CN104970805A - Pertacuneous microneedle array paste and making method thereof - Google Patents
Pertacuneous microneedle array paste and making method thereof Download PDFInfo
- Publication number
- CN104970805A CN104970805A CN201410128793.5A CN201410128793A CN104970805A CN 104970805 A CN104970805 A CN 104970805A CN 201410128793 A CN201410128793 A CN 201410128793A CN 104970805 A CN104970805 A CN 104970805A
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- Prior art keywords
- bur
- thin slice
- perforation
- micropin
- microneedle array
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Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medical Informatics (AREA)
- General Health & Medical Sciences (AREA)
- Pathology (AREA)
- Surgery (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Hematology (AREA)
- Optics & Photonics (AREA)
- Dermatology (AREA)
- Anesthesiology (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
Abstract
The invention discloses a pertacuneous microneedle array paste and a making method thereof, so pertacuneous object molecule concentration can be measured; the pertacuneous microneedle array paste comprises a substrate, a microneedle unit, a signal processing unit and a power supply unit; the microneedle unit at least comprises a first microneedle group and a second microneedle group arranged on the substrate, wherein the first microneedle group serves as a work electrode, and the second microneedle group serves as a reference electrode; each microneedle group at least comprises one microneedle; the first microneedle group comprises at least one sheet, each sheet is at least provided with one through hole, a through hole edge is provided with a piercing, wherein one through hole on one sheet allows the piercings, of through hole edges on corresponding positions of the rest sheets, to pass, and the piercings are mutually separated. The microneedle of the microneedle group of the pertacuneous microneedle array paste can penetrate the skin for sensing, and the microneedle can remain intact.
Description
Technical field
The present invention relates to the patch of percutaneous microneedle array, be particularly to a kind ofly measure subcutaneous concentration of target molecules to know the percutaneous microneedle array patch of physiology signal.
Background technology
Subcutaneous tissue is the main place of human tissue liquid flow distribution, the refuse etc. that amino acid, sugar, fatty acid, coenzyme, hormone, neurotransmitter, salt and cell produce is rich in tissue fluid, being the main pipe that cell exchanges with blood, is therefore one of method judging physiological situation by the concentration of composition each in tissue fluid.
Take or injection medicine time, medicine can in tissue fluid for a long time and discharge slowly, in the clinical experiment process of drug development and use, often need the change constantly monitoring medicine concentration in tissue fluid, also therefore sample tissue fluid to carry out detecting or analyzing, be seen everywhere in medical procedure.
Physiological detection equipment seen by market now, or the method for medical personnel's sampling tissue liquid, mostly adopt and have an acupuncture treatment and wear out horny layer, carry out extracting interstitial fluid to detect to carry out analysis, but this kind destroys the sampling method of skin surface, except easily making patient feels pain, and then germinating is repelled outside sense, a large amount of microorganisms of skin surface, also easy in the destroyed situation of skin surface, enter human body and then infection.In order to improve have an acupuncture treatment and wear out horny layer sampling shortcoming, have proposition transcutaneous sensor, it utilizes the micropin of array format to carry out skin penetrating, and low invasive puncture effectively can alleviate the pain of user, reach again simultaneously sampling tissue fluid object.
The micropin making of transcutaneous sensor is common utilizes the semiconductor technologies such as micro-shadow and etching, such as US Patent No. 7,344, and the 2nd section, description the 12nd hurdle of 499B1 discloses a kind of technique of silicon micropin.First, a Silicon Wafer of the first photoresist layer it being coated with patterning is provided.Then, utilize isotropic etching mode to etch, form a perforation.Then, be coated with a layers of chrome in crystal column surface, afterwards one second photoresist layer of coated pattern, to such an extent as to cover in perforation, and form a circular shield for subsequent etch.Then, carry out being etched with the outer cone wall forming micropin.But due to the fragility containing silicon semiconductor material, when micropin skin puncture senses, micropin easily ruptures.
In addition, there is the mode proposing to use Laser Micro-Machining, the bur of resin formation is holed, to make hollow microneedles.First, use such as polyimide resin or polyether-ether-ketone resin to carry out extrusion molding, form the thin slice it with multiple bur, then use laser to hole to bur, can hollow microneedles be obtained.But because micropin size is superfine little, during extrusion molding, bur may produce burr, no matter and be off-axis perforation or central hole, use laser form unified aperture and not readily.
Summary of the invention
The object of the present invention is to provide the patch of a kind of percutaneous microneedle array and manufacture method thereof, when the micropin skin puncture of its micropin group is sensed, micropin can remain intact.
In order to reach above-mentioned object, the invention provides the patch of a kind of percutaneous microneedle array, in order to measure the concentration of subcutaneous target molecule, this percutaneous microneedle array patch comprises: substrate, microneedle unit, signal processing unit and power subsystem.Microneedle unit at least comprises and is arranged in the first micropin group on substrate and the second micropin group, this the first micropin group is as working electrode, the described micropin of this first micropin group is arranged on this substrate in the form of an array, this the second micropin group is as reference electrode, each micropin group at least comprises a micropin, first micropin group comprises at least one thin slice, each thin slice at least arranges a perforation, perforated edge is provided with a bur, perforation wherein on a thin slice is passed for the bur of the perforated edge of relative position on remaining thin slice, and those burs are disconnected from each other.Signal processing unit to be arranged on this substrate and to be electrically connected with this first micropin group and this second micropin group.Power subsystem supply working power gives this percutaneous microneedle array patch.
Wherein, this the first micropin group is by one first thin slice and one second thin slice is stacked forms, this first thin slice is at least arranged one first perforation, this first perforated edge is provided with one first bur, and this second thin slice is at least arranged one second perforation, this second perforated edge is provided with one second bur, and this second bur is relative with this first bur through this first perforation of relative position on this first thin slice.
Wherein, this the first micropin group is by one first thin slice, one second thin slice and one the 3rd thin slice is stacked forms, this first thin slice is at least arranged one first perforation, this first perforated edge is provided with one first bur, this second thin slice is at least arranged one second perforation, this second perforated edge is provided with one second bur, and the 3rd thin slice at least arranges one the 3rd perforation, 3rd perforated edge is provided with one the 3rd bur, and this second bur and the 3rd bur are triangular pyramidal through this first perforation on this first thin slice and this first bur.
Wherein, this the first micropin group is by one first thin slice, one second thin slice, one the 3rd thin slice and one the 4th thin slice is stacked forms, this first thin slice is at least arranged one first perforation, this first perforated edge is provided with one first bur, this second thin slice is at least arranged one second perforation, this second perforated edge is provided with one second bur, 3rd thin slice is at least arranged one the 3rd perforation, 3rd perforated edge is provided with on one the 3rd bur and the 4th thin slice and at least arranges one the 4th perforation, 4th perforated edge is provided with one the 4th bur, this second bur, 3rd bur and the 4th bur are corner taper through this first perforation on this first thin slice and this first bur.
Wherein, each bur of this first micropin group comprises a point and a substrate, and the top of the described point of this micropin that the perforation wherein on a thin slice is formed after the bur of the perforated edge of relative position on remaining thin slice passes is not at sustained height.
Wherein, each bur of this first micropin group comprises a point and a substrate, and the top of the described point of this micropin that the perforation wherein on a thin slice is formed after the bur of the perforated edge of relative position on remaining thin slice passes has sustained height.
Wherein, the micropin of this first micropin group and this second micropin group is formed by punching press or etch process.
Wherein, the inner surface of described bur scribbles sensing macromolecule.
Wherein, the outer surface of described bur scribbles the medicine of anti-skin allergy.
Wherein, more comprise a test-paper, be placed between this first micropin group and this substrate, this test-paper comprises a conductive layer and is positioned at the multiple test zones on this conductive layer, coating sensing macromolecule on described test zone, and align with this perforation in this first micropin group.
Wherein, this sensing macromolecule is antibody, fit, recombinate monomer (ScFv), carbohydrate, glucoseoxidase (Glucose Oxidase) or hydroxybutyric dehydrogenase (HBHD).
Wherein, the material of described bur is selected from rustless steel, nickel, nickel alloy, titanium, titanium alloy, CNT or silicon materials, and has the metal of bio-compatibility in surface deposition.
Wherein, the material of described bur is resin, and has the metal of bio-compatibility in surface deposition.
The present invention also provides the manufacture method of a kind of percutaneous microneedle array patch, comprises the following steps: provide aforesaid substrate and microneedle unit; There is in the bur surface deposition of the first micropin group of microneedle unit a metal level of bio-compatibility; Form a self-assembled monolayer on this metal level; Bound antibody or fit on this self-assembled monolayer; Apply to intercept molecule, fill up and do not connect antibody or fit self-assembled monolayer.
Wherein, be more contained in metal level and mix CNT.
Percutaneous microneedle array provided by the invention patch, the micropin of its micropin group is formed by punching press or etch process, and have enough mechanical strengths, when the micropin skin puncture of micropin group senses, micropin can remain intact.And the structure of working electrode micropin group of the present invention is conducive to inner surface sensing macromolecule being coated on micro needlepoint end, when the micropin skin puncture of working electrode micropin group senses, can reduce and sense high molecular peeling off.
The working electrode microneedle surface of percutaneous microneedle array of the present invention patch can carry out upgrading according to target molecule, wherein, target molecule can be biomolecule, such as blood glucose, hydrocortisone, fatty acid etc., target molecule also can be drug molecule such as antibiotic, when the patch of percutaneous microneedle array can provide chronic disease medicine or certain drug to take, carry out drug monitoring, improve the compliance that sufferer is taken medicine, further can personal drug metabolism situation, determine dosage and take frequency, to reach the object of individualized medicine.
Compared to prior art, micropin of the present invention has enough mechanical strengths, and when the micropin skin puncture of micropin group senses, micropin can remain intact.And the technique of microneedle unit of the present invention is simple, is conducive to a large amount of production.
Describe the present invention below in conjunction with the drawings and specific embodiments, but not as a limitation of the invention.
Accompanying drawing explanation
Fig. 1 is the explosive decomposition Tu ﹔ of one embodiment of the invention percutaneous microneedle array patch
Fig. 2 is the explosive decomposition figure of one embodiment of the invention percutaneous microneedle array patch of view direction 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 another embodiment working electrode micropin group again of the present invention;
Fig. 8 is the combination schematic appearance of one embodiment of the invention percutaneous microneedle array patch;
Fig. 9 is the combination generalized section of one embodiment of the invention percutaneous microneedle array patch;
Figure 10 is the partial cutaway schematic of Fig. 9, wherein senses macromolecule and is coated on the bur of micropin;
Figure 11 is the partial cutaway schematic of Fig. 9, wherein senses macromolecule and is coated on test-paper;
Figure 12 is the combination partial cutaway schematic of one embodiment of the invention percutaneous microneedle array patch, wherein leads handle and is electrically connected through the contact of part bending directly and on circuit board, and do not use conductive pole.
Wherein, Reference numeral:
10 substrate 102 holes
104 slot 20 microneedle units
21,23,25 conductive pole 22 first micropin groups
222 first thin slice 2221 points
2222 first perforation 2223 substrates
2224 first bur 224 second thin slices
2242 second perforation 2,244 second burs
Handle led by 2246 barbs 2248
226 the 3rd thin slices 2262 the 3rd are bored a hole
2264 the 3rd bur 228 the 4th thin slices
2282 the 4th perforation 2284 the 4th burs
24 second micropin group 242 first thin slices
2422 first perforation 2,424 first burs
Handle led by 2426 barbs 2428
26 the 3rd micropin group 262 first thin slices
2622 first perforation 2,624 first burs
Handle led by 2626 barbs 2628
30 pliability pad 32 openings
40 circuit board 41 signal processing units
42,44,46 electric contact 43 power subsystems
50 enclosing cover 92 conductive layers
94 test zone 96 resin sheets
98 adhesion layers
Detailed description of the invention
Detailed description for the present invention and technology contents, coordinate graphic being described as follows, but institute's accompanying drawings only provides reference and explanation use, is not used for being limited the present invention.
Please refer to Fig. 1 and Fig. 2, Fig. 1 and Fig. 2 is the explosive decomposition figure being watched the patch of one embodiment of the invention percutaneous microneedle array respectively by different directions.Percutaneous microneedle array of the present invention patch comprises: substrate 10, microneedle unit 20, pliability pad 30, signal processing unit 41, power subsystem 43 and enclosing cover 50, and wherein signal processing unit 41 and power subsystem 43 are arranged on circuit board 40.
According to one embodiment of the invention, microneedle unit 20 comprises and to be arranged on substrate 10 as the first micropin group 22 of working electrode, as with reference to the second micropin group 24 of electrode, and as the 3rd micropin group 26 of antielectrode.Those micropins of first micropin group 22 can be such as that array format is on substrate 10.Pliability pad 30 has an opening 32 to pass through for microneedle unit 20, and microneedle unit 20 is electrically connected with the electric contact 42,44,46 on conductive pole 21,23,25 and circuit board 40.Because the present invention has pliability pad 30, during operation can with the muscle profile syntype of user, close contact.
Signal processing unit 41 and microneedle unit 20 are electrically connected to receive the concentration of target molecules that micropin sense, and after computing judgement, information being converted to a sensing signal, is also a kind of signal that can reflect user physiological status instantly.Power subsystem 43 supplies power for operation to percutaneous microneedle array of the present invention patch.
Please refer to Fig. 3, Fig. 3 is the schematic diagram of one embodiment of the invention microneedle unit.First micropin group 22 is by the first thin slice 222 and the second thin slice 224 is stacked forms, first thin slice 222 is at least arranged one first perforation 2222, these the first perforation 2222 edges are provided with one first bur 2224, and second thin slice 224 is at least arranged one second perforation 2242, it is relative with the first bur 2224 through the first perforation 2222 of relative position on the first thin slice 222 that second perforated edge is provided with one second bur 2244, second bur 2244.In addition, the second thin slice 224 edge of the first micropin group 22 can arrange barb 2246 engage with the hole 102 on substrate 10.In an embodiment, the second thin slice 224 edge of the first micropin group 22 can be arranged and lead handle 2248 and insert slot 104 on substrate 10, be electrically connected by circuit and conductive pole 21.
In like manner, the second micropin group 24 also has and the first thin slice 242, first thin slice 242 at least arranges one first perforation the 2422, first perforated edge and be provided with one first bur 2424.In addition, the first thin slice 242 edge of the second micropin group 24 can arrange barb 2426 engage with the hole 102 on substrate 10.In an embodiment, the first thin slice 242 edge of the second micropin group 24 can be arranged and lead handle 2428 and insert slot 104 on substrate 10, be electrically connected by circuit and conductive pole 23.
In like manner, the 3rd micropin group 26 also has and the first thin slice 262, first thin slice 262 at least arranges one first perforation 2622, first perforation 2622 edges and be provided with one first bur 2624.In addition, the first thin slice 262 edge of the 3rd micropin group 26 can arrange barb 2626 engage with the hole 102 on substrate 10.In an embodiment, the first thin slice 262 edge of the 3rd micropin group 26 can be arranged and lead handle 2628 and insert slot 104 on substrate 10, be electrically connected by circuit and conductive pole 25.
One embodiment of the invention, the micropin of the first micropin group 22, second micropin group 24 and the 3rd micropin group 26 is formed by punching press or etch process.The material of those burs is selected from rustless steel, nickel, nickel alloy, titanium, titanium alloy, CNT or silicon materials, and has the metal of bio-compatibility in surface deposition, such as gold, palladium.The material of those burs also can be resin is such as Merlon, polymethacrylic acid copolymer, ethylene/vinyl acetate copolymer, Teflon (politef) or polyesters, and has the metal of bio-compatibility in surface deposition, such as gold, palladium.The height of those burs is 300-600 micron, base widths is 150-450 micron.The point of those burs be spaced apart 500-3000 micron.
Please refer to Fig. 4 to Fig. 6.Fig. 4 is the structure partial top view of one embodiment of the invention working electrode micropin group.First micropin group 22 is by the first thin slice 222 and the second thin slice 224 is stacked forms, first thin slice 222 is at least arranged one first perforation 2222, first perforation 2222 edges are provided with one first bur 2224, and second thin slice 224 is at least arranged one second perforation 2242, it is relative with the first bur 2224 through the first perforation 2222 of relative position on the first thin slice 222 that second perforated edge is provided with one second bur 2244, second bur 2244.
Fig. 5 is the structure partial top view of another embodiment of the present invention working electrode micropin group.First micropin group 22 is by the first thin slice 222, second thin slice 224 and the 3rd thin slice 226 is stacked forms, first thin slice 222 is at least arranged the first perforation 2222, first perforation 2222 edges are provided with one first bur 2224, second thin slice 224 is at least arranged one second perforation 2242, second perforation 2242 edges are provided with one second bur 2244, and the 3rd thin slice 226 is at least arranged one the 3rd perforation 2262, 3rd perforation 2262 edges are provided with one the 3rd bur 2264, second bur 2244 and the 3rd bur 2264 are positive triangular pyramidal through the first perforation 2222 on the first thin slice 222 and the first bur 2224.
Fig. 6 is the structure partial top view of another embodiment of the present invention working electrode micropin group.First micropin group 22 by the first thin slice 222, second thin slice 224, the 3rd thin slice 226 is stacked forms, wherein the first thin slice 222 is at least arranged one first perforation 2222, first perforation 2222 edges and is provided with one first bur 2224; Second thin slice 224 is at least arranged one second perforation 2242, second perforation 2242 edges and be provided with one second bur 2244; And the 3rd thin slice 226 is at least arranged one the 3rd perforation 2262,3rd perforation 2262 edges are provided with one the 3rd bur 2264, second bur 2244 and the 3rd bur 2264 are passed the first perforation 2222 and the first bur 2224 arranged adjacent on the first thin slice 222, in the taper of isosceles right angle trigonometry.
Fig. 7 is the structure partial top view of another embodiment working electrode micropin group again of the present invention.First micropin group 22 is by the first thin slice 222, second thin slice 224, 3rd thin slice 226 and the 4th thin slice 228 is stacked forms, first thin slice 222 is at least arranged one first perforation 2222, first perforation 2222 edges are provided with one first bur 2224, second thin slice 224 is at least arranged one second perforation 2242, second perforation 2242 edges are provided with one second bur 2244, 3rd thin slice 226 is at least arranged one the 3rd perforation 2262, 3rd perforation 2262 edges are provided with on one the 3rd bur 2264 and the 4th thin slice 228 and at least arrange one the 4th perforation 2282, 4th perforation 2282 edges are provided with one the 4th bur 2284, second bur 2244, 3rd bur 2264 and the 4th bur 2284 are corner taper through the first perforation 2222 on the first thin slice 222 and the first bur 2224.
In shown in Fig. 4 to Fig. 7 four embodiment, each bur 2224 of first micropin group 22 comprises point 2221 and a substrate 2223, and the top of those points of this micropin that the perforation wherein on a thin slice is formed after the bur of the perforated edge of relative position on remaining thin slice passes is not at sustained height.Or, can according to the order of those thin slice overlaps, design the height of its bur in advance, the top of those points of this micropin that the perforation on a wherein thin slice is formed after the bur of the perforated edge of relative position on remaining thin slice passes has sustained height.
Then, please refer to Fig. 8 and Fig. 9.Fig. 8 is the combination schematic appearance of one embodiment of the invention percutaneous microneedle array patch.Fig. 9 is the combination generalized section of one embodiment of the invention percutaneous microneedle array patch.The first micropin group 22 in the present embodiment is by the first thin slice 222 and the second thin slice 224 is stacked forms, and such as can apply the surrounding of a stamping press in the first thin slice 222 and the second thin slice 224 with both combining.Second micropin group 24 only has the first thin slice 242.3rd micropin group 26 also only has the first thin slice 262.Because the present invention has pliability pad 30, during operation can with the muscle profile syntype of user, close contact.
The microneedle surface of the working electrode micropin group 22 of percutaneous microneedle array of the present invention patch can carry out upgrading according to target molecule, wherein, target molecule can be biomolecule, such as blood glucose, hydrocortisone, fatty acid etc., target molecule also can be drug molecule such as antibiotic, when the patch of percutaneous microneedle array can provide chronic disease medicine or certain drug to take, carry out drug monitoring, improve the compliance that sufferer is taken medicine, further can personal drug metabolism situation, determine dosage and take frequency, to reach the object of individualized medicine.
In order to make the micropin of working electrode micropin group 22, there is specificity (specificity), the microneedle surface of working electrode micropin group 22 can have the characteristic of surfaction, it carries out upgrading according to the target molecule detected, microneedle surface in working electrode micropin group 22 can be connected with one of the following option, comprises antibody, fit (aptamer), restructuring monomer (ScFv) or carbohydrate etc.Such as, when measuring blood glucose, can be carried out it by fixing Fructus Vitis viniferae candy oxidation Enzyme (glucose oxidase, Gox) in the microneedle surface of working electrode micropin group 22; And general antibody or fit connected mode are the golden watch layers of the micropin to working electrode micropin group 22, apply self-assembled monolayer (self-assemble monolayer, SAM) bound antibody or fit after, then apply again to intercept molecule, fill up and do not connect antibody or fit self-assembled monolayer, to ensure its specificity, as sensitivity will be increased, CNT can be mixed further in golden watch layer.Below illustrate the manufacture method of various modified gold electrode.
The making step of avidin modified gold electrode is as follows, and the working electrode that is coated with layer gold of coming to the surface to form a self-assembled monolayer (SAM), uses distilled water thoroughly to clean with 3,3 ' dithiodipropionic acids 200 milli mole concentration process 30 minutes afterwards.N-(3-the dimethylaminopropyl)-N-ethylcarbodiimine (EDC) of use 100 milli mole concentration and the N-hydroxysuccinimide (NHS) of 1 milli mole concentration carry out the activation of carboxylic acid group after cultivating 1 hour on electrode.Afterwards, electrode uses the cultivation of the avidin of 1 mg/ml to spend the night in the phosphate buffer solution (PBS) of pH value 7.5.The ethanolamine of 100 milli mole concentration is used to cultivate 20 minutes cofree carboxylic acid groups of blocking electrode.Finally, the electrode that the biotin DNA aptamer of 10 how mole concentration is coated with in avidin is cultivated 40 minutes, uses distilled water thoroughly to clean afterwards.
Below illustrate the occupation mode of avidin modified gold electrode, tetracycline is a kind of antibiotic, be usually used in the sufferer of organ irritation, for trace tetracycline in sufferer bulk concentration over time time, can select microneedle surface connect there is the percutaneous microneedle array patch of narrow spectrum biotin DNA aptamer to detect tetracycline concentration for tetracycline.Therefore, when percutaneous microneedle array of the present invention patch can provide chronic disease medicine or certain drug to take, drug monitoring is carried out, improve the compliance that sufferer is taken medicine, further can personal drug metabolism situation, determine dosage and take frequency, to reach the object of individualized medicine.
For increasing sensitivity, CNT can be mixed further in golden watch layer.The making step of multiple-wall carbon nanotube (MWCNT) chemically modified electrode is as follows, and the carboxylic acid derivatives of CNT can obtain by commercially available MWCNT in the backflow of 4M salpeter solution.The above-mentioned MWCNT20 milligram obtaining oxidation refluxes 12 hours thionyl chloride 10 milliliters.The mixture obtained is poured out, and excessive thionyl chloride removes in vacuum.Add mercaptoethanol solution (2 milliliters, 30 milli moles) and triethylamine (1 milliliter, the 7 in the least moles) solution at dichloromethane (10 milliliters), and mixture refluxes 24 hours.Carry out centrifugal to suspension, and solids reuse ethanol purge with given MWCNT derivant 10 milligrams.Clean gold electrode is immersed the CNT of 3 milligrams in the suspension of the dimethyl sulfoxide (DMSO) of 1 milliliter 48 hours of sound wave concussion by being prepared as of multiple-wall carbon nanotube chemically modified electrode.Finally, the biotin DNA aptamer of 10 how mole concentration is cultivated 40 minutes on MWCNT chemically modified electrode, uses distilled water thoroughly to clean afterwards.
The making step of SWNT (SWCNT) chemically modified electrode is as follows, and the carboxylic acid derivatives of CNT can obtain by commercially available SWCNT in the backflow of 4M salpeter solution.Combine a cystamine monolayer on gold electrode, to form a self-assembled monolayer (SAM), then the SWNT with carboxylic acid group (reactant 2a) sound wave concussion being scattered in 3 milligrams of the dimethyl formamide (DMF) of 1 milliliter is linked to and has coupling agent 1, the SAM of 3 dicyclohexylcarbodiimides (DCC) 3 milligrams on the surface, obtains product 2b.Afterwards, the mercaptoethanol solution adding 2 milli mole concentration is at the DCC of DMF and 3 milligram of 1 milliliter, and mercaptoethanol, by use DCC, is coupled to the carboxylic acid group of the free edge of product 2b, obtains SWCNT chemically modified electrode.Finally, the biotin DNA aptamer of 10 how mole concentration is cultivated 40 minutes on SWCNT chemically modified electrode, uses distilled water thoroughly to clean afterwards.
Then, please refer to Figure 10, Figure 10 is the partial cutaway schematic of Fig. 9, wherein senses macromolecule and is coated on the bur of micropin.Specifically, sensing macromolecule is coated on the inner surface of bur, the outer surface of bur is coated with the medicine of anti-skin allergy.In the present embodiment, sensing macromolecule is such as antibody, fit, recombinate monomer (ScFv), carbohydrate, glucoseoxidase (Glucose Oxidase) or hydroxybutyric dehydrogenase (HBHD).A surface scribbles the percutaneous microneedle array patch sensing high molecular micropin, can in order to the concentration of target molecules in detection of skin top layer, and this concentration can be used as one of index judging physiological status.
Figure 11 is the partial cutaway schematic of Fig. 9, wherein senses macromolecule and is coated on test-paper.The present embodiment and difference embodiment illustrated in fig. 10 are, the first micropin group 22 of the present embodiment, as the instrument of extraction interstitial fluid, bur is not coated with sensing macromolecule, and sensing macromolecule is coated on the surface of the test-paper be positioned at below the first micropin group 22.In the present embodiment, test-paper system is placed between the first micropin group 22 and substrate 10, multiple test zones 94 that test-paper comprises a conductive layer 92 and is positioned on conductive layer 92, coating sensing macromolecule on those test zones 94, and align with the perforation 2222 in the first micropin group 22.The present embodiment uses resin sheet 96 to define those test zones 94 thereon.In addition, the first micropin group 22 engages by an adhesion layer 98 with test-paper.In order to avoid sensing macromolecule or the medicine of anti-skin allergy are subject to environmental pollution, can on the surface of the medicine of sensing macromolecule or anti-skin allergy formation one protective layer, protective layer is such as epoxy resin-Polyurethane formyl resin (Epoxy-PU) film.In addition, because ammeter electrochemical method is generally than less selectivity, many common chaff interferences are present in blood plasma, among meeting lead-in signal.In order to realize high subcutaneous target molecular selectivity, on the surface of electrode, first forming a semipermeable membrane or there is the film of low oxygen permeability.
One embodiment of percutaneous microneedle array of the present invention patch more comprises a wireless transmission unit (not shown), be electrically connected at signal processing unit 41, when signal processing unit 41 often produces a sensing signal, wireless transmission unit just receives and externally transfers to outside doctor end, need process immediately will assign instruction when doctor analyzes, wireless transmission unit, through receiving outside command signal, can remind user its physiological situation deeply concerned or this drug administration.
Then, please refer to Figure 12, Figure 12 is the combination partial cutaway schematic of one embodiment of the invention percutaneous microneedle array patch.In the present embodiment, lead handle 2248 and be electrically connected through the contact 42 of part bending directly and on circuit board 40, and do not use conductive pole.
Certainly; the present invention also can have other various embodiments; when not deviating from the present invention's spirit and essence thereof; those of ordinary skill in the art can make various corresponding change and distortion according to the present invention, but these change accordingly and are out of shape the protection domain that all should belong to the claims in the present invention.
Claims (15)
1. a percutaneous microneedle array patch, in order to measure the concentration of subcutaneous target molecule, is characterized in that, comprising:
One substrate;
One microneedle unit, at least comprise and be arranged in one first micropin group on this substrate and one second micropin group, this the first micropin group is as working electrode, the described micropin of this first micropin group is arranged on this substrate in the form of an array, this the second micropin group is as reference electrode, each micropin group at least comprises a micropin, this the first micropin group comprises at least one thin slice, each thin slice at least arranges a perforation, this perforated edge is provided with a bur, perforation wherein on a thin slice is passed for the bur of the perforated edge of relative position on remaining thin slice, and described bur is disconnected from each other,
One signal processing unit, to be arranged on this substrate and with this first micropin group and this second micropin group electricity Lian Jie ﹔ and
One power subsystem, supply working power gives this percutaneous microneedle array patch.
2. percutaneous microneedle array patch as claimed in claim 1, it is characterized in that, this the first micropin group is by one first thin slice and one second thin slice is stacked forms, this first thin slice is at least arranged one first perforation, this first perforated edge is provided with one first bur, and this second thin slice at least being arranged one second perforation, this second perforated edge is provided with one second bur, and this second bur is relative with this first bur through this first perforation of relative position on this first thin slice.
3. percutaneous microneedle array patch as claimed in claim 1, it is characterized in that, this the first micropin group is by one first thin slice, one second thin slice and one the 3rd thin slice is stacked forms, this first thin slice is at least arranged one first perforation, this first perforated edge is provided with one first bur, this second thin slice is at least arranged one second perforation, this second perforated edge is provided with one second bur, and the 3rd thin slice at least arranges one the 3rd perforation, 3rd perforated edge is provided with one the 3rd bur, this second bur and the 3rd bur are triangular pyramidal through this first perforation on this first thin slice and this first bur.
4. percutaneous microneedle array patch as claimed in claim 1, it is characterized in that, this the first micropin group is by one first thin slice, one second thin slice, one the 3rd thin slice and one the 4th thin slice is stacked forms, this first thin slice is at least arranged one first perforation, this first perforated edge is provided with one first bur, this second thin slice is at least arranged one second perforation, this second perforated edge is provided with one second bur, 3rd thin slice is at least arranged one the 3rd perforation, 3rd perforated edge is provided with on one the 3rd bur and the 4th thin slice and at least arranges one the 4th perforation, 4th perforated edge is provided with one the 4th bur, this second bur, 3rd bur and the 4th bur are corner taper through this first perforation on this first thin slice and this first bur.
5. the percutaneous microneedle array patch according to any one of Claims 1-4, it is characterized in that, each bur of this first micropin group comprises a point and a substrate, and the top of the described point of this micropin that the perforation wherein on a thin slice is formed after the bur of the perforated edge of relative position on remaining thin slice passes is not at sustained height.
6. the percutaneous microneedle array patch according to any one of Claims 1-4, it is characterized in that, each bur of this first micropin group comprises a point and a substrate, and the top of the described point of this micropin that the perforation wherein on a thin slice is formed after the bur of the perforated edge of relative position on remaining thin slice passes has sustained height.
7. percutaneous microneedle array patch as claimed in claim 1, is characterized in that, the micropin of this first micropin group and this second micropin group is formed by punching press or etch process.
8. percutaneous microneedle array patch as claimed in claim 1, is characterized in that, the inner surface of described bur scribbles sensing macromolecule.
9. percutaneous microneedle array patch as claimed in claim 1, is characterized in that, the outer surface of described bur scribbles the medicine of anti-skin allergy.
10. percutaneous microneedle array patch as claimed in claim 1, it is characterized in that, more comprise a test-paper, be placed between this first micropin group and this substrate, this test-paper comprises a conductive layer and is positioned at the multiple test zones on this conductive layer, coating sensing macromolecule on described test zone, and align with this perforation in this first micropin group.
11. percutaneous microneedle array patches as described in claim 8 or 10, is characterized in that, this sensing macromolecule is antibody, fit, restructuring monomer, carbohydrate, glucoseoxidase or hydroxybutyric dehydrogenase.
12. percutaneous microneedle array patches as claimed in claim 1, it is characterized in that, the material of described bur is selected from rustless steel, nickel, nickel alloy, titanium, titanium alloy, CNT or silicon materials, and has the metal of bio-compatibility in surface deposition.
13. percutaneous microneedle array patches as claimed in claim 1, is characterized in that, the material of described bur is resin, and has the metal of bio-compatibility in surface deposition.
The manufacture method of 14. 1 kinds of percutaneous microneedle arrays patch, is characterized in that, comprise the following steps:
Substrate and the microneedle unit of claim 1 are provided;
There is in the bur surface deposition of the first micropin group of microneedle unit a metal level of bio-compatibility;
Form a self-assembled monolayer on this metal level;
Bound antibody or fit on this self-assembled monolayer; And
Apply to intercept molecule, fill up and do not connect antibody or fit self-assembled monolayer.
The manufacture method of 15. percutaneous microneedle array patches as claimed in claim 14, is characterized in that, be more contained in metal level and mix CNT.
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Cited By (4)
| 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 |
| CN109328032A (en) * | 2017-05-19 | 2019-02-12 | 深圳市得道健康管理有限公司 | Microneedle electrodes, channels and collaterals detection device and its method for customizing |
| CN110090351A (en) * | 2018-01-30 | 2019-08-06 | 京东方光科技有限公司 | Wearable beautifying skin device and wearable eye sticker |
| CN110114675A (en) * | 2016-12-28 | 2019-08-09 | (株)纳斯摩仕 | The preparation method and patch of diagnosis skin patch based on the micropin coated with aptamers |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104970804B (en) * | 2014-04-01 | 2018-05-04 | 微凸科技股份有限公司 | Continuous percutaneous micropin 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 |
| CN110114675A (en) * | 2016-12-28 | 2019-08-09 | (株)纳斯摩仕 | The preparation method and patch of diagnosis skin patch based on the micropin coated with aptamers |
| CN109328032A (en) * | 2017-05-19 | 2019-02-12 | 深圳市得道健康管理有限公司 | Microneedle electrodes, channels and collaterals detection device and its method for customizing |
| CN110090351A (en) * | 2018-01-30 | 2019-08-06 | 京东方光科技有限公司 | Wearable beautifying skin device and wearable eye sticker |
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