技术领域technical field
本发明涉及经皮微针阵列贴布，特别有关于一种量测皮下的目标分子浓度以获知人体生理信号的经皮微针阵列贴布。The invention relates to a percutaneous microneedle array patch, in particular to a percutaneous microneedle array patch for measuring the concentration of target molecules under the skin to obtain physiological signals of a human body.
背景技术Background technique
皮下组织是人类组织液流动分布的主要地方，组织液中富含有胺基酸、糖、脂肪酸、辅酶、激素、神经递质、盐及细胞产生的废物等，是细胞与血液交流的主要管道，因此通过组织液中各成份的浓度是用以判断生理状况的方法之一。The subcutaneous tissue is the main place for the flow and distribution of human interstitial fluid. Interstitial fluid is rich in amino acids, sugars, fatty acids, coenzymes, hormones, neurotransmitters, salts, and wastes produced by cells. It is the main channel for cells to communicate with blood. The concentration of each component in interstitial fluid is one of the methods used to judge the physiological condition.
服用或施打药物时，药物会在组织液中长时间且缓慢的释放，在药物开发及使用的临床实验过程中，往往需不断地监控药物于组织液中浓度的变化，也因此取样组织液以进行检测或分析，在医疗程序中是随处可见的。When taking or injecting drugs, the drugs will be released slowly and for a long time in the interstitial fluid. During the clinical trials of drug development and use, it is often necessary to continuously monitor the changes in the concentration of the drug in the interstitial fluid, so sampling the interstitial fluid for detection Or analysis, is ubiquitous in medical procedures.
现今市面所见的生理检测器材，或医护人员采样组织液的方法，多半采扎针并穿破角质层，来抽取组织液以进行分析检测，然而此种破坏皮肤表层的取样方法，除了容易使患者感觉疼痛，进而萌生排斥感外，皮肤表层的大量微生物，也容易在皮肤表层遭破坏的情况下，进入人体进而感染。为了改善扎针并穿破角质层取样的缺点，有提出经皮传感器，其利用阵列形式的微针进行皮肤穿刺，低侵入性的穿刺能够有效减轻使用者的疼痛感，又同时达到取样组织液的目的。Most of the physiological testing equipment seen in the market today, or the method of sampling tissue fluid by medical staff, is to prick a needle and pierce the stratum corneum to extract tissue fluid for analysis and testing. , In addition to creating a sense of rejection, a large number of microorganisms on the surface of the skin can easily enter the human body and cause infection when the surface of the skin is damaged. In order to improve the shortcomings of needling and piercing the stratum corneum for sampling, a transdermal sensor has been proposed, which uses microneedles in the form of an array to puncture the skin. The low-invasive puncture can effectively reduce the pain of the user and at the same time achieve the purpose of sampling tissue fluid. .
经皮传感器的微针制作常见有利用微影及蚀刻等半导体工艺，例如美国专利US7,344,499B1的说明书第12栏第2段揭示一种硅微针的工艺。首先，提供其上覆盖有图案化的第一光刻胶层的一硅晶圆。接着，利用等向性蚀刻方式进行蚀刻，形成一穿孔。接着，于晶圆表面涂布一铬层，之后涂布图案化的一第二光刻胶层，以至于覆盖在穿孔上，及形成一圆形屏蔽供后续蚀刻。接着，进行蚀刻以形成微针的外锥壁。然而，由于含硅半导体材料的脆性，当微针穿刺皮肤进行感测时，微针容易断裂。Microneedles for transdermal sensors are often produced by using semiconductor processes such as lithography and etching. For example, the second paragraph of column 12 of the description of US Patent No. 7,344,499B1 discloses a silicon microneedle process. First, a silicon wafer covered with a patterned first photoresist layer is provided. Next, etching is performed by isotropic etching to form a through hole. Then, a chromium layer is coated on the surface of the wafer, and then a patterned second photoresist layer is coated so as to cover the through hole and form a circular shield for subsequent etching. Next, etching is performed to form the outer tapered walls of the microneedles. However, due to the brittleness of silicon-containing semiconductor materials, the microneedles are easily broken when they penetrate the skin for sensing.
另外，有提出使用激光微加工的方式，对树脂形成的突刺钻孔，以制作中空微针。首先，使用例如聚酰亚胺树脂或聚醚醚酮树脂进行挤出成型，形成其上具有多个突刺的薄片，接着使用激光对突刺钻孔，即可得到中空微针。然而，由于微针尺寸极细小，挤出成型时突刺可能产生毛边，而且不论是偏轴穿孔或中心穿孔，使用激光形成统一的孔径并非容易。In addition, it has been proposed to use laser micromachining to drill holes in resin-formed thorns to produce hollow microneedles. First, polyimide resin or polyetheretherketone resin is used for extrusion molding to form a thin sheet with a plurality of thorns on it, and then a laser is used to drill holes in the thorns to obtain a hollow microneedle. However, due to the extremely small size of the microneedles, the protrusions may produce burrs during extrusion, and it is not easy to form a uniform pore size with a laser, whether it is off-axis perforation or central perforation.
发明内容Contents of the invention
本发明的目的在于提供一种经皮微针阵列贴布及其制造方法，使其微针组的微针穿刺皮肤进行感测时，微针能保持完好。The purpose of the present invention is to provide a percutaneous microneedle array patch and a manufacturing method thereof, so that when the microneedles of the microneedle group puncture the skin for sensing, the microneedles can remain intact.
为了达成上述的目的，本发明提供一种经皮微针阵列贴布，用以量测皮下目标分子的浓度，该经皮微针阵列贴布包含:基板、微针单元、信号处理单元及电源单元。微针单元至少包含排列于基板上的第一微针组以及第二微针组，该第一微针组作为工作电极，该第一微针组的所述微针以阵列形式排列于该基板上，该第二微针组作为参考电极，每一微针组至少包含一微针，第一微针组包含至少一薄片，每一薄片上至少设置一穿孔，穿孔边缘设置有一突刺，其中一薄片上的穿孔供其余的薄片上相对位置的穿孔边缘的突刺穿过，且该些突刺互相分离。信号处理单元设置于该基板上并与该第一微针组和该第二微针组电性连接。电源单元供应工作电源予该经皮微针阵列贴布。In order to achieve the above object, the present invention provides a transdermal microneedle array patch for measuring the concentration of subcutaneous target molecules, the transdermal microneedle array patch comprising: a substrate, a microneedle unit, a signal processing unit and a power supply unit. The microneedle unit at least includes a first microneedle group and a second microneedle group arranged on the substrate, the first microneedle group serves as a working electrode, and the microneedles of the first microneedle group are arranged on the substrate in an array Above, the second microneedle group is used as a reference electrode, each microneedle group includes at least one microneedle, the first microneedle group includes at least one sheet, each sheet is provided with at least one perforation, and the edge of the perforation is provided with a thorn, one of which The perforations in one sheet are passed through by the protrusions of the oppositely positioned perforation edges on the remaining sheets, and the protrusions are separated from each other. The signal processing unit is arranged on the substrate and electrically connected with the first microneedle group and the second microneedle group. The power supply unit supplies working power to the percutaneous microneedle array patch.
其中，该第一微针组由一第一薄片和一第二薄片叠置而成，该第一薄片上至少设置一第一穿孔，该第一穿孔边缘设置有一第一突刺，及该第二薄片上至少设置一第二穿孔，该第二穿孔边缘设置有一第二突刺，该第二突刺穿过该第一薄片上相对位置的该第一穿孔与该第一突刺相对。Wherein, the first microneedle group is formed by stacking a first sheet and a second sheet, the first sheet is provided with at least a first perforation, the edge of the first perforation is provided with a first thorn, and the second At least one second perforation is provided on the thin sheet, and a second protrusion is arranged on the edge of the second perforation, and the second protrusion passes through the first perforation at the opposite position on the first sheet and is opposite to the first protrusion.
其中，该第一微针组由一第一薄片、一第二薄片和一第三薄片叠置而成，该第一薄片上至少设置一第一穿孔，该第一穿孔边缘设置有一第一突刺，该第二薄片上至少设置一第二穿孔，该第二穿孔边缘设置有一第二突刺，及该第三薄片上至少设置一第三穿孔，该第三穿孔边缘设置有一第三突刺，该第二突刺和该第三突刺穿过该第一薄片上的该第一穿孔与该第一突刺呈三角锥形。Wherein, the first microneedle group is formed by stacking a first thin sheet, a second thin sheet and a third thin sheet, at least one first perforation is set on the first thin sheet, and a first puncture is arranged on the edge of the first perforation. , the second sheet is provided with at least one second perforation, the second perforation edge is provided with a second thorn, and the third sheet is at least provided with a third perforation, the third perforation edge is provided with a third thorn, the first The second thorn and the third thorn pass through the first perforation on the first sheet and form a triangular cone shape with the first thorn.
其中，该第一微针组由一第一薄片、一第二薄片、一第三薄片和一第四薄片叠置而成，该第一薄片上至少设置一第一穿孔，该第一穿孔边缘设置有一第一突刺，该第二薄片上至少设置一第二穿孔，该第二穿孔边缘设置有一第二突刺，该第三薄片上至少设置一第三穿孔，该第三穿孔边缘设置有一第三突刺及该第四薄片上至少设置一第四穿孔，该第四穿孔边缘设置有一第四突刺，该第二突刺、该第三突刺和该第四突刺穿过该第一薄片上的该第一穿孔与该第一突刺呈四角锥形。Wherein, the first microneedle group is formed by stacking a first sheet, a second sheet, a third sheet and a fourth sheet, and at least one first perforation is set on the first sheet, and the edge of the first perforation is A first thorn is provided, at least a second perforation is provided on the second sheet, a second puncture is provided on the edge of the second perforation, at least a third perforation is provided on the third sheet, and a third perforation is provided on the edge of the third sheet. At least one fourth perforation is set on the thorn and the fourth sheet, a fourth thorn is arranged on the edge of the fourth perforation, and the second thorn, the third thorn and the fourth thorn pass through the first hole on the first sheet. The perforation and the first protrusion are in the shape of a quadrangular pyramid.
其中，该第一微针组的每一突刺包含一尖端部及一基底，其中一薄片上的穿孔经其余的薄片上相对位置的穿孔边缘的突刺穿过后形成的该微针的所述尖端部的顶部不在同一高度。Wherein, each stabbing of the first microneedle group includes a tip and a base, wherein the tip of the microneedle is formed after the perforation on a thin sheet passes through the stabbing edge of the corresponding perforation edge on the remaining sheet are not at the same height.
其中，该第一微针组的每一突刺包含一尖端部及一基底，其中一薄片上的穿孔经其余的薄片上相对位置的穿孔边缘的突刺穿过后形成的该微针的所述尖端部的顶部具有同一高度。Wherein, each stabbing of the first microneedle group includes a tip and a base, wherein the tip of the microneedle is formed after the perforation on a thin sheet passes through the stabbing edge of the corresponding perforation edge on the remaining sheet have the same height at the top.
其中，该第一微针组和该第二微针组的微针借由冲压或蚀刻工艺形成。Wherein, the microneedles of the first microneedle group and the second microneedle group are formed by stamping or etching process.
其中，所述突刺的内表面上涂有感测高分子。Wherein, the inner surface of the thorn is coated with a sensing polymer.
其中，所述突刺的外表面上涂有抗皮肤过敏的药物。Wherein, anti-skin allergy medicine is coated on the outer surface of the thorn.
其中，更包含一试纸片，安置于该第一微针组与该基板之间，该试纸片包含一导电层及位于该导电层上的多个测试区域，所述测试区域上涂布感测高分子，且与该第一微针组上的该穿孔对齐。Among them, a test paper sheet is further included, arranged between the first microneedle group and the substrate, the test paper sheet includes a conductive layer and a plurality of test areas on the conductive layer, the test area is coated with sensing polymer, and aligned with the perforation on the first microneedle group.
其中，该感测高分子是抗体、适体、重组单体(ScFv)、醣类、葡萄糖氧化酶（GlucoseOxidase）或羟基丁酸脱氢酶（HBHD）。Wherein, the sensing polymer is antibody, aptamer, recombinant monomer (ScFv), carbohydrate, glucose oxidase (GlucoseOxidase) or hydroxybutyrate dehydrogenase (HBHD).
其中，所述突刺的材料选自不锈钢、镍、镍合金、钛、钛合金、纳米碳管或硅材料，且于表面沉积具有生物兼容性的金属。Wherein, the material of the spike is selected from stainless steel, nickel, nickel alloy, titanium, titanium alloy, carbon nanotube or silicon material, and biocompatible metal is deposited on the surface.
其中，所述突刺的材料为树脂，且于表面沉积具有生物兼容性的金属。Wherein, the material of the thorn is resin, and metal with biocompatibility is deposited on the surface.
本发明还提供一种经皮微针阵列贴布的制造方法，包括以下步骤：提供上述基板及微针单元；于微针单元的第一微针组的突刺表面沉积具有生物兼容性的一金属层；形成一自组装单层于该金属层上；于该自组装单层上接合抗体或适体；施加阻隔分子，填补未接上抗体或适体的自组装单层。The present invention also provides a method for manufacturing a percutaneous microneedle array patch, which includes the following steps: providing the substrate and the microneedle unit; depositing a biocompatible metal on the stabbing surface of the first microneedle group of the microneedle unit. layer; forming a self-assembled monolayer on the metal layer; binding antibodies or aptamers to the self-assembled monolayer; applying barrier molecules to fill the self-assembled monolayer not attached to antibodies or aptamers.
其中，更包含于金属层中混合纳米碳管。Wherein, it further includes mixing carbon nanotubes in the metal layer.
本发明提供的经皮微针阵列贴布，其微针组的微针借由冲压或蚀刻工艺形成，具有足够的机械强度，当微针组的微针穿刺皮肤进行感测时，微针能保持完好。而且，本发明的工作电极微针组的结构有利于将感测高分子涂布在微针尖端部的内表面，于工作电极微针组的微针穿刺皮肤进行感测时，可减少感测高分子的剥落。In the percutaneous microneedle array patch provided by the present invention, the microneedles of the microneedle group are formed by stamping or etching processes, and have sufficient mechanical strength. When the microneedles of the microneedle group puncture the skin for sensing, the microneedles can Keep it intact. Moreover, the structure of the working electrode microneedle group of the present invention is conducive to coating the sensing polymer on the inner surface of the tip of the microneedle, which can reduce the amount of sensing when the microneedle of the working electrode microneedle group punctures the skin for sensing. Exfoliation of polymers.
本发明经皮微针阵列贴布的工作电极微针表面可依照目标分子进行改质，其中，目标分子可以是生物分子，例如血糖、皮质醇、脂肪酸等，目标分子也可以是药物分子例如抗生素，经皮微针阵列贴布能提供慢性病药物或特定药物服用时，进行药物监控，提高病患服药的顺从性，更进一步可针对个人的药物代谢状况，决定用药剂量及服用频率，以达到个人化药物的目的。The surface of the working electrode microneedle of the percutaneous microneedle array patch of the present invention can be modified according to the target molecule, wherein the target molecule can be a biomolecule, such as blood sugar, cortisol, fatty acid, etc., and the target molecule can also be a drug molecule such as an antibiotic , the percutaneous microneedle array patch can provide chronic disease drugs or specific drugs, drug monitoring, improve patient drug compliance, and furthermore, according to the individual drug metabolism status, determine the dosage and frequency of medication, so as to achieve personal purpose of chemical drugs.
相较于现有技术，本发明的微针具有足够的机械强度，当微针组的微针穿刺皮肤进行感测时，微针能保持完好。而且，本发明的微针单元的工艺简单，有利于大量生产。Compared with the prior art, the microneedles of the present invention have sufficient mechanical strength, and when the microneedles of the microneedle group puncture the skin for sensing, the microneedles can remain intact. Moreover, the process of the microneedle unit of the present invention is simple, which is beneficial to mass production.
以下结合附图和具体实施例对本发明进行详细描述，但不作为对本发明的限定。The present invention will be described in detail below in conjunction with the accompanying drawings and specific embodiments, but not as a limitation of the present invention.
附图说明Description of drawings
图1为本发明的一实施例经皮微针阵列贴布的爆炸分解图﹔Fig. 1 is an exploded exploded view of a percutaneous microneedle array patch according to an embodiment of the present invention;
图2为与图1不同观看方向的本发明的一实施例经皮微针阵列贴布的爆炸分解图；Fig. 2 is an exploded exploded view of a percutaneous microneedle array patch according to an embodiment of the present invention viewed in a different direction from Fig. 1;
图3为本发明的一实施例微针单元的示意图﹔Fig. 3 is the schematic diagram of the microneedle unit of an embodiment of the present invention;
图4为本发明的一实施例工作电极微针组的结构局部上视图；Fig. 4 is a partial top view of the structure of the working electrode microneedle group according to an embodiment of the present invention;
图5为本发明的另一实施例工作电极微针组的结构局部上视图；5 is a partial top view of the structure of the working electrode microneedle group according to another embodiment of the present invention;
图6为本发明的又一实施例工作电极微针组的结构局部上视图；6 is a partial upper view of the structure of the working electrode microneedle group in another embodiment of the present invention;
图7为本发明的又另一实施例工作电极微针组的结构局部上视图；Fig. 7 is a partial upper view of the structure of the working electrode microneedle group according to yet another embodiment of the present invention;
图8为本发明的一实施例经皮微针阵列贴布的组合外观示意图；Fig. 8 is a schematic diagram of the combined appearance of the percutaneous microneedle array patch according to an embodiment of the present invention;
图9为本发明的一实施例经皮微针阵列贴布的组合剖面示意图；Fig. 9 is a combined cross-sectional schematic diagram of a percutaneous microneedle array patch according to an embodiment of the present invention;
图10为图9的局部剖面示意图，其中感测高分子涂布在微针的突刺上；FIG. 10 is a partial cross-sectional schematic diagram of FIG. 9, wherein the sensing polymer is coated on the thorn of the microneedle;
图11为图9的局部剖面示意图，其中感测高分子涂布在试纸片上；Fig. 11 is a partial cross-sectional schematic diagram of Fig. 9, wherein the sensing polymer is coated on the test paper sheet;
图12为本发明的一实施例经皮微针阵列贴布的组合局部剖面示意图，其中导柄经部分弯折直接与电路板上的接点电性连接，而不使用导电柱。Fig. 12 is a partial cross-sectional schematic diagram of a combined transdermal microneedle array patch according to an embodiment of the present invention, in which the guide handle is directly electrically connected to the contacts on the circuit board through partial bending, without using conductive columns.
其中，附图标记：Among them, reference signs:
10基板 102孔穴10 substrates 102 holes
104插槽 20微针单元104 slots 20 microneedle units
21、23、25导电柱 22第一微针组21, 23, 25 Conductive column 22 The first microneedle group
222第一薄片 2221尖端部222 first sheet 2221 tip
2222第一穿孔 2223基底2222 first perforation 2223 base
2224第一突刺 224第二薄片2224 first stab 224 second slice
2242第二穿孔 2244第二突刺2242 second piercing 2244 second thrust
2246倒钩 2248导柄2246 barb 2248 guide handle
226第三薄片 2262第三穿孔226 third sheet 2262 third perforation
2264第三突刺 228第四薄片2264 Third Spike 228 Fourth Flake
2282第四穿孔 2284第四突刺2282 fourth piercing 2284 fourth thrust
24第二微针组 242第一薄片24 the second microneedle group 242 the first sheet
2422第一穿孔 2424第一突刺2422 First piercing 2424 First thrust
2426倒钩 2428导柄2426 barb 2428 guide handle
26第三微针组 262第一薄片26 The third microneedle group 262 The first sheet
2622第一穿孔 2624第一突刺2622 First piercing 2624 First thrust
2626倒钩 2628导柄2626 barb 2628 guide handle
30可挠性垫片 32开口30 flexible gasket 32 opening
40电路板 41信号处理单元40 circuit board 41 signal processing unit
42、44、46电接点 43电源单元42, 44, 46 electrical contacts 43 power supply unit
50外盖 92导电层50 outer cover 92 conductive layer
94测试区域 96树脂片94 test areas 96 resin pieces
98黏着层98 adhesive layer
具体实施方式detailed description
有关本发明的详细说明及技术内容，配合图式说明如下，然而所附图式仅提供参考与说明用，并非用来对本发明加以限制。The detailed description and technical content of the present invention are described below with the accompanying drawings, but the attached drawings are only for reference and illustration, and are not intended to limit the present invention.
请参照图1和图2，图1和图2为分别由不同方向观看本发明的一实施例经皮微针阵列贴布的爆炸分解图。本发明的经皮微针阵列贴布包含:基板10、微针单元20、可挠性垫片30、信号处理单元41、电源单元43及外盖50，其中信号处理单元41和电源单元43设置于电路板40上。Please refer to Fig. 1 and Fig. 2, Fig. 1 and Fig. 2 are exploded views of an embodiment of the percutaneous microneedle array patch of the present invention viewed from different directions. The percutaneous microneedle array patch of the present invention comprises: a substrate 10, a microneedle unit 20, a flexible spacer 30, a signal processing unit 41, a power supply unit 43 and an outer cover 50, wherein the signal processing unit 41 and the power supply unit 43 are set on the circuit board 40.
根据本发明的一实施例，微针单元20包含排列于基板10上作为工作电极的第一微针组22、作为参考电极的第二微针组24，以及作为反电极的第三微针组26。第一微针组22的该些微针可以例如是阵列形式排列于基板10上。可挠性垫片30上具有一开口32供微针单元20通过，且微针单元20以导电柱21、23、25与电路板40上的电接点42、44、46电性连接。由于本发明具有可挠性垫片30，操作时可与使用者的肌肉轮廓共型，紧密接触。According to an embodiment of the present invention, the microneedle unit 20 includes a first microneedle group 22 arranged on the substrate 10 as a working electrode, a second microneedle group 24 as a reference electrode, and a third microneedle group as a counter electrode 26. The microneedles of the first microneedle group 22 can be arranged on the substrate 10 in the form of an array, for example. The flexible gasket 30 has an opening 32 for the microneedle unit 20 to pass through, and the microneedle unit 20 is electrically connected to the electrical contacts 42 , 44 , 46 on the circuit board 40 through the conductive posts 21 , 23 , 25 . Since the present invention has the flexible spacer 30, it can conform to the contour of the user's muscles and be in close contact with it during operation.
信号处理单元41与微针单元20电性连接以接收微针感测的目标分子浓度，经运算判定后，将信息转换成一感测信号，也是一种能够反映使用者当下的生理状态的信号。电源单元43供应工作电力至本发明的经皮微针阵列贴布。The signal processing unit 41 is electrically connected to the microneedle unit 20 to receive the concentration of the target molecule sensed by the microneedle, and after calculation and determination, convert the information into a sensing signal, which is also a signal that can reflect the user's current physiological state. The power supply unit 43 supplies working power to the transdermal microneedle array patch of the present invention.
请参照图3，图3为本发明的一实施例微针单元的示意图。第一微针组22由第一薄片222和第二薄片224叠置而成，第一薄片222上至少设置一第一穿孔2222，该第一穿孔2222边缘设置有一第一突刺2224，及第二薄片224上至少设置一第二穿孔2242，第二穿孔边缘设置有一第二突刺2244，第二突刺2244穿过第一薄片222上相对位置的第一穿孔2222与第一突刺2224相对。此外，第一微针组22的第二薄片224边缘上可设置倒钩2246与基板10上的孔穴102卡合。在一实施例，第一微针组22的第二薄片224边缘上可设置导柄2248插入基板10上的插槽104，借由电路与导电柱21电性连接。Please refer to FIG. 3 , which is a schematic diagram of a microneedle unit according to an embodiment of the present invention. The first microneedle group 22 is formed by stacking a first sheet 222 and a second sheet 224. At least one first perforation 2222 is provided on the first sheet 222, and a first thorn 2224 is provided on the edge of the first perforation 2222, and a second At least one second perforation 2242 is disposed on the sheet 224 , and a second protrusion 2244 is disposed on the edge of the second perforation. In addition, barbs 2246 can be provided on the edge of the second sheet 224 of the first microneedle group 22 to engage with the holes 102 on the substrate 10 . In one embodiment, a guide handle 2248 can be provided on the edge of the second sheet 224 of the first microneedle set 22 to be inserted into the slot 104 on the substrate 10 , and electrically connected to the conductive column 21 through a circuit.
同理，第二微针组24也具有第一薄片242，第一薄片242上至少设置一第一穿孔2422，第一穿孔边缘设置有一第一突刺2424。此外，第二微针组24的第一薄片242边缘上可设置倒钩2426与基板10上的孔穴102卡合。在一实施例，第二微针组24的第一薄片242边缘上可设置导柄2428插入基板10上的插槽104，借由电路与导电柱23电性连接。Similarly, the second microneedle group 24 also has a first sheet 242 , at least one first perforation 2422 is provided on the first sheet 242 , and a first protrusion 2424 is provided on the edge of the first perforation. In addition, barbs 2426 can be provided on the edge of the first sheet 242 of the second microneedle group 24 to engage with the holes 102 on the substrate 10 . In one embodiment, a guide handle 2428 can be provided on the edge of the first sheet 242 of the second microneedle set 24 to be inserted into the slot 104 on the substrate 10 , and electrically connected to the conductive column 23 through a circuit.
同理，第三微针组26也具有第一薄片262，第一薄片262上至少设置一第一穿孔2622，第一穿孔2622边缘设置有一第一突刺2624。此外，第三微针组26的第一薄片262边缘上可设置倒钩2626与基板10上的孔穴102卡合。在一实施例，第三微针组26的第一薄片262边缘上可设置导柄2628插入基板10上的插槽104，借由电路与导电柱25电性连接。Similarly, the third microneedle group 26 also has a first sheet 262 , at least one first perforation 2622 is provided on the first sheet 262 , and a first protrusion 2624 is provided on the edge of the first perforation 2622 . In addition, barbs 2626 can be provided on the edge of the first sheet 262 of the third microneedle group 26 to engage with the holes 102 on the substrate 10 . In one embodiment, a guide handle 2628 can be provided on the edge of the first sheet 262 of the third microneedle set 26 to be inserted into the slot 104 on the substrate 10 , and electrically connected to the conductive column 25 through a circuit.
本发明的一实施例，第一微针组22、第二微针组24和第三微针组26的微针借由冲压或蚀刻工艺形成。该些突刺的材料选自不锈钢、镍、镍合金、钛、钛合金、纳米碳管或硅材料，并于表面沉积具有生物兼容性的金属，例如金、钯。该些突刺的材料也可以是树脂例如是聚碳酸酯、聚甲基丙烯酸共聚物、乙烯/醋酸乙烯酯共聚物、铁氟龙（聚四氟乙烯）或聚酯类，并于表面沉积具有生物兼容性的金属，例如金、钯。该些突刺的高度为300-600微米、基底宽度为150-450微米。该些突刺的尖端部的间隔为500-3000微米。In one embodiment of the present invention, the microneedles of the first microneedle group 22 , the second microneedle group 24 and the third microneedle group 26 are formed by punching or etching. The materials of the spikes are selected from stainless steel, nickel, nickel alloy, titanium, titanium alloy, carbon nanotubes or silicon materials, and biocompatible metals such as gold and palladium are deposited on the surface. The material of these spikes can also be resin such as polycarbonate, polymethacrylic acid copolymer, ethylene/vinyl acetate copolymer, Teflon (polytetrafluoroethylene) or polyester, and deposited on the surface with biological Compatible metals such as gold, palladium. The spikes have a height of 300-600 microns and a base width of 150-450 microns. The distance between the tips of the spikes is 500-3000 microns.
请参考图4至图6。图4为本发明的一实施例工作电极微针组的结构局部上视图。第一微针组22由第一薄片222和第二薄片224叠置而成，第一薄片222上至少设置一第一穿孔2222，第一穿孔2222边缘设置有一第一突刺2224，及第二薄片224上至少设置一第二穿孔2242，第二穿孔边缘设置有一第二突刺2244，第二突刺2244穿过第一薄片222上相对位置的第一穿孔2222与第一突刺2224相对。Please refer to Figure 4 to Figure 6. Fig. 4 is a partial upper view of the structure of the working electrode microneedle group according to an embodiment of the present invention. The first microneedle group 22 is formed by stacking a first sheet 222 and a second sheet 224. At least one first perforation 2222 is provided on the first sheet 222, and a first thorn 2224 is provided on the edge of the first perforation 2222, and the second sheet At least one second perforation 2242 is disposed on the 224 , and a second protrusion 2244 is disposed on the edge of the second perforation. The second protrusion 2244 passes through the first perforation 2222 opposite to the first protrusion 2224 on the first sheet 222 .
图5为本发明的另一实施例工作电极微针组的结构局部上视图。第一微针组22由第一薄片222、第二薄片224和第三薄片226叠置而成，第一薄片222上至少设置第一穿孔2222，第一穿孔2222边缘设置有一第一突刺2224，第二薄片224上至少设置一第二穿孔2242，第二穿孔2242边缘设置有一第二突刺2244，及第三薄片226上至少设置一第三穿孔2262，第三穿孔2262边缘设置有一第三突刺2264，第二突刺2244和第三突刺2264穿过第一薄片222上的第一穿孔2222与第一突刺2224呈正三角锥形。Fig. 5 is a partial top view of the structure of the working electrode microneedle group according to another embodiment of the present invention. The first microneedle group 22 is formed by stacking a first sheet 222, a second sheet 224, and a third sheet 226. The first sheet 222 is provided with at least a first perforation 2222, and the edge of the first perforation 2222 is provided with a first thorn 2224. At least one second perforation 2242 is provided on the second sheet 224, and a second puncture 2244 is provided on the edge of the second perforation 2242, and at least one third perforation 2262 is provided on the third sheet 226, and a third puncture 2264 is provided on the edge of the third perforation 2262 , the second thorns 2244 and the third thorns 2264 pass through the first perforation 2222 on the first sheet 222 and the first thorns 2224 form an equilateral triangular cone.
图6为本发明的又一实施例工作电极微针组的结构局部上视图。第一微针组22由第一薄片222、第二薄片224、第三薄片226叠置而成，其中第一薄片222上至少设置一第一穿孔2222，第一穿孔2222边缘设置有一第一突刺2224；第二薄片224上至少设置一第二穿孔2242，第二穿孔2242边缘设置有一第二突刺2244；及第三薄片226上至少设置一第三穿孔2262，第三穿孔2262边缘设置有一第三突刺2264，将第二突刺2244和第三突刺2264穿过第一薄片222上的第一穿孔2222与第一突刺2224相邻排列，呈等腰直角三角锥形。Fig. 6 is a partial top view of the structure of the working electrode microneedle group according to another embodiment of the present invention. The first microneedle group 22 is formed by stacking a first sheet 222, a second sheet 224, and a third sheet 226, wherein at least one first perforation 2222 is provided on the first sheet 222, and a first thrust is provided on the edge of the first perforation 2222. 2224; at least one second perforation 2242 is provided on the second sheet 224, and a second thorn 2244 is provided on the edge of the second perforation 2242; and at least one third perforation 2262 is provided on the third sheet 226, and a third perforation 2262 is provided on the edge The thorns 2264, the second thorns 2244 and the third thorns 2264 pass through the first perforation 2222 on the first sheet 222 and are arranged adjacent to the first thorns 2224, forming an isosceles right triangle pyramid.
图7为本发明的又另一实施例工作电极微针组的结构局部上视图。第一微针组22由第一薄片222、第二薄片224、第三薄片226和第四薄片228叠置而成，第一薄片222上至少设置一第一穿孔2222，第一穿孔2222边缘设置有一第一突刺2224，第二薄片224上至少设置一第二穿孔2242，第二穿孔2242边缘设置有一第二突刺2244，第三薄片226上至少设置一第三穿孔2262，第三穿孔2262边缘设置有一第三突刺2264及第四薄片228上至少设置一第四穿孔2282，第四穿孔2282边缘设置有一第四突刺2284，第二突刺2244、第三突刺2264和第四突刺2284穿过第一薄片222上的第一穿孔2222与第一突刺2224呈四角锥形。Fig. 7 is a partial top view of the structure of the working electrode microneedle group according to yet another embodiment of the present invention. The first microneedle group 22 is formed by stacking a first sheet 222, a second sheet 224, a third sheet 226, and a fourth sheet 228. At least one first perforation 2222 is provided on the first sheet 222, and the edge of the first perforation 2222 is arranged There is a first thorn 2224, at least one second perforation 2242 is provided on the second sheet 224, and a second puncture 2244 is provided on the edge of the second perforation 2242, and at least one third perforation 2262 is provided on the third sheet 226, and a third perforation 2262 is provided on the edge. There is a third thorn 2264 and at least a fourth perforation 2282 is set on the fourth sheet 228, the edge of the fourth perforation 2282 is provided with a fourth thorn 2284, the second thorn 2244, the third thorn 2264 and the fourth thorn 2284 pass through the first sheet The first perforation 2222 on the 222 and the first protrusion 2224 form a quadrangular pyramid.
图4至图7所示的四个实施例中，第一微针组22的每一突刺2224包含一尖端部2221及一基底2223，其中一薄片上的穿孔经其余的薄片上相对位置的穿孔边缘的突刺穿过后形成的该微针的该些尖端部的顶部不在同一高度。或者，可以依照该些薄片重叠的次序，预先设计其突刺的高度，使其中一薄片上的穿孔经其余的薄片上相对位置的穿孔边缘的突刺穿过后形成的该微针的该些尖端部的顶部具有同一高度。In the four embodiments shown in Fig. 4 to Fig. 7, each thrust 2224 of the first microneedle group 22 comprises a tip portion 2221 and a base 2223, wherein the perforation on one sheet is passed through the perforation at the opposite position on the remaining sheet The tops of the tips of the microneedles formed after the spurs of the edges pass through are not at the same height. Or, the height of the thorns can be pre-designed according to the overlapping order of the sheets, so that the perforations on one of the sheets pass through the piercing edges of the corresponding perforations on the remaining sheets to form the tips of the microneedles. The tops have the same height.
接着，请参考图8和图9。图8为本发明的一实施例经皮微针阵列贴布的组合外观示意图。图9为本发明的一实施例经皮微针阵列贴布的组合剖面示意图。本实施例中的第一微针组22由第一薄片222和第二薄片224叠置而成，可例如施加一冲压力于第一薄片222和第二薄片224的四周以结合两者。第二微针组24只具有第一薄片242。第三微针组26也只具有第一薄片262。由于本发明具有可挠性垫片30，操作时可与使用者的肌肉轮廓共型，紧密接触。Next, please refer to FIG. 8 and FIG. 9 . Fig. 8 is a schematic diagram of the combined appearance of a transdermal microneedle array patch according to an embodiment of the present invention. Fig. 9 is a combined cross-sectional schematic diagram of a percutaneous microneedle array patch according to an embodiment of the present invention. The first microneedle set 22 in this embodiment is formed by stacking the first sheet 222 and the second sheet 224 , for example, a stamping force can be applied to the surroundings of the first sheet 222 and the second sheet 224 to combine them. The second microneedle group 24 only has the first sheet 242 . The third microneedle group 26 also only has the first sheet 262 . Since the present invention has the flexible spacer 30, it can conform to the contour of the user's muscles and be in close contact with it during operation.
本发明经皮微针阵列贴布的工作电极微针组22的微针表面可依照目标分子进行改质，其中，目标分子可以是生物分子，例如血糖、皮质醇、脂肪酸等，目标分子也可以是药物分子例如抗生素，经皮微针阵列贴布能提供慢性病药物或特定药物服用时，进行药物监控，提高病患服药的顺从性，更进一步可针对个人的药物代谢状况，决定用药剂量及服用频率，以达到个人化药物的目的。The microneedle surface of the working electrode microneedle group 22 of the percutaneous microneedle array patch of the present invention can be modified according to the target molecule, wherein the target molecule can be a biomolecule, such as blood sugar, cortisol, fatty acid, etc., and the target molecule can also be For drug molecules such as antibiotics, the percutaneous microneedle array patch can provide chronic disease drugs or specific drugs, drug monitoring, improve patient drug compliance, and further determine the dosage and dosage of drugs according to the individual's drug metabolism. frequency for the purpose of personalizing medicine.
为了使工作电极微针组22的微针具有专一性(specificity)，工作电极微针组22的微针表面可具有表面改质的特性，其依照检测的目标分子进行改质，于工作电极微针组22的微针表面可连接有下列选项之一，包括抗体、适体(aptamer)、重组单体(ScFv)或醣类等。例如，量测血糖时，可以通过固定葡萄醣氧化脢(glucose oxidase，Gox)于工作电极微针组22的微针表面实行之；而一般抗体或适体的连接方式是对工作电极微针组22的微针的金表层，施加自组装单层(self-assemble monolayer，SAM)之后接合抗体或适体，接着再施加阻隔分子，填补未接上抗体或适体的自组装单层，以保证其专一性，如要增加灵敏度，可进一步于金表层中混合纳米碳管。以下具体说明各种修饰金电极的制造方法。In order to make the microneedles of the working electrode microneedle group 22 have specificity (specificity), the surface of the microneedles of the working electrode microneedle group 22 can have the characteristics of surface modification, which is modified according to the detected target molecule, and the microneedle surface of the working electrode microneedle group 22 can be modified. The surface of the microneedles of the microneedle set 22 can be connected with one of the following options, including antibodies, aptamers (aptamers), recombinant monomers (ScFv) or carbohydrates. For example, when measuring blood sugar, it can be carried out by immobilizing glucose oxidase (Gox) on the microneedle surface of the working electrode microneedle set 22; The gold surface layer of the microneedle, after applying a self-assembled monolayer (self-assembled monolayer, SAM) is combined with antibodies or aptamers, and then barrier molecules are applied to fill the self-assembled monolayer that is not connected with antibodies or aptamers to ensure its Specificity, if you want to increase the sensitivity, you can further mix carbon nanotubes in the gold surface layer. The manufacturing methods of various modified gold electrodes are specifically described below.
卵白素修饰金电极的制作步骤如下，表面化镀有金层的工作电极以3,3’二硫代二丙酸200毫莫耳浓度处理30分钟以形成一自组装单层(SAM)，之后使用蒸馏水彻底洗净。使用100毫莫耳浓度的N-(3-二甲氨丙基)-N-乙基碳化二亚胺(EDC)和1毫莫耳浓度的N-羟基丁二酰亚胺(NHS)培育1小时之后，于电极上进行羧酸基的活化。之后，电极在pH值7.5的磷酸缓冲溶液(PBS)中使用1毫克/毫升的卵白素培育过夜。使用100毫莫耳浓度的乙醇胺培育20分钟阻断电极上自由的羧酸基。最后，10奈莫耳浓度的生物素DNA适体于卵白素涂布的电极上培育40分钟，之后使用蒸馏水彻底洗净。The manufacturing steps of the avidin-modified gold electrode are as follows. The working electrode coated with a gold layer on the surface is treated with 200 millimolar concentration of 3,3'dithiodipropionic acid for 30 minutes to form a self-assembled monolayer (SAM), and then used Rinse thoroughly with distilled water. Incubate 1 with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) at a concentration of 100 millimolar and N-hydroxysuccinimide (NHS) at a concentration of 1 millimolar. After hours, activation of the carboxylic acid groups was carried out on the electrodes. Afterwards, the electrodes were incubated overnight with 1 mg/ml avidin in phosphate buffered solution (PBS) at pH 7.5. Free carboxylic acid groups on the electrode were blocked by incubation with 100 millimolar ethanolamine for 20 minutes. Finally, 10 nmol concentration of biotin-DNA aptamer was incubated on the avidin-coated electrode for 40 minutes, and then washed thoroughly with distilled water.
以下举例说明卵白素修饰金电极的使用方式，四环素是一种抗生素，常用于器官发炎的病患，欲追查四环素于病患体内浓度随时间的变化时，可选用微针表面连接对于四环素具有专一性的生物素DNA适体的经皮微针阵列贴布以检测四环素浓度。因此，本发明的经皮微针阵列贴布能提供慢性病药物或特定药物服用时，进行药物监控，提高病患服药的顺从性，更进一步可针对个人的药物代谢状况，决定用药剂量及服用频率，以达到个人化药物的目的。The following example illustrates the use of avidin-modified gold electrodes. Tetracycline is an antibiotic that is often used in patients with organ inflammation. When you want to track the change of tetracycline concentration in the patient's body over time, you can use the microneedle surface connection. Transdermal microneedle array patching of a specific biotinylated DNA aptamer to detect tetracycline concentration. Therefore, the percutaneous microneedle array patch of the present invention can provide drug monitoring when taking chronic disease drugs or specific drugs, improve the compliance of patients taking drugs, and further determine the dosage and frequency of taking drugs according to the individual drug metabolism status. , in order to achieve the purpose of personalized medicine.
欲增加灵敏度，可进一步于金表层中混合纳米碳管。多壁纳米碳管(MWCNT)化学修饰电极的制作步骤如下，纳米碳管的羧酸基衍生物可借由市售可得的MWCNT在4M硝酸溶液回流取得。上述取得氧化的MWCNT20毫克在二氯亚砜10毫升回流12小时。获得的混合物倒出，过量的二氯亚砜于真空中移除。加入巯基乙醇溶液(2毫升，30毫莫耳)和三乙胺(1毫升，7毫莫耳)在二氯甲烷(10毫升)的溶液，及混合物回流24小时。对悬浮液进行离心，及固体物重复使用乙醇清洗以给定MWCNT衍生物10毫克。多壁纳米碳管化学修饰电极的制备为将干净的金电极浸入音波震荡的3毫克的纳米碳管于1毫升的二甲基亚砜（DMSO)的悬浮液中48小时。最后，10奈莫耳浓度的生物素DNA适体于MWCNT化学修饰电极上培育40分钟，之后使用蒸馏水彻底洗净。To increase the sensitivity, carbon nanotubes can be further mixed into the gold surface layer. The fabrication steps of multi-walled carbon nanotubes (MWCNT) chemically modified electrodes are as follows. The carboxylic acid derivatives of carbon nanotubes can be obtained by refluxing commercially available MWCNTs in 4M nitric acid solution. The above obtained 20 mg of oxidized MWCNT was refluxed in 10 ml of thionyl chloride for 12 hours. The resulting mixture was decanted and excess thionyl chloride was removed in vacuo. A solution of mercaptoethanol (2 mL, 30 mmol) and triethylamine (1 mL, 7 mmol) in dichloromethane (10 mL) was added, and the mixture was refluxed for 24 hours. The suspension was centrifuged, and the solid was washed repeatedly with ethanol to give 10 mg of the MWCNT derivative. The preparation of the multi-walled carbon nanotubes chemically modified electrode was to immerse a clean gold electrode in a suspension of 3 mg of carbon nanotubes in 1 ml of dimethyl sulfoxide (DMSO) vibrated by sonic waves for 48 hours. Finally, 10 nanomolar concentration of biotin DNA aptamer was incubated on the MWCNT chemically modified electrode for 40 minutes, and then washed thoroughly with distilled water.
单壁纳米碳管（SWCNT）化学修饰电极的制作步骤如下，纳米碳管的羧酸基衍生物可借由市售可得的SWCNT在4M硝酸溶液回流取得。组合一胱胺单层于金电极上，以形成一自组装单层(SAM)，接着将音波震荡分散于1毫升的二甲基甲酰胺（DMF)的3毫克的带有羧酸基的单壁纳米碳管(反应物2a)连结至存在有偶合剂1,3二环己基碳二亚胺（DCC）3毫克的SAM表面上，得到产物2b。之后，加入2毫莫耳浓度的巯基乙醇溶液在1毫升的DMF及3毫克的DCC，巯基乙醇借由使用DCC，偶合至产物2b的自由边缘的羧酸基，得到SWCNT化学修饰电极。最后，10奈莫耳浓度的生物素DNA适体于SWCNT化学修饰电极上培育40分钟，之后使用蒸馏水彻底洗净。The fabrication steps of single-walled carbon nanotubes (SWCNT) chemically modified electrodes are as follows. The carboxylic acid derivatives of carbon nanotubes can be obtained by refluxing commercially available SWCNTs in 4M nitric acid solution. A monolayer of cystamine was assembled on a gold electrode to form a self-assembled monolayer (SAM), followed by sonication of 3 mg of monolayers with carboxylic acid groups in 1 ml of dimethylformamide (DMF). Walled carbon nanotubes (reactant 2a) were attached to the surface of SAM in the presence of 3 mg of coupling agent 1,3 dicyclohexylcarbodiimide (DCC) to give product 2b. Afterwards, 2 millimolar concentration of mercaptoethanol solution was added in 1 ml of DMF and 3 mg of DCC, and mercaptoethanol was coupled to the carboxylic acid group of the free edge of product 2b by using DCC to obtain a SWCNT chemically modified electrode. Finally, 10 nanomolar concentration of biotin DNA aptamer was incubated on the SWCNT chemically modified electrode for 40 minutes, and then washed thoroughly with distilled water.
接着，请参考图10，图10为图9的局部剖面示意图，其中感测高分子涂布在微针的突刺上。具体而言，感测高分子涂布在突刺的内表面上，突刺的外表面上涂布有抗皮肤过敏的药物。本实施例中，感测高分子例如是抗体、适体、重组单体(ScFv)、醣类、葡萄糖氧化酶（Glucose Oxidase）或羟基丁酸脱氢酶（HBHD）。一个表面涂有感测高分子的微针的经皮微针阵列贴布，可用以检测皮肤表层中的目标分子浓度，且此浓度可作为判定生理状态的指标之一。Next, please refer to FIG. 10 , which is a partial cross-sectional schematic diagram of FIG. 9 , wherein the sensing polymer is coated on the puncture of the microneedle. Specifically, the sensing polymer is coated on the inner surface of the thorn, and the anti-allergic drug is coated on the outer surface of the thorn. In this embodiment, the sensing polymer is, for example, antibody, aptamer, recombinant monomer (ScFv), carbohydrate, glucose oxidase (Glucose Oxidase) or hydroxybutyrate dehydrogenase (HBHD). A transdermal microneedle array patch coated with sensing polymer microneedles can be used to detect the concentration of target molecules in the surface layer of the skin, and this concentration can be used as one of the indicators to determine the physiological state.
图11为图9的局部剖面示意图，其中感测高分子涂布在试纸片上。本实施例与图10所示实施例的差异在于，本实施例的第一微针组22作为萃取间质液的工具，突刺上并不涂布感测高分子，感测高分子涂布在位于第一微针组22下方的试纸片的表面上。本实施例中，试纸片系安置于第一微针组22与基板10之间，试纸片包含一导电层92及位于导电层92上的多个测试区域94，该些测试区域94上涂布感测高分子，且与第一微针组22上的穿孔2222对齐。本实施例使用树脂片96于其上定义出该些测试区域94。此外，第一微针组22借由一黏着层98与试纸片接合。为了避免感测高分子或抗皮肤过敏的药物受到环境污染，可于感测高分子或抗皮肤过敏的药物的表面上形成一保护层，保护层例如是环氧树脂-聚胺酯甲酸基树脂（Epoxy-PU）膜。此外，由于安培计电化学方法一般比较不具选择性，许多常见的干扰物存在于血浆中，会导入信号之中。为了实现高的皮下目标分子选择性，于电极的表面上先形成一半透膜或是具有低透氧性的膜。FIG. 11 is a schematic partial cross-sectional view of FIG. 9 , where the sensing polymer is coated on the test paper sheet. The difference between this embodiment and the embodiment shown in FIG. 10 is that the first microneedle group 22 of this embodiment is used as a tool for extracting interstitial fluid, and the sensing polymer is not coated on the puncture, and the sensing polymer is coated on the It is located on the surface of the test paper sheet below the first microneedle group 22 . In this embodiment, the test paper sheet is arranged between the first microneedle group 22 and the substrate 10. The test paper sheet includes a conductive layer 92 and a plurality of test areas 94 on the conductive layer 92, and these test areas 94 are coated with The polymer is sensed and aligned with the perforation 2222 on the first microneedle set 22 . In this embodiment, a resin sheet 96 is used to define the test areas 94 thereon. In addition, the first microneedle set 22 is bonded to the test paper sheet through an adhesive layer 98 . In order to prevent the sensing polymer or the anti-skin allergy drug from being polluted by the environment, a protective layer can be formed on the surface of the sensing polymer or the anti-skin allergy drug. -PU) film. In addition, since amperometric electrochemical methods are generally less selective, many common interferents are present in plasma and will be introduced into the signal. In order to achieve high selectivity of subcutaneous target molecules, a semi-permeable membrane or a membrane with low oxygen permeability is first formed on the surface of the electrode.
本发明经皮微针阵列贴布的一实施例更包含一无线传输单元(图未示)，电性连接于信号处理单元41，当信号处理单元41每产生一次感测信号，无线传输单元就接收并对外传输至外部医师端，当医师分析需立即处理就会下达指令，无线传输单元经接收外部的指令信号，会提醒使用者关切其生理状况或该服用药物了。An embodiment of the percutaneous microneedle array patch of the present invention further includes a wireless transmission unit (not shown), which is electrically connected to the signal processing unit 41. When the signal processing unit 41 generates a sensing signal, the wireless transmission unit Receive and transmit externally to the external doctor's terminal, when the doctor analyzes and needs to deal with it immediately, he will issue an order, and the wireless transmission unit will remind the user to care about their physiological condition or take medicine after receiving the external order signal.
接着，请参考图12，图12为本发明的一实施例经皮微针阵列贴布的组合局部剖面示意图。本实施例中，导柄2248经部分弯折直接与电路板40上的接点42电性连接，而不使用导电柱。Next, please refer to FIG. 12 . FIG. 12 is a combined partial cross-sectional schematic diagram of a percutaneous microneedle array patch according to an embodiment of the present invention. In this embodiment, the guide handle 2248 is directly electrically connected to the contact 42 on the circuit board 40 through partial bending, without using a conductive post.
当然，本发明还可有其它多种实施例，在不背离本发明精神及其实质的情况下，熟悉本领域的技术人员可根据本发明作出各种相应的改变和变形，但这些相应的改变和变形都应属于本发明权利要求的保护范围。Certainly, the present invention also can have other multiple embodiments, without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and deformations according to the present invention, but these corresponding changes All changes and modifications should belong to the protection scope of the claims of the present invention.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410128793.5ACN104970805B (en) | 2014-04-01 | 2014-04-01 | Transdermal micro-needle array patch and manufacturing method thereof |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410128793.5ACN104970805B (en) | 2014-04-01 | 2014-04-01 | Transdermal micro-needle array patch and manufacturing method thereof |
| Publication Number | Publication Date |
|---|---|
| CN104970805A CN104970805A (en) | 2015-10-14 |
| CN104970805Btrue CN104970805B (en) | 2017-09-29 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410128793.5AActiveCN104970805B (en) | 2014-04-01 | 2014-04-01 | Transdermal micro-needle array patch and manufacturing method thereof |
| Country | Link |
|---|---|
| CN (1) | CN104970805B (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104970804A (en)* | 2014-04-01 | 2015-10-14 | 微凸科技股份有限公司 | Continuous percutaneous microneedle monitoring system |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106110490A (en)* | 2016-06-21 | 2016-11-16 | 唐晨 | The method and device that a kind of soft capsule micro-spray formula is microneedle cutaneous |
| EP3564672A4 (en)* | 2016-12-28 | 2020-09-09 | Nexmos Co., Ltd. | Method for fabricating microneedle-based diagnostic skin patch coated with aptamer and patch |
| CN109328032B (en)* | 2017-05-19 | 2022-12-13 | 深圳市大富智慧健康科技有限公司 | Microneedle electrode, meridian detection device and customization method thereof |
| CN110090351B (en)* | 2018-01-30 | 2020-11-10 | 京东方光科技有限公司 | Wearable Skin Beauty Devices and Wearable Eye Patches |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1905920A (en)* | 2003-11-13 | 2007-01-31 | 阿尔扎公司 | System and method for transdermal delivery |
| TWM427950U (en)* | 2011-09-23 | 2012-05-01 | Univ Nat Taipei Technology | Transdermal sensor |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049346A2 (en)* | 1999-12-30 | 2001-07-12 | Redeon, Inc. | Stacked microneedle systems |
| US7785301B2 (en)* | 2006-11-28 | 2010-08-31 | Vadim V Yuzhakov | Tissue conforming microneedle array and patch for transdermal drug delivery or biological fluid collection |
| US8588884B2 (en)* | 2010-05-28 | 2013-11-19 | Emkinetics, Inc. | Microneedle electrode |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1905920A (en)* | 2003-11-13 | 2007-01-31 | 阿尔扎公司 | System and method for transdermal delivery |
| TWM427950U (en)* | 2011-09-23 | 2012-05-01 | Univ Nat Taipei Technology | Transdermal sensor |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104970804A (en)* | 2014-04-01 | 2015-10-14 | 微凸科技股份有限公司 | Continuous percutaneous microneedle monitoring system |
| Publication number | Publication date |
|---|---|
| CN104970805A (en) | 2015-10-14 |
| Publication | Publication Date | Title |
|---|---|---|
| TWI519781B (en) | Transdermal microneedle array patch | |
| US11830955B2 (en) | Transdermal microneedle continuous monitoring system | |
| TWI730504B (en) | Percutaneous microneedle monitoring system | |
| Teymourian et al. | Lab under the skin: microneedle based wearable devices | |
| Zhao et al. | Flexible and stretchable electrochemical sensors for biological monitoring | |
| Saifullah et al. | Sampling dermal interstitial fluid using microneedles: a review of recent developments in sampling methods and microneedle‐based biosensors | |
| CN104970805B (en) | Transdermal micro-needle array patch and manufacturing method thereof | |
| US9987427B1 (en) | Diagnostic/drug delivery “sense-respond” devices, systems, and uses thereof | |
| Lee et al. | A patch type non-enzymatic biosensor based on 3D SUS micro-needle electrode array for minimally invasive continuous glucose monitoring | |
| US8333874B2 (en) | Flexible apparatus and method for monitoring and delivery | |
| TWM427950U (en) | Transdermal sensor | |
| CN103269641B (en) | Method for providing effective biosensors | |
| Vasylieva et al. | Silicon/SU8 multi-electrode micro-needle for in vivo neurochemical monitoring | |
| Abdullah et al. | Tackling the challenges of developing microneedle-based electrochemical sensors | |
| JP2022508576A (en) | Electrode equipment | |
| Li et al. | Microneedles-based theranostic platform: from the past to the future | |
| Dervisevic et al. | Microneedles with recessed microcavities for electrochemical sensing in dermal interstitial fluid | |
| Pereira et al. | Polymeric microneedles for health care monitoring: an emerging trend | |
| TWI666034B (en) | Transdermal microneedle array patch | |
| Wang et al. | Advances in microneedles for transdermal diagnostics and sensing applications | |
| CN104970804B (en) | Continuous percutaneous microneedle monitoring system | |
| CN113977829A (en) | Preparation method of hollow microneedle array biosensor | |
| Garg et al. | Recent advancements in the expedition of microneedles: from lab worktops to diagnostic care centers | |
| Chen et al. | Skin-like nanostrucutred biosensor system for noninvasive blood glucose monitoring | |
| CN118203359A (en) | A microneedle sensor integrating drug delivery and multi-substance multi-channel detection and its preparation method |
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | Effective date of registration:20220825 Address after:10, 2 floor, 8 Taiyuan street, Hsinchu, Taiwan, China Patentee after:RICHHEALTH TECHNOLOGY Corp. Address before:Taipei, Taiwan, China Zhongshan North Road 2 paragraph 46, No. 4, building 5 Patentee before:WEITU TECHNOLOGY Co.,Ltd. | |
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right | Effective date of registration:20240708 Address after:California, USA Patentee after:Qian Dahong Country or region after:U.S.A. Address before:10, Floor 2, No. 8, Taiyuan 1st Street, Zhubei City, Hsinchu County, Taiwan, China, China Patentee before:RICHHEALTH TECHNOLOGY Corp. Country or region before:TaiWan, China | |
| TR01 | Transfer of patent right |