Microneedle, microneedle array and production method therefor
09597490 ยท 2017-03-21
Assignee
Inventors
- Johan Willem Berenschot (Ratum, NL)
- Jeroen Mathijn Wissink (Enschede, NL)
- Niels Roelof Tas (Enschede, NL)
- Meint Jelle DeBoer (Enschede, NL)
Cpc classification
International classification
Abstract
The present invention provides a microneedle, comprising a shaft of a monocrystalline material having at least three walls which are formed by a crystal plane of the monocrystalline material; and a tip connected to an end of the shaft comprising at least three walls which are formed by a crystal plane of the material. The material is preferably silicon. Two of the walls of the tip are formed by the same crystal planes as two walls of the shaft. These two walls are formed by a <111> crystal plane. Preferably, three walls of the tip are formed by a <111> crystal plane.
Claims
1. An in-plane microneedle made from a monocrystalline material, comprising: a shaft, comprising at least three walls, each of the at least three walls being <111> crystal planes of the monocrystalline material; and a tip connected to an end of the shaft and comprising at least three walls, each of the at least three walls being <111> crystal planes of the monocrystalline material, wherein at least three of the walls of the tip are adjoining and at least three of the walls of the tip are formed by the same <111> crystal planes as the at least three walls of the shaft, wherein the tip comprises at least two cutting edges, the at least two cutting edges each being formed by lines of intersection where a pair of the <111> crystal planes of the tip adjoin one another, wherein said <111> crystal planes of the tip and the shaft are atomically flat, and wherein said cutting edges are atomically sharp.
2. The microneedle according to claim 1, wherein the <111> crystal planes are not parallel to one another.
3. The microneedle according to claim 2, wherein the tip comprises a fourth wall which is identical to a surface of a substrate of the monocrystalline material from which the microneedle is made.
4. The microneedle according to claim 1, wherein the microneedle is formed from a monocrystalline silicon substrate having surfaces of a crystal orientation matching the sharpness of the tip.
5. The microneedle according to claim 1, wherein the monocrystalline material is one of the following: monocrystalline silicon <100>, monocrystalline silicon <211> or monocrystalline silicon <110>.
6. The microneedle according to claim 1, wherein a channel is provided in at least one of the shaft and the tip.
7. The microneedle according to claim 6, in which the channel is open in the longitudinal direction.
8. The microneedle according to claim 1, wherein said <111> crystal planes of the tip converge into an end of the tip.
9. The microneedle according to claim 8, wherein said <111> crystal planes of the tip converge into the end of the tip in an atomically sharp manner.
10. The microneedle according to claim 8, wherein said <111> crystal planes of the tip converge into the end of the tip at an internal acute angle.
11. An in-plane microneedle made from a monocrystalline material, comprising: a shaft, comprising at least two walls, each of the at least two walls being <111> crystal planes of the monocrystalline material; and a tip connected to an end of the shaft and comprising at least three walls, each of the at least three walls being <111> crystal planes of the monocrystalline material, wherein the at least three walls of the tip are adjoining and the three walls of the tip converge at one end in an approximately atomically sharp manner and the at least three walls adjoin one another at an internal angle of about 70, wherein the tip comprises at least two cutting edges, the at least two cutting edges each being formed by lines of intersection where a pair of the <111> crystal planes of the tip adjoin one another, wherein said <111> crystal planes of the tip and the shaft are atomically flat, and wherein said cutting edges are atomically sharp.
12. The microneedle according to claim 11, wherein the <111> crystal planes are not parallel to one another.
13. The microneedle according to claim 12, wherein the tip comprises a fourth wall which is identical to a surface of a substrate of the monocrystalline material from which the microneedle is made.
14. The microneedle according to claim 11, wherein the microneedle is formed from a monocrystalline silicon substrate having surfaces of a crystal orientation matching the sharpness of the tip.
15. The microneedle according to claim 11, wherein the monocrystalline material is one of the following: monocrystalline silicon <100>, monocrystalline silicon <211> or monocrystalline silicon <110>.
16. The microneedle according to claim 11, wherein a channel is provided in at least one of the shaft and the tip.
17. The microneedle according to claim 16, in which the channel is open in the longitudinal direction.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) The accompanying drawings, which are included to provide a further understanding of the invention, are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the detailed description serve to explain the principles of the invention. No attempt is made to show structural details of the invention in more detail than may be necessary for a fundamental understanding of the invention and the various ways in which it may be practiced. In the drawings:
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DETAILED DESCRIPTION OF THE INVENTION
(17) The embodiments of the invention and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments and examples that are described and/or illustrated in the accompanying drawings and detailed in the following description. It should be noted that the features illustrated in the drawings are not necessarily drawn to scale, and features of one embodiment may be employed with other embodiments as the skilled artisan would recognize, even if not explicitly stated herein. Descriptions of well-known components and processing techniques may be omitted so as to not unnecessarily obscure the embodiments of the invention. The examples used herein are intended merely to facilitate an understanding of ways in which the invention may be practiced and to further enable those of skill in the art to practice the embodiments of the invention. Accordingly, the examples and embodiments herein should not be construed as limiting the scope of the invention, which is defined solely by the appended claims and applicable law. Moreover, it is noted that like reference numerals represent similar parks throughout the several views of the drawings.
(18) In an embodiment shown in
(19) The shaft 14 has a shape which is approximately triangular in cross section, having at least three walls 18, 20, 22 which adjoin one another. The plane 18, just like the plane 24 of the base 16, corresponds to a surface of the substrate and is, in the illustrated embodiment, thus a <100> crystal plane. The planes 20 and 22 are <111> crystal planes of the silicon.
(20) The tip 12 comprises three adjoining walls 20, 22 and 25. The planes 20 and 22 also form a side wall of the shaft. The plane 25 is a <111> crystal plane which, from a line of intersection 26 with the plane 18, extends obliquely in the direction of a pointed end 28 of the tip 12. The outer circumference of the shaft 14 has a cross section which is equal to the cross section of the widest part of the tip 12, at the location of the line of intersection 26.
(21) Optionally, a channel 30 is provided in the microneedle 10, through which for example medicinal products and liquids can be transported.
(22) A plane 32 of the base, which plane 32 is opposite the plane 24, also forms part of the surface of the substrate. Thus, the plane 32 is a <100> plane. The plane 25 is at an internal angle with respect to the plane 32 of approximately 54.74, and also with respect to the line of intersection 34 of the walls 20, 22.
(23) In another embodiment shown in
(24) In cross section, the shaft 114 is approximately trapezium-shaped. In top or bottom view, the shaft 114 widens, viewed from the dividing iine 126 with the tip 112. The shaft 114 comprises four walls 118, 120,122 and 123. The walls 118 and 123 correspond to surfaces of the substrate and, in the present embodiment, are <211> crystal planes. The walls 120, 122 are <111> crystal planes which are at an angle with respect to the walls 118, 123.
(25) The tip 112 comprises three adjoining walls 120, 122, 125 and a part of the wall 123. The walls 120 and 122 also form a side wall of the shaft. The plane 125 is a <111> crystal plane which, from a line of intersection 126 with the plane 118, extends obliquely in the direction of a pointed end 128 of the tip 112. The wall 125 is at an internal angle of approximately 19.47 to the wall 123. This angle can therefore be chosen by using a substrate having a certain crystal orientation at the surface as starting material.
(26) In order that it can be used, the microneedle 110 shown in
(27) In an embodiment shown in
(28) In cross section, the shaft 214 approximately has the shape of a pentagon, with walls 218, 220, 222, 223, 224 and 225, which adjoin one another. Just like plane 217 of the base 216, plane 218 corresponds to a surface of the substrate and, in the illustrated embodiment, is thus a <100> crystal plane. The plane 223 is also a <100> crystal plane and is situated parallel to 218. The planes 225, 220, 222, 224 and 226 are <111> crystal planes of the silicon.
(29) The tip 212 comprises the walls 218, 220, 222, 223, 224, 225 and 226. The plane 226 is a <111> crystal plane which adjoins the planes 218, 225, 220, 223, 222, 224 and, from a line of intersection with the plane 218, extends obliquely in the direction of a pointed end, where it adjoins wall 223.
(30) An advantage of this embodiment may be that the needle has an advantageous circumference relative to the cross section. As a result thereof, the required force of penetration for a certain channel size with a certain circulation is limited. In addition, the cut in the skin which a microneedle according to this embodiment causes, is also limited.
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(32) In another embodiment shown in
(33) The shaft 414 comprises four walls 418, 420, 422 and 423. The walls 418 and 423 correspond to surfaces of the substrate and, in the present embodiment, are <110> crystal planes. In the present embodiment, the walls 420 and 422 are slow-etching <111> crystal planes.
(34) The tip 412 comprises five walls 418, 420, 422, 423 and 425 adjoining each other, i.e. all planes of the shaft, and the <111> plane 425. The walls 420 and 422 are slow-etching <111> planes and also form a side wall of the shaft. The plane 425 is a <111> crystal plane which, from a line of intersection with the plane 422, extends obliquely in the direction of a pointed end of tip 412.
(35) It may be an advantage of this embodiment that the microneedle has a relatively small aperture angle, as a result of which the required force of penetration is smaller than with needles having relatively large angles. In this context, this is referred to as a sharper needle or tip.
(36) Since the above-described microneedles are in-plane needles, see
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(38) Preferably, the holder 202 comprises a thermoplastic, such as PE and/or PP. The microneedles are, for example, fused into the apertures. Fusing can be achieved by heating a microneedle until the plastic of the holder melts locally around the aperture in which the microneedle is arranged. By then allowing the respective microneedle to cool down, the molten plastic sets again and forms a water-tight and air-tight connection between the microneedle and the holder. A microneedle may, for example, be heated in a contactless manner by means of a light or laser beam focussed on the microneedle. By heating the microneedles contactlessly, assembly is significantly simplified and the risk of damage is minimized.
(39) The production of the above-described microneedles is described below. In the description, the terms which are customary in the processing of a semiconductor material such as silicon are used. For a detailed description of the terms used, reference is made to Silicon Micromachining by M. Elwenspoek, H. V. Jansen, Cambridge University Press 1998.
(40) The microneedle according to the present invention is made from a substrate of monocrystalline material, for example a semiconductor, having surfaces which correspond to a certain crystal plane. The shape of the microneedle depends on the orientation of the crystal planes in the substrate. The present invention provides a sharper microneedle by etching free certain crystal planes in monocrystalline substrates with a certain orientation.
(41) The (two-dimensional (2D) photolithographic) production techniques used in this invention are based on the monocrystalline substrates. The substrates are sawn from a bulk material which essentially comprises a single crystal. Usually, the substrate is a round disc or a wafer. The plane which results on the surface of the substrate after sawing determines the crystal direction with respect to the surface of the substrate. Since the surface of the substrate is determined by the direction of sawing, the crystal plane at the surface of the substrate can be chosen arbitrarily with respect to the crystal direction in the substrate. This surface is usually a crystal plane. The crystal plane is referred to by Miller indices, e.g. a <100>, <110>, <111> plane. A crystal plane is any plane in the crystal in which the atoms form a repeating pattern. A substrate is inter alia referred to by the crystal plane of the surface, for example a <100> oriented silicon substrate, or simply <100> silicon or silicon <100>. Any other arbitrary crystal plane, such as <211> or <310> is also possible, however.
(42) The choice of crystal plane for the surface of the substrate partly determines the internal angles of the tip of the microneedle.
(43) Operations are carried out on the surfaces of the substrates, for example making lithographic images, etching material away and depositing material, as a result of which structures are created on the substrate surface and/or in the bulk of the substrate.
(44) The monocrystalline substrates comprise crystal planes which may have mutually different etching speeds, so-called anisotropic etching processes. Relatively slow etching crystal planes thus form atomically flat crystal planes during anisotropic etching processes. As a result of a particular selection and sequence of the 2D lithographic steps and etching processes, examples of which are given, but to which the invention is not limited, these crystal planes form the atomically flat walls of a microneedle according to the present invention.
(45) The surfaces of the substrates are finished by mechanical and/or chemical polishing in order to ensure a certain degree of flatness. This surface is usually not slow etching, but by the finishing treatment of the surface of the substrate, the latter is usually flat to atomically flat, at least atomic flatness can be approached.
(46) Both the top and the bottom side of a substrate can be polished. Substrates are also designated thereby and the degree of flatness may also be designated.
(47) Monocrystalline silicon is the material which is preferred, but the invention is not limited to silicon. Monocrystalline silicon forms a cubic crystal, in which the atoms form a structure or a tetrahedron which is comparable to diamond. Other suitable substrates comprise, for example, a monocrystalline semiconductor or quartz.
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(49) In one embodiment (
(50) In a first step, a buried channel 30 is provided at the location where a microneedle is to be produced (
(51) The buried channel may be arranged on the side of the surface 324 or of the surface 332 of the substrate, as desired. However, it is preferred if the buried channel 30 is arranged on the side of the surface 324.
(52) In a subsequent step (
(53) Potassium hydroxide (KOH) which etches silicon selectively is a suitable anisotropic wet-etching agent. KOH is able to etch the silicon approximately 400 times more quickly in the direction of the <100> crystal planes than in the direction of the <111> planes. In other words, the <111> planes etch more slowly than other crystal planes. Another suitable etching agent is EDP (an aqueous solution of ethylene diamine and pyrocatechol). EDP etches p-doped silicon approximately at a ratio of 50:3 in the direction of the <100> crystal planes compared to the direction of the <111> planes. Tetramethylammoniumhydroxide (TMAH) can also be used, but the selectivity between <100> and <111> planes is worse than that of EDP. Since KOH etches most selectively, it is preferred for the present invention.
(54) The etching agent etches away the silicon through the aperture in the protective layer, in which process the relatively slow etching <111> planes become visible. The etching step is terminated as soon as the protective layer on the other side 324 of the substrate is reached. The <111> crystal planes 20, 350, 352, and 354 together form an elongate well 356 in the substrate (
(55) In a next step (
(56) The etching agent etches away the silicon through the aperture in the protective layer, in which process the relatively slow etching <111> planes become visible. The etching step is terminated as soon as the protective layer on the other side 324 of the substrate is reached. The <111> crystal planes 22, 360, 362, and 364 together form an elongate well 366 in the substrate (
(57) In a next step (
(58) In a next step (
(59) Subsequently, the microneedle 10 is detached from the substrate. The microneedle 10 can for example be removed from the substrate by etching (result shown in
(60) In the case of etching, a protective layer is first provided at the top of the substrate. In the protective layer, an aperture (not shown) is provided on the bottom side 324 or the top side 332 of the substrate where the substrate is not covered for etching the base 16. Thereafter, an etching agent (for example KOH) is used to anisotropically etch the silicon of the substrate through the aperture until the base 16 remains.
(61) Another, more simple method for producing a microneedle according to the invention is shown in
(62) The steps shown in
(63) The difference relates to the step shown in
(64) Subsequently, the substrate 300 is etched anisotropically. The etching agent etches the silicon away through the two apertures in the protective layer, in which process the slow etching <111> planes become visible. The etching step is terminated as soon as the protective layer on the other side 324 of the substrate is reached. The <111> crystal planes 20, 350, 352, 354 together form the elongate well 356 in the substrate (
(65) The microneedle which has been produced according to the method from
(66) The tip 12 of the microneedle which has been produced according to the method of
(67) The tip 12 according to the present invention is formed by walls which comprise crystal planes of the substrate. The walls adjoin one another at lines of intersection, and taper off into an end 28. The lines of intersection and the end are approximately atomically sharp, that is to say that the radius of curvature of the end 28 and/or of the lines of intersection between the walls 20, 22, 23 and/or 25 have a radius of curvature in the order of the radius of an atom. The radius of curvature is, for example, in the order of 1-100 nm. As a result of the small radius of curvature, the microneedle is sharp. Due to the small radius of curvature of the lines of intersection which, in addition, extend along the entire length of the tip 12, the entire tip of the microneedle cuts into the skin. Consequently, a smaller force is required to penetrate the skin than is the case with known microneedles. Since the shaft 14 also has walls of crystal planes which adjoin one another at lines of intersection, the shaft also has a cutting action on the skin. The walls 18, 20, 22, 23 and 25 of the microneedle approximately correspond to a crystal plane of the silicon, and can be approximately atomically flat. An atomically flat wall causes less friction on the skin than a rougher wall, as a result of which the microneedle according to the invention experiences less counterforce from the skin and damages the skin to a lesser degree.
(68) An embodiment of the method for the production of a microneedle which can result in microneedles shown in
(69) Another method for producing a microneedle which can result in microneedles shown in
(70) After the microneedle has been produced, a coating layer may still be applied on the outer surface thereof in order to allow the microneedle to slide into the skin more easily. The coating layer comprises, for example, a silicone oil. The silicone oil may, for example, be applied by submerging the microneedles in a bath of silicone oil. In addition, the microneedles may be taken to a chamber in which the silicone oil is then applied in vapour form or by means of a fine mist or spray.
(71) While the invention has been described in terms of exemplary embodiments, those skilled in the art will recognize that the invention can be practiced with modifications in the spirit and scope of the appended claims. These examples given above are merely illustrative and are not meant to be an exhaustive list of all possible designs, embodiments, applications or modifications of the invention.