitivity index (m value) of the metal being drawn should be set to a strain rate of 0.0001 s at an absolute temperature of 1 / 2 or more of the absolute temperature at which the metal liquefies. -1 Over 100s -1 It must be 0.00001 or greater within the following range.

[0035] These multiple processes can be performed economically using the same equipment, i.e., the dieless drawing equipment described below.

[0036] The absolute temperature of the localized heating in Figures 2(B), 2(C), 3(B), and 3(C) varies depending on the metal used, but may be, for example, an absolute temperature equal to or higher than half the absolute temperature at which the metal liquefies. By heating the tube at this absolute temperature, the tube can be drawn to reduce its diameter. For example, when a TiNi alloy containing 56 mass% Ni and the remainder consisting of Ti and unavoidable impurities is used, the melting point is 1583 K (1310 °C), so the localized heating temperature is 792 K (519 °C) or higher.

[0037] In addition, the pulling speed during diameter reduction by drawing in Figures 2(B), 2(C), 3(B), and 3(C) TIFF2025177329000028.tif42 is the supply speed The feed rate is not particularly limited as long as it is equal to or greater than 43 mm / s, but may be set within the range of 0.05 mm / s to 20 mm / s, for example. TIFF2025177329000030.tif43 is not particularly limited, but may be set within the range of 0.01 mm / s or more and 10 mm / s or less, for example. <How to derive the strain rate sensitivity index (m value)>

[0038] Strain rate 0.0001 s -1 Over 100s -1 The strain rate sensitivity index (m value) in the following range is -1 , 0.001s -1 , 0.01s -1 , 0.1s -1 , 1s -1 , 10s -1 , 100s -1 The flow stress can be obtained from the nominal stress and nominal strain curve obtained by the tensile test.

[0039] If the flow stress obtained from a tensile test with a strain rate of ε' is σ(ε'), the slope of the log σ(ε') and log ε' curve corresponds to the strain rate sensitivity index (m value). -1 , 0.001s -1 , 0.01s -1 , 0.1s -1 , 1s -1 , 10s -1 , 100s -1 If the log σ(ε') from the tensile test is plotted at log ε' of -4, -3, -2, -1, -0, +1, and +2, the strain rate sensitivity index (m value) can be calculated from the slope.

[0040] In the present invention, the strain rate sensitivity index (m value) determined in this manner must be 0.00001 or more and 0.3 or less at an absolute temperature equal to or higher than half the liquefaction temperature. Here, the absolute temperature equal to or higher than half the liquefaction temperature refers to the strain rate sensitivity index (m value) determined from a tensile test carried out at 100 K intervals at an absolute temperature equal to or higher than half the liquefaction temperature. <Dieless drawing equipment>

[0041] An example of a dieless drawing device consisting of the minimum necessary equipment capable of performing the dieless drawing shown in Figures 2(B) to 2(D) and 3(B) to 3(D) is shown in a schematic diagram in Figure 4. This dieless drawing device is composed of two rod-type electric actuators, two floating joints, two chuck devices, two halogen heaters, etc.

[0042] The two rod-type electric actuators must be connected to a control device such as a programmable logic controller so that they can be controlled independently. This allows for independent control of the pulling speed and feeding speed, making pulling possible.

[0043] Due to the need for localized heating, a relatively inexpensive halogen heater that can focus light into a point is used as the heat source. However, to ensure a uniform temperature in the heated area, two or more halogen heaters must be used so that they can heat from different directions. If it is desired to carry out the processes shown in Figures 2(E) and 3(E) using the dieless drawing device, it is necessary to install a cutting machine at an appropriate position on the dieless drawing device. Also, if necessary, a radiation thermometer may be installed on the dieless drawing device. <Seamless hollow microneedle>

[0044] Figure 5 shows a seamless hollow microneedle obtained by the manufacturing method of the present invention. Referring to Figure 5, the "ratio of the outer diameter of the tip portion to the outer diameter of the base portion" of the seamless hollow microneedle is defined as α. The ratio α of the outer diameter D2 of the tip portion 1B of the seamless hollow microneedle 1 to the outer diameter D1 of the base portion 1A of the seamless hollow microneedle 1 is defined as α = (outer diameter D2 of the tip portion 1B / outer diameter D1 of the base portion 1A) × 100. The value of α can be, for example, 90% or less. The upper limit of α may be 80% or less, 70% or less, or 60% or less. The lower limit of this ratio may be greater than 5%. The outer diameter D1 of the base portion 1A and the outer diameter D2 of the tip portion 1B can be measured from a photograph taken with a microscope.

[0045] The outer diameter D1 of the base portion 1A of the seamless hollow microneedle 1 shown in Fig. 5 is not particularly limited, but may be, for example, more than 0.1 mm and not more than 6 mm. The lower limit of the outer diameter D1 of the base portion 1A may be more than 0.2 mm, more than 0.3 mm, or more than 0.5 mm, and the upper limit of the outer diameter D1 may be not more than 5 mm, not more than 4 mm, or not more than 3 mm. The inner diameter of the base portion 1A is also not particularly limited, but may be more than 0.02 mm and not more than 5 mm.

[0046] The outer diameter D2 of the tip portion 1B of the seamless hollow microneedle 1 shown in Figure 5 is not particularly limited, but may be, for example, more than 0.02 mm and not more than 2 mm. The lower limit of the outer diameter D2 of the tip portion 1B may be more than 0.02 mm, more than 0.03 mm, more than 0.04 mm, or more than 0.05 mm, and the upper limit of the outer diameter D2 may be not more than 1 mm, not more than 0.5 mm, not more than 0.2 mm, or not more than 0.1 mm. The inner diameter of the tip portion 1B is also not particularly limited, but may be more than 0.02 mm and not more than 1 mm.

[0047] The seamless hollow microneedle 1 shown in Figure 5 is useful not only for applications in the medical and biochemical fields, but also as a tool for animal experiments and for manipulating cells, fish eggs, and other eggs. In addition to the physical puncture properties of the needle itself, a conductive metal seamless hollow microneedle can be treated as a needle electrode by applying an electric pulse signal, further improving its ability to puncture cell membranes with a small force. Furthermore, seamless metal hollow microneedles can also be used as electrodes for measuring biosignals or as emitters of electrons or ionic liquids.

[0048] The seamless hollow microneedle 1 shown in Fig. 5 is hollow, and therefore can inject liquid into cells or eggs. For example, the seamless hollow microneedle 1 can inject medicines or cryopreservatives into fish eggs. Furthermore, the seamless hollow microneedle 1 can not only inject liquids but also aspirate any liquids.

[0049] According to the present invention, the strain rate sensitivity index (m value) is 0.0001 s at an absolute temperature equal to or higher than half the absolute temperature at which the material liquefies. -1 Over 100s -1 A seamless hollow microneedle made of metal with different outer diameters at both ends and conductivity can be obtained by sequentially performing a series of steps, one or more times, including a step of locally heating a seamless tube or seamless hollow needle made of metal within the range of 0.00001 to 0.3 and performing dieless drawing to differentiate the outer diameters at both ends of the seamless tube or seamless hollow needle, a step of stopping dieless drawing, and a step of cutting the seamless hollow needle. Furthermore, because the seamless hollow microneedle is made of metal, it has improved puncture properties, excellent toughness, and is less likely to break when punctured, even if the outer diameter of the tip is thin. In particular, using a superelastic metal can prevent bending due to plastic deformation, which rarely occurs. [Example]

[0050] In order to explain the present invention in detail, examples are given below, but the present invention is not limited to these descriptions. Example 1

[0051] The raw material was a superelastic metal TiNi alloy containing 56 mass% Ni with the remainder being Ti and unavoidable impurities. Several seamless tubes of the superelastic metal with an outer diameter D of 0.33 mm and an inner diameter d of 0.24 mm were prepared.

[0052] Using a part of the prepared seamless tube of the superelastic metal, a tensile test was carried out at a strain rate of 0.0001 s at an absolute temperature of 792 K or higher. -1 Over 100s -1 The strain rate sensitivity index (m value) was calculated and was found to be between 0.00001 and 0.3.

[0053] A schematic diagram of the dieless drawing device used in Examples 1 to 3 is shown in Figure 4. The dieless drawing device is composed of two rod-type electric actuators, two floating joints, two chuck devices, two halogen heaters, etc. No cooling device was installed, and cooling was performed by air cooling. The rod-type electric actuators are connected to a programmable logic controller, allowing them to be controlled independently. The halogen heater is capable of focusing light into a point, with a focal length of 30 mm, a focal diameter of 8 mm, and a maximum output of 450 W per unit. The halogen heater was used by adjusting the focus so that it was aligned with the tube.

[0054] The contents carried out in Example 1 are shown below in order. (a) Both ends of the seamless tube were held by the chuck device. (b) The output was set to 150 W and the seamless tube was locally heated using two of the halogen heaters. (c) To stabilize the temperature of the seamless tube, the diameter is not reduced by drawing, and the supply speed is TIFF2025177329000031.tif43 and tensile speed TIFF2025177329000032.tif42 were both set to 2.0 mm / s and maintained for several seconds. (d) Supply speed TIFF2025177329000033.tif43 was left unchanged at 2.0 mm / s, and the tensile speed TIFF2025177329000034.tif42 was increased to 3.3 mm / s and the diameter reduction by drawing began. (e) When the length of the diameter-reduced portion due to drawing reaches 150 mm, the local heating by the two halogen heaters is stopped and the supply speed is reduced. TIFF2025177329000035.tif43 and tensile speed TIFF2025177329000036.tif42 were both set to 0.0 mm / s. (f) The product manufactured from the seamless tube as described above was removed from the chuck device and cut with a laser at appropriate positions between the part that was reduced in diameter due to drawing and the part that was not reduced in diameter due to drawing, to obtain a seamless hollow microneedle made of superelastic metal. Several seamless hollow microneedles were manufactured from superelastic metal in the manner described above. The outer diameter of the manufactured seamless microneedles is shown in Figure 6. The "ratio of the outer diameter of the tip to the outer diameter of the base" was 76%. Tensile test pieces 1 and 2 were cut out from the portion of the manufactured seamless hollow microneedle shown in Figure 6, and a tensile test was performed at a test speed of 2% / min, with a gauge length of approximately 3 mm, in which a stress of 6% strain was applied and then unloaded. As a result, the residual strain of tensile test pieces 1 and 2 was 1.0% or less. As is clear from the above, according to Example 1 of the present invention, seamless hollow microneedles made of metal with different outer diameters at both ends and conductivity can be manufactured at relatively low cost. Because the seamless hollow microneedles are made of metal, they have excellent toughness, and because the metal is a superelastic metal, they can be prevented from bending due to plastic deformation. <Example 2>

[0055] Since the appropriate outer diameter of a seamless hollow microneedle depends on the application, it is necessary to be able to manufacture a wide range of outer diameters in order to make seamless hollow microneedles practical. Therefore, in Examples 2 and 3, we investigated whether it was possible to increase the range of the difference in outer diameter between both ends.

[0056] As raw materials, a plurality of seamless hollow microneedles were prepared by cutting in steps (a) to (f) of Example 1 so that the length of the diameter-reduced portion due to pulling was 110 mm or more.

[0057] Using a part of the prepared seamless hollow microneedle, a tensile test was performed on the diameter-reduced part by pulling, and the strain rate was 0.0001 s at an absolute temperature of 792 K or higher. -1 Over 100s -1 The strain rate sensitivity index (m value) was calculated and was found to be between 0.00001 and 0.3.

[0058] The dieless drawing device used was the same as that used in Example 1, and was adjusted so that the focus of the halogen heater was on the seamless hollow microneedles.

[0059] The following describes the steps carried out in Example 2. (a) Both ends of the prepared seamless hollow microneedle were held by the chuck device. (b) The output was set to 150 W and the seamless hollow microneedles were locally heated using two of the halogen heaters. (c) To stabilize the temperature of the seamless hollow microneedle, the diameter is not reduced by pulling, and the supply speed is TIFF2025177329000037.tif43 and tensile speed Both TIFF2025177329000038.tif42 were maintained at 2.0 mm / s for several seconds. (d) Supply speed TIFF2025177329000039.tif43 was left unchanged at 2.0 mm / s, and the tensile speed TIFF2025177329000040.tif42 was increased to 2.9 mm / s and the diameter reduction by drawing was started. (e) When the length of the diameter-reduced portion due to drawing reaches 100 mm, the local heating by the two halogen heaters is stopped and the supply speed is reduced. TIFF2025177329000041.tif43 and tensile speed TIFF2025177329000042.tif42 were both set to 0.0 mm / s. (f) The product manufactured from the seamless hollow microneedle as described above was removed from the chuck device and cut with a laser at appropriate positions in the part that had been reduced in diameter by pulling out and the part that had not been reduced in diameter by pulling out, thereby obtaining a seamless hollow microneedle made of a superelastic metal. Several seamless hollow microneedles were manufactured from superelastic metal in the manner described above. The outer diameter of the manufactured seamless hollow microneedles is shown in Figure 7. The "ratio of the outer diameter of the tip to the outer diameter of the base" was 64%. Tensile test pieces 3, 4, and 5 were cut out from the portion of the manufactured seamless hollow microneedle shown in Figure 7, and a tensile test was performed at a test speed of 2% / min, with a gauge length of approximately 3 mm, in which a stress of 6% strain was applied and then unloaded. As a result, the residual strain of tensile test pieces 3, 4, and 5 was 1.0% or less. As is clear from the above, according to Example 2 of the present invention, a seamless hollow metal microneedle having a larger difference in outer diameter between both ends than in Example 1 and having electrical conductivity can be manufactured from metal at relatively low cost. Because the seamless hollow microneedle is made of metal, it has excellent toughness, and furthermore, because the metal is a superelastic metal, bending due to plastic deformation can be prevented. Example 3

[0060] As raw materials, a plurality of seamless hollow microneedles were prepared by cutting in steps (a) to (f) of Example 2 so that the length of the diameter-reduced portion due to pulling was 60 mm or more.

[0061] Using a part of the prepared seamless hollow microneedle, a tensile test was performed on the diameter-reduced part by pulling, and the strain rate was 0.0001 s at an absolute temperature of 792 K or higher. -1 Over 100s -1 The strain rate sensitivity index (m value) was calculated and was found to be between 0.00001 and 0.3.

[0062] The dieless drawing device used was the same as that used in Example 1, and was adjusted so that the focus of the halogen heater was on the seamless hollow microneedles.

[0063] The steps carried out in Example 3 are shown below in order. (a) Both ends of the prepared seamless hollow microneedle were held by the chuck device. (b) The output was set to 170 W and the seamless hollow microneedles were locally heated using two of the halogen heaters. (c) To stabilize the temperature of the seamless hollow microneedle, the diameter is not reduced by pulling, and the supply speed is TIFF2025177329000043.tif43 and tensile speed TIFF2025177329000044.tif42 were both set to 5.0 mm / s and maintained for several seconds. (d) Supply speed TIFF2025177329000045.tif43 was left unchanged at 5.0 mm / s, and the tensile speed TIFF2025177329000046.tif42 was increased to 6.3 mm / s and the diameter reduction by drawing began. (e) When the length of the diameter-reduced portion due to drawing reaches 50 mm, the local heating by the two halogen heaters is stopped and the supply speed is reduced. TIFF2025177329000047.tif43 and tensile speed TIFF2025177329000048.tif42 were both set to 0.0 mm / s. (f) The product manufactured from the seamless hollow microneedle as described above was removed from the chuck device and cut with a laser at appropriate positions in the part that had been reduced in diameter by pulling out and the part that had not been reduced in diameter by pulling out, thereby obtaining a seamless hollow microneedle made of a superelastic metal. Several seamless hollow microneedles were manufactured from superelastic metal in the manner described above. The outer diameters of the manufactured seamless hollow microneedles are shown in Figure 8. The "ratio of the outer diameter of the tip to the outer diameter of the base" was 56%. Tensile test pieces 6, 7, 8, and 9 were cut out from the portion of the manufactured seamless hollow microneedle shown in Figure 8, and a tensile test was performed at a test speed of 2% / min, with a gauge length of approximately 3 mm, in which a stress of 6% strain was applied and then unloaded. As a result, the residual strain of tensile test pieces 6, 7, 8, and 9 was 1.0% or less. As is clear from the above, according to Example 3 of the present invention, a seamless hollow microneedle made of metal having a larger difference in outer diameter between both ends than in Example 2 and having electrical conductivity can be manufactured at relatively low cost. Because the seamless hollow microneedle is made of metal, it has excellent toughness, and furthermore, because the metal is a superelastic metal, bending due to plastic deformation can be prevented. Example 4

[0064] According to the present invention, it is possible to stably produce seamless hollow microneedles that are less likely to bend due to plastic deformation, for example, but if the seamless hollow microneedles produced according to the present invention were more difficult to puncture than conventional hollow microneedles, they would not be practical. Therefore, the puncture resistance of the seamless hollow microneedles produced according to the present invention was compared with that of commercially available hollow microneedles that are among the finest in the world.

[0065] As an example of the invention, a seamless hollow microneedle was used, the tip of which was processed into a lancet by a laser, as produced in Example 3. As a comparative example, a hollow microneedle was used, which was made by rolling and joining stainless steel plates manufactured by Company A. The outer diameter of the tip of the comparative example was 0.18 mm.

[0066] The puncture resistance was compared by measuring the resistance force exerted when a hollow microneedle was inserted perpendicularly to the surface of a polydimethylsiloxane sheet to a depth of 1.5 mm, and dividing the measured value by the minimum outer diameter of the needle tube excluding the tip. The thickness of the polydimethylsiloxane sheet was 5 mm, and the puncture speed was 0.1 mm / s.

[0067] Figure 9 shows the results of a comparison of puncture resistance, and the values ​​obtained by dividing the puncture resistance by the outer diameter of the invention example and the comparative example were similar within the range of variation. This result shows that the seamless hollow microneedles produced according to the present invention can be punctured with the same feel as conventional hollow microneedles. [Explanation of symbols]

[0068] 1. Seamless hollow microneedle 1 A … Base 1 B … Tip D 1 , D 2 … Outer diameter

Claims

1. A rod-shaped metal having rotational symmetry at an arbitrary angle, with one hole parallel to the rotation axis of the rotational symmetry, both ends cut off in an arbitrary shape, the ratio of the outer diameter of the tip to the outer diameter of the base being more than 5% but not more than 90%, the maximum outer diameter being 6 mm or less, and the strain rate sensitivity index (m value) of the metal being such that it is 0.0001 s at a strain rate of 0.0001 s at an absolute temperature equal to or higher than half the absolute temperature at which the metal liquefies. －１ Over 100s －１ A seamless hollow microneedle characterized in that the diameter is in the range of 0.00001 or more and 0.3 or less.

2. 2. The seamless hollow microneedle according to claim 1, wherein the metal is a superelastic metal.

3. 2. The seamless hollow microneedle according to claim 1, wherein the metal is a TiNi alloy containing 53 to 59 mass % Ni, with the remainder being Ti and unavoidable impurities.

4. The seamless hollow microneedle according to any one of claims 1 to 3, wherein the outer diameter of the tip portion is greater than 0.02 mm and not greater than 0.5 mm.

5. A rod-shaped metal having rotational symmetry at an arbitrary angle, with one hole parallel to the rotation axis of the rotational symmetry, both ends cut off in an arbitrary shape, the ratio of the outer diameter of the tip to the outer diameter of the base being 5% to 90%, the maximum outer diameter being 6 mm or less, and the strain rate sensitivity index (m value) of the metal being such that it is 0.0001 s at a strain rate of 0.0001 s at an absolute temperature equal to or higher than half the absolute temperature at which the metal liquefies. －１ Over 100s －１ In the production of seamless hollow microneedles, the average diameter is 0.00001 or more and 0.3 or less in the following range: A method for producing the seamless hollow microneedle, characterized in that a rod-shaped metal having rotational symmetry at an arbitrary angle has one hole parallel to the rotation axis of the rotational symmetry, and the metal seamless tube has a minimum outer diameter that is 90% or more of the maximum outer diameter, and the series of steps consisting of [Step 1] to [Step 3] below are carried out once or twice or more in sequence. [Step 1]: A seamless tube having a rod-shaped metal with rotational symmetry at an arbitrary angle, with one hole parallel to the rotation axis of the rotational symmetry, and the minimum outer diameter being 90% or more of the maximum outer diameter. or A seamless hollow needle is provided, which is a rod-shaped metal having rotational symmetry at an arbitrary angle, has one hole parallel to the rotation axis of the rotational symmetry, has both ends cut off in an arbitrary shape, and has a ratio of the outer diameter of the tip to the outer diameter of the base of the needle of 5% to 90%. A dieless drawing process in which local heating is performed and the feeding speed and pulling speed of the seamless tube or the seamless hollow needle are controlled so that the pulling speed is greater than the feeding speed, thereby drawing the seamless tube or the seamless hollow needle to reduce its diameter. [Step 2]: An unloading step in which the diameter reduction is stopped by controlling the feeding speed and the pulling speed to be equal. [Step 3]: A cutting step of cutting the seamless tube or the seamless hollow needle at the portion where the diameter has been reduced by pulling out and the portion where the diameter has not been reduced by not pulling out.

6. 6. The method for producing seamless hollow microneedles according to claim 5, wherein the metal in step 1 is a superelastic metal.

7. The method for producing seamless hollow microneedles according to claim 5, characterized in that the metal in step 1 is a TiNi alloy containing 53 to 59 mass% Ni, with the remainder being Ti and unavoidable impurities.

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