CN104970805B - Percutaneous microneedle array patch and its manufacture method - Google Patents
Percutaneous microneedle array patch and its manufacture method Download PDFInfo
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- CN104970805B CN104970805B CN201410128793.5A CN201410128793A CN104970805B CN 104970805 B CN104970805 B CN 104970805B CN 201410128793 A CN201410128793 A CN 201410128793A CN 104970805 B CN104970805 B CN 104970805B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150015—Source of blood
- A61B5/150022—Source of blood for capillary blood or interstitial fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150977—Arrays of piercing elements for simultaneous piercing
- A61B5/150984—Microneedles or microblades
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4833—Assessment of subject's compliance to treatment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4869—Determining body composition
- A61B5/4881—Determining interstitial fluid distribution or content within body tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0061—Methods for using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2207/00—Methods of manufacture, assembly or production
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Abstract
The present invention discloses a kind of percutaneous microneedle array patch and its manufacture method, the concentration to measure subcutaneous target molecule, comprising:Substrate, microneedle unit, signal processing unit and power subsystem.Microneedle unit comprises at least and is arranged in the first micropin group as working electrode and the second micropin group as reference electrode on substrate, each micropin group comprises at least a micropin, first micropin group includes an at least thin slice, at least provided with a perforation on each thin slice, perforated edge is provided with a bur, perforation on a wherein thin slice is passed through for the bur of the perforated edge of relative position on remaining thin slice, and those burs are disconnected from each other.The percutaneous microneedle array patch of the present invention, when the micropin puncture skin of its micropin group is sensed, micropin can be remained intact.
Description
Technical field
The present invention relates to percutaneous microneedle array patch, measure subcutaneous concentration of target molecules to know particularly with regard to one kind
The percutaneous microneedle array patch of physiology signal.
Background technology
Hypodermis is rich in having Amino acid, sugar, fat in the main place of human tissue liquid flow distribution, tissue fluid
Waste that acid, coenzyme, hormone, neurotransmitter, salt and cell are produced etc., is the main pipe that cell is exchanged with blood, therefore logical
The concentration for crossing each composition in tissue fluid is to judge one of method of physiological status.
Take or during injection medicine, medicine in drug development and can be used in tissue fluid for a long time and slow release
Clinical trial during, often need constantly to monitor the change of medicine concentration in tissue fluid, also therefore sampling tissue fluid with
It is checked or analyzed, is seen everywhere in medical procedure.
Physiological detection equipment seen by market now, or medical personnel's sampling tissue liquid method, adopt mostly and have an acupuncture treatment and wear
Broken cuticula, carrys out extracting interstitial fluid to carry out analysis detection, but the sampling method of such a destruction skin surface, except easily making
Patient feels pain, and then germinate outside rejection feeling, a large amount of microorganisms of skin surface, also easily in the destroyed feelings of skin surface
Under condition, into human body and then infection.In order to improve the shortcoming had an acupuncture treatment and wear out cuticula sampling, there is proposition transcutaneous sensor, its
Skin penetrating is carried out using the micropin of array format, low invasive puncture can effectively mitigate the pain of user, and together
When reach sampling tissue fluid purpose.
The micropin making of transcutaneous sensor is common to be had using semiconductor technologies, such as United States Patent (USP) US7 such as lithographic and etchings,
Disclose a kind of technique of silicon micropin in 344,499B1 the 2nd section of the 12nd column of specification.There is provided thereon covered with patterning first
One Silicon Wafer of the first photoresist layer.Then, it is etched using isotropic etching mode, forms one and perforate.Then, in wafer
Surface is coated with one second photoresist layer of a layers of chrome, afterwards coated pattern, so that being covered in perforation, and forms a circle
Shielding supplies subsequent etch.Then, it is etched to form the outer cone wall of micropin.However, due to the fragility containing silicon semiconductor material,
When micropin, which punctures skin, to be sensed, micropin is easily broken off.
In addition, there is the mode proposed using Laser Micro-Machining, the bur of resin formation is drilled, to make hollow microneedles.
First, extrusion molding is carried out using such as polyimide resin or polyether-ether-ketone resin, forms thin with multiple burs thereon
Piece, is then drilled, you can obtain hollow microneedles using laser to bur.However, because micropin size is superfine small, during extrusion molding
Bur is there may be flash, and whether off-axis perforation or central hole, and unified aperture and not readily are formed using laser.
The content of the invention
It is an object of the invention to provide a kind of percutaneous microneedle array patch and its manufacture method, make the micropin of its micropin group
When puncture skin is sensed, micropin can be remained intact.
In order to reach above-mentioned purpose, the present invention provides a kind of percutaneous microneedle array patch, to measure subcutaneous target point
The concentration of son, the percutaneous microneedle array patch is included:Substrate, microneedle unit, signal processing unit and power subsystem.Microneedle unit
Including at least the first micropin group and the second micropin group being arranged on substrate, the first micropin group is as working electrode, and this
The micropin of one micropin group is arranged on the substrate in the form of an array, and the second micropin group is as reference electrode, each micropin
Group comprises at least a micropin, and the first micropin group is included at least provided with a perforation on an at least thin slice, each thin slice, and perforated edge is set
A bur is equipped with, wherein the perforation on a thin slice is passed through for the bur of the perforated edge of relative position on remaining thin slice, and should
A little burs are disconnected from each other.Signal processing unit is arranged on the substrate and electrically connected with the first micropin group and the second micropin group
Connect.Power subsystem supply working power gives the percutaneous microneedle array patch.
Wherein, the first micropin group is formed by one first thin slice and one second thin slice are stacked, is at least set on first thin slice
One first perforation is put, first perforated edge is provided with one first bur, and second thin slice at least provided with one second perforation,
Second perforated edge is provided with one second bur, first perforation of second bur through relative position on first thin slice
It is relative with first bur.
Wherein, the first micropin group is formed by one first thin slice, one second thin slice and one the 3rd thin slice are stacked, and this is first thin
At least provided with one first perforation on piece, first perforated edge is provided with one first bur, at least provided with one on second thin slice
Second perforation, second perforated edge is provided with one second bur, and at least provided with one the 3rd perforation on the 3rd thin slice, and this
Three perforated edges are provided with one the 3rd bur, and second bur and the 3rd bur pass through first perforation on first thin slice
It is in triangular pyramidal with first bur.
Wherein, the first micropin group by one first thin slice, one second thin slice, one the 3rd thin slice and one the 4th thin slice it is stacked and
Into at least provided with one first perforation on first thin slice, first perforated edge is provided with one first bur, on second thin slice
At least provided with one second perforation, second perforated edge is provided with one second bur, the 3rd thin slice at least provided with one the 3rd
Perforation, the 3rd perforated edge is provided with one the 3rd bur and the 4th thin slice to be worn at least provided with one the 4th perforation, the 4th
Bore edges are provided with one the 4th bur, and second bur, the 3rd bur and the 4th bur pass through being somebody's turn to do on first thin slice
First perforation is in corner taper with first bur.
Wherein, each bur of the first micropin group includes a point and a substrate, wherein the perforation warp on a thin slice
The top of the point for the micropin that the bur of the perforated edge of relative position is formed after passing through on remaining thin slice does not exist
Sustained height.
Wherein, each bur of the first micropin group includes a point and a substrate, wherein the perforation warp on a thin slice
The top of the point for the micropin that the bur of the perforated edge of relative position is formed after passing through on remaining thin slice has
Sustained height.
Wherein, the micropin of the first micropin group and the second micropin group is formed by punching press or etch process.
Wherein, sensing macromolecule is scribbled on the inner surface of the bur.
Wherein, anti-allergic medicine is scribbled on the outer surface of the bur.
Wherein, a test-paper is further included, is placed between the first micropin group and the substrate, the test-paper is conductive comprising one
Layer and multiple test zones on the conductive layer, coating sensing macromolecule on the test zone, and with first micropin
Perforation alignment in group.
Wherein, the sensing macromolecule is antibody, fit, restructuring monomer (ScFv), carbohydrate, glucose oxidase（Glucose
Oxidase）Or hydroxybutyric dehydrogenase（HBHD）.
Wherein, the material of the bur is selected from stainless steel, nickel, nickel alloy, titanium, titanium alloy, CNT or silicon materials, and
The metal with bio-compatibility is deposited in surface.
Wherein, the material of the bur is resin, and deposits the metal with bio-compatibility in surface.
The present invention also provides a kind of manufacture method of percutaneous microneedle array patch, comprises the following steps：Aforesaid substrate is provided
And microneedle unit；In a metal level of the bur surface deposition with bio-compatibility of the first micropin group of microneedle unit；Formed
One self-assembled monolayer is on the metal level；In bound antibody or fit on the self-assembled monolayer；Apply barrier molecule, fill up and do not connect
Upper antibody or fit self-assembled monolayer.
Wherein, further include and CNT is mixed in metal level.
The percutaneous microneedle array patch that the present invention is provided, the micropin of its micropin group is formed by punching press or etch process, tool
There are enough mechanical strengths, when the micropin of micropin group, which punctures skin, to be sensed, micropin can be remained intact.Moreover, of the invention
The structure of working electrode micropin group be conducive to that macromolecule will be sensed and be coated on the inner surface of micropin point, it is micro- in working electrode
When the micropin puncture skin of pin group is sensed, the high molecular peeling of sensing can be reduced.
The working electrode microneedle surface of percutaneous microneedle array patch of the invention can be modified according to target molecule, wherein,
Target molecule can be biomolecule, such as blood glucose, cortisol, aliphatic acid, target molecule can also be drug molecule for example
Antibiotic, percutaneous microneedle array patch can provide chronic medicine or when certain drug is taken, and carry out drug monitoring, improve sufferer
The biddability of medication, can further determine dosage and takes frequency for personal drug metabolism situation, individual to reach
The purpose of people's chemical drug thing.
Compared to prior art, micropin of the invention has enough mechanical strengths, when the micropin of micropin group punctures skin
When being sensed, micropin can be remained intact.Moreover, the technique of the microneedle unit of the present invention is simple, be conducive to a large amount of productions.
Below in conjunction with the drawings and specific embodiments, the present invention will be described in detail, but not as a limitation of the invention.
Brief description of the drawings
Fig. 1 is the explosive decomposition Tu ﹔ of the percutaneous microneedle array patch of one embodiment of the invention
Fig. 2 is the explosive decomposition figure of the percutaneous microneedle array patch of one embodiment of the invention of view directions different from Fig. 1；
Fig. 3 is the Shi Yi Tu ﹔ of one embodiment of the invention microneedle unit
Fig. 4 is the structure partial top view of one embodiment of the invention working electrode micropin group；
Fig. 5 is the structure partial top view of another embodiment of the present invention working electrode micropin group；
Fig. 6 is the structure partial top view of another embodiment of the present invention working electrode micropin group；
Fig. 7 is the structure partial top view of the still another embodiment working electrode micropin group of the present invention；
Fig. 8 is the combination schematic appearance of the percutaneous microneedle array patch of one embodiment of the invention；
Fig. 9 is the combination diagrammatic cross-section of the percutaneous microneedle array patch of one embodiment of the invention；
Figure 10 is Fig. 9 partial cutaway schematic, wherein sensing macromolecule is coated on the bur of micropin；
Figure 11 is Fig. 9 partial cutaway schematic, wherein sensing macromolecule is coated on test-paper；
Figure 12 is the combination partial cutaway schematic of the percutaneous microneedle array patch of one embodiment of the invention, wherein leading handle warp
Part bending is directly electrically connected with the contact on circuit board, and without using conductive pole.
Wherein, reference：
The hole of 10 substrate 102
The microneedle unit of 104 slot 20
21st, the micropin group of 23,25 conductive pole 22 first
The point of 222 first thin slice 2221
2222 first 2223 substrates of perforation
The thin slice of 2224 first bur 224 second
2242 second 2,244 second burs of perforation
2246 barbs 2248 lead handle
226 the 3rd thin slices 2262 the 3rd are perforated
The thin slice of 2264 the 3rd bur 228 the 4th
2282 the 4th 2284 the 4th burs of perforation
The thin slice of 24 second micropin group 242 first
2422 first 2,424 first burs of perforation
2426 barbs 2428 lead handle
The thin slice of 26 the 3rd micropin group 262 first
2622 first 2,624 first burs of perforation
2626 barbs 2628 lead handle
30 pliability pads 32 are open
The signal processing unit of 40 circuit board 41
42nd, the power subsystem of 44,46 electric contact 43
The conductive layer of 50 enclosing cover 92
The resin sheet of 94 test zone 96
98 adhesion layers
Embodiment
Detailed description for the present invention and technology contents, coordinate schema to be described as follows, but institute's accompanying drawings only provide ginseng
Examine and used with explanation, not for being any limitation as to the present invention.
Referring to Fig.1 and 2, Fig. 1 and Fig. 2 is to watch the percutaneous micropin battle array of one embodiment of the invention by different directions respectively
The explosive decomposition figure of row patch.The percutaneous microneedle array patch of the present invention is included:Substrate 10, microneedle unit 20, pliability pad
30th, signal processing unit 41, power subsystem 43 and enclosing cover 50, wherein signal processing unit 41 and power subsystem 43 are arranged at circuit
On plate 40.
According to one embodiment of the invention, microneedle unit 20, which is included, to be arranged on substrate 10 as the first micro- of working electrode
Pin group 22, the second micropin group 24 as reference electrode, and it is used as the 3rd micropin group 26 of counterelectrode.First micropin group 22
Those micropins may, for example, be array format and be arranged on substrate 10.There is an opening 32 to supply microneedle unit on pliability pad 30
20 pass through, and microneedle unit 20 is electrically connected with the electric contact 42,44,46 on conductive pole 21,23,25 and circuit board 40.Due to
The present invention has pliability pad 30, and muscle profile syntype that can be with user during operation is in close contact.
Signal processing unit 41 is electrically connected with microneedle unit 20 to receive the concentration of target molecules of micropin sensing, through computing
After judgement, a sensing signal is converted the information into, is also that a kind of can reflect the signal of the physiological status of user instantly.Power supply
Unit 43 supplies power for operation to the percutaneous microneedle array patch of the present invention.
Fig. 3 is refer to, Fig. 3 is the schematic diagram of one embodiment of the invention microneedle unit.First micropin group 22 is thin by first
The thin slice 224 of piece 222 and second is stacked to be formed, at least provided with one first perforation 2222 on the first thin slice 222, first perforation 2222
Edge is provided with one first bur 2224, and the second thin slice 224 at least provided with one second perforation 2242, and the second perforated edge is set
It is equipped with one second bur 2244, first perforation 2222 and first of second bur 2244 through relative position on the first thin slice 222
Bur 2224 is relative.In addition, barb 2246 and the hole on substrate 10 can be set on the edge of the second thin slice 224 of the first micropin group 22
Cave 102 engages.It can be set in an embodiment, the edge of the second thin slice 224 of the first micropin group 22 and lead the insertion substrate 10 of handle 2248
On slot 104, be electrically connected with by circuit with conductive pole 21.
Similarly, the second micropin group 24 also has on the first thin slice 242, the first thin slice 242 at least provided with one first perforation
2422, the first perforated edge is provided with one first bur 2424.In addition, can on the edge of the first thin slice 242 of the second micropin group 24
Barb 2426 is set to engage with the hole 102 on substrate 10.In an embodiment, the edge of the first thin slice 242 of the second micropin group 24
The upper settable slot 104 led on the insertion substrate 10 of handle 2428, is electrically connected with by circuit with conductive pole 23.
Similarly, the 3rd micropin group 26 also has on the first thin slice 262, the first thin slice 262 at least provided with one first perforation
2622, the first 2622 edges of perforation are provided with one first bur 2624.In addition, the edge of the first thin slice 262 of the 3rd micropin group 26
Upper settable barb 2626 engages with the hole 102 on substrate 10.In an embodiment, the first thin slice 262 of the 3rd micropin group 26
The slot 104 led on the insertion substrate 10 of handle 2628 can be set on edge, be electrically connected with by circuit with conductive pole 25.
One embodiment of the invention, the micropin of the first micropin group 22, the second micropin group 24 and the 3rd micropin group 26 is by punching
Pressure or etch process are formed.The material of those burs is selected from stainless steel, nickel, nickel alloy, titanium, titanium alloy, CNT or silicon material
Material, and the metal with bio-compatibility is deposited in surface, such as gold, palladium.The material of those burs can also be resin for example
It is makrolon, polymethacrylic acid copolymer, ethylene/vinyl acetate copolymer, Teflon（Polytetrafluoroethylene (PTFE)）Or polyester
Class, and the metal with bio-compatibility is deposited in surface, such as gold, palladium.The height of those burs is 300-600 microns, base
Bottom width degree is 150-450 microns.The point of those burs at intervals of 500-3000 microns.
Fig. 4 be refer to Fig. 6.Fig. 4 is the structure partial top view of one embodiment of the invention working electrode micropin group.The
One micropin group 22 is formed by the first thin slice 222 and the second thin slice 224 are stacked, at least provided with one first perforation on the first thin slice 222
2222, the first 2222 edges of perforation are provided with one first bur 2224, and the second thin slice 224 at least provided with one second perforation
2242, the second perforated edge is provided with one second bur 2244, and the second bur 2244 passes through relative position on the first thin slice 222
First perforation 2222 is relative with the first bur 2224.
Fig. 5 is the structure partial top view of another embodiment of the present invention working electrode micropin group.First micropin group 22 by
First thin slice 222, the second thin slice 224 and the 3rd thin slice 226 are stacked to be formed, at least provided with the first perforation on the first thin slice 222
2222, the first 2222 edges of perforation are provided with one first bur 2224, the second thin slice 224 at least provided with one second perforation
2242, the second 2242 edges of perforation are provided with one second bur 2244, and at least provided with one the 3rd perforation on the 3rd thin slice 226
2262, the 3rd 2262 edges of perforation are provided with one the 3rd bur 2264, and the second bur 2244 and the 3rd bur 2264 pass through first
The first perforation 2222 and the first bur 2224 on thin slice 222 are in positive triangular pyramidal.
Fig. 6 is the structure partial top view of another embodiment of the present invention working electrode micropin group.First micropin group 22 by
First thin slice 222, the second thin slice 224, the 3rd thin slice 226 are stacked to be formed, wherein being worn on the first thin slice 222 at least provided with one first
Hole 2222, the first 2222 edges of perforation are provided with one first bur 2224；At least provided with one second perforation on second thin slice 224
2242, the second 2242 edges of perforation are provided with one second bur 2244；And the 3rd on thin slice 226 at least provided with one the 3rd perforation
2262, the 3rd 2262 edges of perforation are provided with one the 3rd bur 2264, by the second bur 2244 and the 3rd bur 2264 through the
The first perforation 2222 and the arranged adjacent of the first bur 2224 on one thin slice 222, in isosceles right angle trigonometry taper.
Fig. 7 is the structure partial top view of the still another embodiment working electrode micropin group of the present invention.First micropin group 22
Formed by the first thin slice 222, the second thin slice 224, the 3rd thin slice 226 and the 4th thin slice 228 are stacked, on the first thin slice 222 at least
Set one first perforation 2222, first perforation 2222 edges be provided with one first bur 2224, the second thin slice 224 at least provided with
One second perforation 2242, the second 2242 edges of perforation are provided with one second bur 2244, the 3rd thin slice 226 at least provided with one the
Three perforation 2262, the 3rd 2262 edges of perforation are provided with one the 3rd bur 2264 and the 4th thin slice 228 at least provided with one the 4th
Perforation 2282, the 4th 2282 edges of perforation are provided with one the 4th bur 2284, the second bur 2244, the 3rd bur 2264 and the 4th
Bur 2284 is through the first perforation 2222 on the first thin slice 222 and the first bur 2224 in corner taper.
In four embodiments shown in Fig. 4 to Fig. 7, each bur 2224 of the first micropin group 22 includes a point 2221
And a substrate 2223, wherein the perforation on a thin slice passed through through the bur of the perforated edge of relative position on remaining thin slice after shape
Into the micropin those points top not in sustained height.Or, order that can be overlapping according to those thin slices, in advance
The height of its bur is designed, bur of the perforation through the perforated edge of relative position on remaining thin slice on a wherein thin slice is worn
The top of those points of the micropin formed later has sustained height.
Then, Fig. 8 and Fig. 9 be refer to.Fig. 8 shows for the combination outward appearance of the percutaneous microneedle array patch of one embodiment of the invention
It is intended to.Fig. 9 is the combination diagrammatic cross-section of the percutaneous microneedle array patch of one embodiment of the invention.First in the present embodiment is micro-
Pin group 22 is formed by the first thin slice 222 and the second thin slice 224 are stacked, can for example apply a stamping press in the first thin slice 222 and the
The surrounding of two thin slices 224 is with both combinations.Second micropin group 24 has the first thin slice 242.3rd micropin group 26 also only has
First thin slice 262.Because the present invention has pliability pad 30, muscle profile syntype that can be with user during operation closely connects
Touch.
The microneedle surface of the working electrode micropin group 22 of percutaneous microneedle array patch of the invention can be carried out according to target molecule
Modification, wherein, target molecule can be biomolecule, such as blood glucose, cortisol, aliphatic acid, and target molecule can also be medicine
Thing molecule such as antibiotic, percutaneous microneedle array patch can provide chronic medicine or when certain drug is taken, and carry out medicine prison
Control, improves the biddability of sufferer medication, can further determine dosage for personal drug metabolism situation and take frequency
Rate, to reach the purpose of individualized medicine.
In order that the micropin of working electrode micropin group 22 has selectivity (specificity), working electrode micropin group 22
Microneedle surface can have surfaction characteristic, it is modified according to the target molecule of detection, in working electrode micropin group
22 microneedle surface can be connected with one of the following option, including antibody, fit (aptamer), restructuring monomer (ScFv) or carbohydrate
Deng.For example, when measuring blood glucose, Enzyme (glucose oxidase, Gox) can be aoxidized by fixed grape candy micro- in working electrode
The microneedle surface of pin group 22 carries out it；And general antibody or fit connected mode are the micropins to working electrode micropin group 22
Golden watch layer, applies bound antibody or fit after self-assembled monolayer (self-assemble monolayer, SAM), then applies again
Plus barrier molecule, fill up and do not connect antibody or fit self-assembled monolayer, to ensure its selectivity, such as to increase sensitivity, can
Further CNT is mixed in golden watch layer.The manufacture method of the various modified gold electrodes of detailed description below.
The making step of avidin modified gold electrode is as follows, comes to the surface and is coated with the working electrode of layer gold with 3,3 ' two thio two
The milli mole concentration of propionic acid 200 handles 30 minutes to form a self-assembled monolayer (SAM), is thoroughly cleaned using distilled water afterwards.Make
With N- (3- the dimethylaminopropyls)-N- ethylcarbodiimines (EDC) and the N- hydroxyls of 1 milli mole concentration of 100 milli mole concentration
After succimide (NHS) is cultivated 1 hour, in the activation that carboxylic acid group is carried out on electrode.Afterwards, phosphorus of the electrode in pH value 7.5
Cultivated and stayed overnight using the avidin of 1 mg/ml in acid buffering solution (PBS).Cultivated using the monoethanolamine of 100 milli mole concentration
20 minutes cofree carboxylic acid groups of blocking electrode.Finally, 10 how the electricity that the biotin DNA aptamer of mole concentration is coated with avidin
It is extremely upper to cultivate 40 minutes, thoroughly cleaned using distilled water afterwards.
The occupation mode of avidin modified gold electrode illustrated below, tetracycline is a kind of antibiotic, is usually used in organ
The sufferer of inflammation, tetracycline to be traced can select microneedle surface connection for four when sufferer bulk concentration changes with time
There is ring element the percutaneous microneedle array patch of the biotin DNA aptamer of selectivity to detect tetracycline concentration.Therefore, it is of the invention
Percutaneous microneedle array patch can provide chronic medicine or when certain drug is taken, and carry out drug monitoring, improve sufferer medication
Biddability, can further determine dosage and takes frequency, to reach personal chemical drug for personal drug metabolism situation
The purpose of thing.
Sensitivity to be increased, further can mix CNT in golden watch layer.Multiple-wall carbon nanotube (MWCNT) chemistry is repaiied
The making step for adoring electrode is as follows, and the carboxylic acid derivatives of CNT can be by commercially available MWCNT in 4M salpeter solutions
Backflow is obtained.The MWCNT20 milligrams of above-mentioned acquirement oxidation flow back 12 hours for 10 milliliters in thionyl chloride.The mixture of acquisition falls
Go out, excessive thionyl chloride is removed in vacuum.Add mercaptoethanol solution (2 milliliters, 30 milli moles) and triethylamine (1 milliliter,
7 milli moles) flowed back 24 hours in the solution of dichloromethane (10 milliliters), and mixture.Suspension is centrifuged, and solids
Ethanol cleaning is reused to give 10 milligrams of MWCNT derivatives.Being prepared as multiple-wall carbon nanotube chemically modified electrode will be dry
3 milligrams of CNT of net gold electrode immersion sound wave concussion is in 1 milliliter of dimethyl sulfoxide (DMSO)（DMSO 48 in suspension)
Hour.Finally, 10 how the biotin DNA aptamer of mole concentration on MWCNT chemically modified electrodes cultivate 40 minutes, use afterwards
Distilled water is thoroughly cleaned.
SWNT（SWCNT）The making step of chemically modified electrode is as follows, the carboxylic acid derivatives of CNT
It can be obtained by commercially available SWCNT in the backflow of 4M salpeter solutions.A cystamine individual layer is combined on gold electrode, to form one certainly
Individual layer (SAM) is assembled, sound wave concussion is then scattered in 1 milliliter of dimethylformamide（DMF 3 milligrams) carry carboxylic acid group
SWNT (reactant 2a) be linked to and there are the dicyclohexylcarbodiimide of coupling agent 1,3（DCC）3 milligrams of SAM
On surface, product 2b is obtained.Afterwards, DMF and 3 milligram of DCC of the mercaptoethanol solution of 2 milli mole concentration at 1 milliliter is added,
Mercaptoethanol is coupled to the carboxylic acid group of product 2b free edge by DCC is used, and obtains SWCNT chemically modified electrodes.Most
Afterwards, 10 how the biotin DNA aptamer of mole concentration on SWCNT chemically modified electrodes cultivate 40 minutes, afterwards using distilled water
Thoroughly clean.
Then, Figure 10 is refer to, Figure 10 is Fig. 9 partial cutaway schematic, wherein sensing macromolecule is coated on micropin
On bur.Specifically, sensing macromolecule is coated on the inner surface of bur, is coated with the outer surface of bur anti-allergic
Medicine.In the present embodiment, sensing macromolecule is, for example, antibody, fit, restructuring monomer (ScFv), carbohydrate, glucose oxidase
（Glucose Oxidase）Or hydroxybutyric dehydrogenase（HBHD）.One surface scribbles the percutaneous micro- of the high molecular micropin of sensing
Pin array patch, can be used to detect the concentration of target molecules in skin surface, and this concentration can be used as the finger for judging physiological status
One of mark.
Figure 11 is Fig. 9 partial cutaway schematic, wherein sensing macromolecule is coated on test-paper.The present embodiment and Figure 10
The difference of illustrated embodiment is, the first micropin group 22 of the present embodiment is not applied on bur as the instrument of extraction interstitial fluid
Cloth senses macromolecule, and sensing macromolecule is coated on the surface of the test-paper of the lower section of the first micropin group 22.In the present embodiment,
Test-paper system is placed between the first micropin group 22 and substrate 10, and test-paper is comprising a conductive layer 92 and on conductive layer 92
On multiple test zones 94, those test zones 94 coating sensing macromolecule, and with 2222 pairs of perforation in the first micropin group 22
Together.The present embodiment defines those test zones 94 thereon using resin sheet 96.In addition, the first micropin group 22 is sticked together by one
Layer 98 and test paper chip bonding., can be high in sensing in order to avoid sensing macromolecule or anti-allergic medicine are by environmental pollution
A protective layer is formed on the surface of molecule or anti-allergic medicine, protective layer is, for example, epoxy resin-Polyurethane formyl
Resin（Epoxy-PU）Film.Further, since ampere meter electrochemical method is general than less selective, many common chaff interferences
It is present in blood plasma, can imports among signal.In order to realize high subcutaneous target molecule selectivity, in first shape on the surface of electrode
Into a pellicle or the film with low oxygen permeability.
One embodiment of percutaneous microneedle array patch of the invention further includes a wireless transmission unit (not shown), is electrically connected with
In signal processing unit 41, when signal processing unit 41 often produces a sensing signal, wireless transmission unit is just received and external
Transmit to outside doctor end, instruction will be assigned when doctor's analysis need to be immediately treated, the finger of the received outside of wireless transmission unit
Signal is made, user's its physiological status deeply concerned or the drug administration can be reminded.
Then, Figure 12 is refer to, Figure 12 is the combination part section of the percutaneous microneedle array patch of one embodiment of the invention
Schematic diagram.In the present embodiment, lead handle 2248 and be directly electrically connected with through part bending with the contact 42 on circuit board 40, and without using
Conductive pole.
Certainly, the present invention can also have other various embodiments, ripe in the case of without departing substantially from spirit of the invention and its essence
Various corresponding changes and deformation, but these corresponding changes and deformation can be made according to the present invention by knowing those skilled in the art
The protection domain of the claims in the present invention should all be belonged to.
Claims (15)
1. a kind of percutaneous microneedle array patch, the concentration to measure subcutaneous target molecule, it is characterised in that including:
One substrate；
One microneedle unit, including at least the one first micropin group and one second micropin group being arranged on the substrate, first micropin
Group is arranged on the substrate in the form of an array as working electrode, the micropin of the first micropin group, and the second micropin group is made
For reference electrode, each micropin group comprises at least a micropin, and the first micropin group is included at least two thin slices, each thin slice at least
One is set to perforate, the perforated edge is provided with a bur, wherein the perforation on a thin slice is for relative position on remaining thin slice
The bur of perforated edge is passed through, and the bur is disconnected from each other；
One signal processing unit, is arranged on the substrate and is electrically connected with the first micropin group and the second micropin group；And
One power subsystem, supply working power gives the percutaneous microneedle array patch.
2. microneedle array patch as claimed in claim 1 percutaneous, it is characterised in that the first micropin group by one first thin slice and
One second thin slice is stacked to be formed, and at least provided with one first perforation on first thin slice, first perforated edge is provided with one first
At least provided with one second perforation on bur, and second thin slice, second perforated edge is provided with one second bur, and this second is dashed forward
Pierce through first perforation of relative position on first thin slice relative with first bur.
3. microneedle array patch as claimed in claim 1 percutaneous, it is characterised in that the first micropin group by one first thin slice,
One second thin slice and one the 3rd thin slice, which are stacked, to be formed, at least provided with one first perforation, first perforated edge on first thin slice
One first bur is provided with, at least provided with one second perforation on second thin slice, second perforated edge is provided with one second and dashed forward
Thorn, and at least provided with one the 3rd perforation on the 3rd thin slice, the 3rd perforated edge is provided with one the 3rd bur, second bur
With the 3rd bur through first perforation on first thin slice and first bur in triangular pyramidal.
4. microneedle array patch as claimed in claim 1 percutaneous, it is characterised in that the first micropin group by one first thin slice,
One second thin slice, one the 3rd thin slice and one the 4th thin slice are stacked forms, at least provided with one first perforation on first thin slice, and this
One perforated edge is provided with one first bur, and at least provided with one second perforation on second thin slice, second perforated edge is set
Have on one second bur, the 3rd thin slice at least provided with one the 3rd perforation, the 3rd perforated edge be provided with one the 3rd bur and
At least provided with one the 4th perforation on 4th thin slice, the 4th perforated edge is provided with one the 4th bur, second bur, this
Three burs and the 4th bur are through first perforation on first thin slice with first bur in corner taper.
5. the percutaneous microneedle array patch as any one of Claims 1-4, it is characterised in that the first micropin group
Each bur includes a point and a substrate, wherein punching edge of the perforation through relative position on remaining thin slice on a thin slice
The top of the point for the micropin that the bur of edge is formed after passing through is not in sustained height.
6. the percutaneous microneedle array patch as any one of Claims 1-4, it is characterised in that the first micropin group
Each bur includes a point and a substrate, wherein punching edge of the perforation through relative position on remaining thin slice on a thin slice
The top of the point for the micropin that the bur of edge is formed after passing through has sustained height.
7. percutaneous microneedle array patch as claimed in claim 1, it is characterised in that the first micropin group and the second micropin group
Micropin formed by punching press or etch process.
8. percutaneous microneedle array patch as claimed in claim 1, it is characterised in that sensing is scribbled on the inner surface of the bur
Macromolecule.
9. percutaneous microneedle array patch as claimed in claim 1, it is characterised in that anti-skin is scribbled on the outer surface of the bur
The medicine of skin allergy.
10. microneedle array patch as claimed in claim 1 percutaneous, it is characterised in that further include a test-paper, be placed in this
Between one micropin group and the substrate, the test-paper includes a conductive layer and multiple test zones on the conductive layer, described
Coating sensing macromolecule on test zone, and alignd with the perforation in the first micropin group.
11. the percutaneous microneedle array patch as described in claim 8 or 10, it is characterised in that the sensing macromolecule is antibody, fitted
Body, restructuring monomer, carbohydrate, glucose oxidase or hydroxybutyric dehydrogenase.
12. microneedle array patch as claimed in claim 1 percutaneous, it is characterised in that the material of the bur be selected from stainless steel,
Nickel, nickel alloy, titanium, titanium alloy, CNT or silicon materials, and deposit the metal with bio-compatibility in surface.
13. percutaneous microneedle array patch as claimed in claim 1, it is characterised in that the material of the bur is resin, and in
Metal of the surface deposition with bio-compatibility.
14. a kind of manufacture method of percutaneous microneedle array patch, it is characterised in that comprise the following steps:
The substrate and microneedle unit of claim 1 are provided；
In a metal level of the bur surface deposition with bio-compatibility of the first micropin group of microneedle unit；
A self-assembled monolayer is formed on the metal level；
In bound antibody or fit on the self-assembled monolayer；And
Apply barrier molecule, fill up and do not connect antibody or fit self-assembled monolayer.
15. the manufacture method of percutaneous microneedle array patch as claimed in claim 14, it is characterised in that further include in metal level
Middle mixing CNT.
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| CN104970804A (en) * | 2014-04-01 | 2015-10-14 | 微凸科技股份有限公司 | Continuous percutaneous microneedle monitoring system |
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| 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 |
| JP2020504749A (en) * | 2016-12-28 | 2020-02-13 | ネクスモス カンパニー リミテッドＮｅｘｍｏｓ Ｃｏ．，Ｌｔｄ． | Method of producing microneedle-based diagnostic skin patches coated with aptamers and patches thereof |
| WO2018209711A1 (en) * | 2017-05-19 | 2018-11-22 | 深圳市得道健康管理有限公司 | Microneedle electrode, meridian detecting device and customizing method therefor |
| CN110090351B (en) * | 2018-01-30 | 2020-11-10 | 京东方光科技有限公司 | Wearable skin beauty device and wearable eye patch |
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| 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 |
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| AU2736501A (en) * | 1999-12-30 | 2001-07-16 | 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 |
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| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104970804A (en) * | 2014-04-01 | 2015-10-14 | 微凸科技股份有限公司 | Continuous percutaneous microneedle monitoring system |
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