CN118203359A - Microneedle sensor integrating drug delivery and multi-substance multi-channel detection and preparation method thereof - Google Patents
Microneedle sensor integrating drug delivery and multi-substance multi-channel detection and preparation method thereof Download PDFInfo
- Publication number
- CN118203359A CN118203359A CN202410307934.3A CN202410307934A CN118203359A CN 118203359 A CN118203359 A CN 118203359A CN 202410307934 A CN202410307934 A CN 202410307934A CN 118203359 A CN118203359 A CN 118203359A
- Authority
- CN
- China
- Prior art keywords
- array
- micro
- microelectrode
- microneedle
- layer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000001514 detection method Methods 0.000 title claims abstract description 45
- 238000012377 drug delivery Methods 0.000 title claims abstract description 35
- 239000000126 substance Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000000758 substrate Substances 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 210000003722 extracellular fluid Anatomy 0.000 claims abstract description 11
- 239000002086 nanomaterial Substances 0.000 claims abstract description 9
- 229920002120 photoresistant polymer Polymers 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 11
- 238000005516 engineering process Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000003491 array Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 8
- 239000004626 polylactic acid Substances 0.000 claims description 8
- 238000004528 spin coating Methods 0.000 claims description 7
- 239000000090 biomarker Substances 0.000 claims description 6
- 238000001259 photo etching Methods 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 238000004080 punching Methods 0.000 claims description 6
- 238000004544 sputter deposition Methods 0.000 claims description 6
- 238000000835 electrochemical detection Methods 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052581 Si3N4 Inorganic materials 0.000 claims description 4
- 229910052804 chromium Inorganic materials 0.000 claims description 4
- 239000011651 chromium Substances 0.000 claims description 4
- 238000004070 electrodeposition Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 238000001179 sorption measurement Methods 0.000 claims description 4
- 239000013076 target substance Substances 0.000 claims description 4
- 239000004568 cement Substances 0.000 claims description 3
- 238000000970 chrono-amperometry Methods 0.000 claims description 3
- 238000011161 development Methods 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000002048 multi walled nanotube Substances 0.000 claims description 3
- 238000001020 plasma etching Methods 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- HQVNEWCFYHHQES-UHFFFAOYSA-N silicon nitride Chemical compound N12[Si]34N5[Si]62N3[Si]51N64 HQVNEWCFYHHQES-UHFFFAOYSA-N 0.000 claims description 3
- 229910001220 stainless steel Inorganic materials 0.000 claims description 3
- 239000010935 stainless steel Substances 0.000 claims description 3
- 238000010146 3D printing Methods 0.000 claims description 2
- 239000004925 Acrylic resin Substances 0.000 claims description 2
- 229920000178 Acrylic resin Polymers 0.000 claims description 2
- 229920000557 Nafion® Polymers 0.000 claims description 2
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 2
- 238000005229 chemical vapour deposition Methods 0.000 claims description 2
- 238000009792 diffusion process Methods 0.000 claims description 2
- 238000009713 electroplating Methods 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 claims description 2
- 239000011810 insulating material Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 238000005459 micromachining Methods 0.000 claims description 2
- 239000002052 molecular layer Substances 0.000 claims description 2
- 238000000016 photochemical curing Methods 0.000 claims description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 2
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 2
- 238000006479 redox reaction Methods 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000010409 thin film Substances 0.000 claims description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 238000000151 deposition Methods 0.000 claims 1
- 238000005553 drilling Methods 0.000 claims 1
- 239000000155 melt Substances 0.000 claims 1
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- 239000010408 film Substances 0.000 description 7
- 238000010586 diagram Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000623 plasma-assisted chemical vapour deposition Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000004506 ultrasonic cleaning Methods 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- -1 Polydimethylsiloxane Polymers 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012625 in-situ measurement Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000010884 ion-beam technique Methods 0.000 description 1
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 238000001053 micromoulding Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 238000000059 patterning Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229960003351 prussian blue Drugs 0.000 description 1
- 239000013225 prussian blue Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0045—Devices for taking samples of body liquids
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
- G01N27/3277—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a redox reaction, e.g. detection by cyclic voltammetry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
- G01N27/3278—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction involving nanosized elements, e.g. nanogaps or nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0045—Devices for taking samples of body liquids
- A61B2010/008—Interstitial fluid
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Pathology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Electrochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medical Informatics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nanotechnology (AREA)
- Dermatology (AREA)
- Anesthesiology (AREA)
- Surgery (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
Abstract
The invention discloses a microneedle sensor integrating drug delivery and multi-substance multi-channel detection and a preparation method thereof, comprising the following steps: an insulating substrate on which a microelectrode array is formed, wherein the microelectrodes of the microelectrode array are equally divided into a plurality of groups, and each group of microelectrodes is provided with a reference electrode corresponding to the microelectrode array; the surface of the microelectrode array is modified with a biological recognition molecule layer for specifically recognizing a target detection object in interstitial fluid and a nano material for improving the detection quality of electrochemical signals. The contacts are distributed around the insulating substrate, and the microelectrode array and the reference electrode are connected to the contacts through leads. All the lead surfaces are covered with an insulating layer. The micro-needle array is adhered to the micro-electrode array by a thin adhesive, wherein the micro-needle array is used for extracting the liquid to be detected and consists of a plurality of hollow rectangular pyramids distributed at equal intervals, the vertexes of the pyramids are distributed at the center of the side of the square bottom surface, and the micro-groove structure at the back of the micro-needle array is used for storing the liquid to be detected so as to be contacted with the micro-electrode array to finish detection.
Description
Technical Field
The present invention relates to the fields of bioelectronics, biosensing, microelectromechanical systems (MEMS) micromachining and 3D printing technologies. In particular to a microneedle sensor integrating drug delivery and multi-substance multi-channel detection and a preparation method thereof.
Background
The interstitial fluid (INTERSTITIAL FLUID, ISF) is considered an ideal target biological fluid, whose composition can rapidly equilibrate with the composition of whole body blood, can rapidly reflect changes in biomarker concentration in blood, and thus can be used for real-time molecular concentration monitoring. ISF contains various metabolites that can be used as biomarkers, such as glucose concentration abnormality leading to diabetes, lactic acid excess leading to cell dysfunction, hormonal level representing endocrine status, etc., and concentration changes of these substances are important indicators for diagnosing diseases and measuring health status. In addition, since ISF is present in the skin epidermis layer without vascularization, this allows for minimally invasive and even painless detection of target analytes in ISF.
Microneedles (Microneedles, MNs) are tiny needles that are applied to the skin in a minimally invasive manner to facilitate transdermal drug delivery or to aspirate interstitial fluid from the skin, which can be subsequently analyzed or biosensing in real-time on site for disease diagnosis and drug monitoring after collection. Microneedles play a central role in personalized medicine, biomedical research, and biotechnology applications due to their minimal trauma and low skin pain permeability. However, at present, microneedles are mostly used for subcutaneous drug delivery, even if being used for subcutaneous substance detection, the microneedles are used for in-vitro detection after in-vivo extraction through a series of complicated and time-consuming operations, and the concentration of various target substances can be rarely detected at the same time. Thus further improving the technology of completing the timely detection of multiple target substances in multiple channels in subcutaneous tissue and simultaneously integrating the drug delivery function can help doctors to quickly diagnose and treat the physical health condition of patients.
Disclosure of Invention
It is an object of the present invention to provide a microneedle sensor integrating drug delivery and multi-substance multi-channel detection. The micro-needle array in the sensor is used as a minimally invasive device to be integrated with an electrochemical sensor, and the micro-needle array is used for extracting subcutaneous ISF and delivering medicines by utilizing numerical control processing and micro-molding technology; the microelectrode array manufactured by the MEMS technology is utilized to realize the multichannel electrochemical detection of the biomarker. Such an integrated device allows continuous, accurate and rapid in situ measurement directly within the tissue, allows analysis and monitoring of biomarkers, metabolites, drug release and other parameters involved in biological processes and present in tissue fluids, and allows drug delivery to achieve drug intervention under specific requirements.
In order to achieve the purpose, the invention adopts the following technical scheme:
A microneedle sensor integrating drug delivery and multi-substance multi-channel detection comprises an insulating substrate, a microelectrode array, a reference electrode, a lead, a contact, an insulating layer, a microneedle array, a nanomaterial, a biological recognition molecule layer, a microneedle array back micro-groove and a drug delivery channel.
An insulating substrate on which a microelectrode array is formed, wherein the microelectrode array comprises microelectrodes which are equally divided into a plurality of groups, and each group of microelectrodes is provided with a reference electrode corresponding to the microelectrode array; the surface of the microelectrode array is modified with a biological recognition molecular layer for recognizing a target detection object in interstitial fluid and a nano material for further improving the detection quality of electrochemical signals; the contacts are distributed around the insulating substrate, and the microelectrode array and the reference electrode are connected to the contacts through leads; wherein, all the surfaces of the leads are covered with an insulating layer; the micro-needle array is adhered to the micro-electrode array, wherein the micro-needle array consists of a plurality of hollow rectangular pyramids which are equidistantly distributed (the number is determined according to the amount and the speed of interstitial fluid sucked by a target), a micro-groove structure is arranged at the back and used for storing a certain amount of interstitial fluid so as to be in contact with the micro-electrode array for completing detection, and a drug delivery channel is arranged at the back and used for drug delivery.
The microelectrode array is further formed by 10-20 circular microelectrodes and is equally divided into 2-4 groups, wherein the diameter of the electrodes is 150-500 mu m, the distance between the electrodes in each group is 500-2500 mu m, and the interval between the groups is 2250-7250 mu m; microelectrode arrays are used to detect electrochemical signals.
Further, the number of the reference electrodes is matched with the number of the microelectrode groups, and the reference electrodes are round, and the diameter of the reference electrodes is 1.5-3 times of that of the microelectrodes, so that the reference electrodes are used for providing reference potential and keeping potential stability.
Further, the insulating substrate is made of square quartz glass, the side length is 3-5cm, and the thickness is 1-5mm.
Further, the conductive film material selected for the microelectrode array is metal with excellent conductivity such as gold, platinum, chromium and the like; the insulating layer is made of inorganic insulating material with good biocompatibility, and is silicon dioxide or silicon nitride.
The invention provides a preparation method of a microneedle sensor for integrated drug delivery and multi-substance multi-channel detection, which comprises the steps of preparing a microneedle electrode array and preparing a microelectrode array, wherein the preparation of the microelectrode array part comprises the following steps:
a) Spin-coating a layer of photoresist on the cleaned insulating substrate, wherein the thickness of the photoresist is more than three times that of the conductive film to be sputtered, and forming patterns of a microelectrode array, a reference electrode, a lead and a contact after photoetching development;
b) Sputtering a conductive film with a layer thickness of 300-500 nm on the surface of the photoresist pattern, and sputtering chromium or titanium with a thickness of 10-50 nm in advance to serve as a seed layer if the metal used in the conductive layer is gold so as to increase the adhesiveness between the conductive film layer and the substrate;
c) Removing the redundant film layer by adopting a stripping process, and leaving a needed microelectrode array, a reference electrode, a lead and a contact;
D) Coating an insulating layer on the surface of the insulating substrate on which the conductive thin film layer is prepared by plasma enhanced chemical vapor deposition of silicon oxide and silicon nitride;
e) Exposing the microelectrode array, the reference electrode, the lead and the contact by photoetching and ion beam etching methods, and reserving all insulating layers covered on the surfaces of the leads;
F) The method comprises the steps of modifying nano materials or biological recognition molecule layers on the surfaces of microelectrodes with different detection functions by electrochemical deposition or physical dripping and adsorption, and designing a Polydimethylsiloxane (PDMS) film with a specific shape for modifying the biological recognition molecule layers in the microelectrode arrays in a partitioning way because one biological recognition molecule layer is required to be modified in each of the two groups of microelectrode arrays.
Further, the microneedle array is in a quadrangular pyramid shape, but not in a regular rectangular pyramid shape, and the vertexes of the pyramids are distributed at the midpoints of square sides of the bottom surface, so that the needles can be conveniently inserted into the skin, and the hollow pore diameter can be increased, and the preparation method specifically comprises the following steps:
A) Firstly, preparing a female die of a microneedle array by micro-nano numerical control processing, wherein the female die is made of stainless steel and consists of a plurality of rectangular pyramids, the bottom of each pyramid is square with the side length of 300-600 mu m, the height of each pyramid is 600-800 mu m, the interval is 600-1000 mu m, and the thickness of the bottom layer is 1-1.5cm;
B) Selecting a microneedle at the edge in a mould, fixing a needle head of a syringe on the mould, pouring solid PLA (polylactic acid), photo-curing resin, PMMA (acrylic resin) and other polymer particles with high biocompatibility and certain mechanical strength into the mould, heating the polymer in vacuum for 20-40 minutes according to the melting temperature of a required substance until the polymer is melted, taking out the polymer, pressing the polymer by a tabletting with matched size to fill the mould, standing at room temperature until the polymer solidifies, and demoulding, wherein the needle head of the syringe is fixed on the mould to form a drug delivery channel, and pressing the mould by the tabletting with matched size to form a microneedle array back micro-groove structure;
C) Punching on the prepared solid micro-needle array by using a laser, controlling the hollow aperture to be 60-110 mu m, cleaning the solid micro-needle array by using alcohol in an ultrasonic cleaning machine for 15-30 minutes after laser punching, and taking out the solid micro-needle array.
Furthermore, glass cement is coated on the bottom of the micro-needle array, and the micro-needle array and the micro-electrode array are aligned and bonded to form the micro-needle sensor for integrated drug delivery and multi-substance multi-channel detection, the micro-needle array is used for extracting the liquid to be detected and delivering the drugs, and the micro-electrode array is used for the subsequent multi-channel electrochemical detection of various biomarkers in the liquid to be detected.
Further, the multichannel detection function is that the multichannel detection function is connected with a microelectrode array through an electrochemical workstation, and a three-electrode system is used for giving a certain potential (chronoamperometry) to a working electrode to detect the current when the target substance undergoes the oxidation-reduction reaction, so that the concentration of the target detection substance is judged; the multi-substance detection function is based on modification of different biological recognition molecules in different groups of microelectrode arrays, so that specific recognition of different substances is realized.
The invention has the following beneficial technical effects:
The micro-needle array for extracting the liquid to be detected and the micro-electrode array for electrochemically detecting the target object are integrated together, so that the integrated structure is small, and the problems of liquid extraction to be detected and multi-substance multi-channel detection integration are solved; innovating in the structural design of the microneedle array, changing the common regular quadrangular microneedle into an inclined quadrangular pyramid with the vertex distributed on the center of the square edge of the bottom surface, so that the puncture strength of the microneedle can be further improved and the hollow aperture range can be enlarged; channels for drug delivery are designed on the microneedle array, allowing the sensor to integrate the test fluid extraction function as well as the drug delivery function.
Drawings
FIG. 1 is a schematic diagram of the structure of a microneedle sensor for integrated drug delivery and multi-substance multi-channel detection of the present invention;
FIG. 2 is a schematic diagram of the structure of a microelectrode array portion of the present invention;
FIG. 3 is a schematic view of a portion of the structure of a microneedle array according to the present invention;
FIG. 4 illustrates a process for preparing a microelectrode array portion of the present invention;
FIG. 5 is a mold and platen for preparing a microneedle array; wherein 5a is a mold for preparing a microneedle array; 5b is a platen for preparing a microneedle array.
Reference numerals illustrate:
An insulating substrate 1, a microelectrode array 2, a reference electrode 3, a lead 4, a contact 5, an insulating layer 6, a microneedle array 7, a nanomaterial 8, a biological recognition molecule layer 9, a microneedle array back micro-groove 10 and a drug delivery channel 11.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings and specific embodiments. The following examples do not constitute a limitation of the present invention.
Fig. 1 is a schematic diagram showing the structure of a microneedle sensor for integrated drug delivery and multi-substance multi-channel detection according to the present invention. The microneedle sensor is composed of a microelectrode structure A and a microneedle array structure B. The contact 5 of the microelectrode structure is connected with an electrochemical workstation, and the microneedle array sucks interstitial fluid to the surface of the microelectrode array so as to complete electrochemical detection.
Fig. 2 is a schematic diagram of a microelectrode structure a provided by the present invention. The microelectrode structure A includes: an insulating substrate 1, a microelectrode array 2, a reference electrode 3, a lead 4, a contact 5, an insulating layer 6, a nano material 8 and a biological recognition molecule layer 9; fig. 3 is a schematic diagram showing a microneedle array structure B according to the present invention, which includes a microneedle array 7, a microneedle array backside micro-groove 10, and a drug delivery channel 11.
The insulating substrate 1 is made of square quartz glass, the side length is 5cm, and the thickness is 1-5mm. The microelectrode array 2 is distributed on the insulating substrate 1, wherein microelectrodes included in the microelectrode array 2 are equally divided into two groups, seven microelectrodes are arranged in one group, the radius of each microelectrode is 250 mu m, the interval is 2000 mu m, each group of microelectrodes is provided with a reference electrode 3 corresponding to the microelectrode, the radius of the reference electrode 3 is 500 mu m, and the group-to-group interval is 6250 mu m; the surface of the microelectrode array 2 is modified with a biological recognition molecule layer 9 for recognizing a target detection object in interstitial fluid and a nano material 8 for further improving the detection quality of electrochemical signals; the microelectrode array 2 and the reference electrode 3 are connected with the contacts 5 distributed around the insulating substrate 1 through the leads 4, so that electrochemical signals detected by the microelectrode array 2 are led out from the contacts 5, the contacts 5 are square, the side length is 1000 mu m, and the distance between the contacts is 12700 mu m; all the leads 4 are covered on their surfaces with an insulating layer 6.
Fig. 3 shows a specific preparation flow of the microelectrode structure a:
a) Spin coating a layer of SPR220 photoresist on the surface of the quartz glass after pickling, and then carrying out first photoetching;
b) Imaging the microelectrode array, the reference electrode, the lead and the contact on the surface of quartz glass after development;
c) Sputtering a layer of chromium with the thickness of 30nm as a seed layer and 300nm of platinum as a conductive layer on the surface of the photoresist pattern by adopting a sputtering process;
d) Stripping the photoresist-containing part by using an acetone solution and an ethanol solution to leave a conductive layer, and adopting plasma chemical vapor deposition (PECVD, 300 ℃) to deposit SiO 2(300nm)/Si3N4 (500 nm) as an insulating layer;
e) Spin-coating a layer of SPR220 photoresist and then performing second photoetching;
f) Patterning the lead part by developing to expose the microelectrode array, the reference electrode and the insulating layer above the contact;
g) Selectively removing the microelectrode array, the reference electrode and the insulating layer above the contact by CHF 3 Reactive Ion Etching (RIE);
h) Washing the residual photoresist by using an acetone solution and an ethanol solution;
i) Electroplating a layer of Multi-walled carbon nanotubes (Multi-Walled Carbon Nanotubes, MWCNTS) on the microelectrode array detection electrode by adopting an electrochemical chronoamperometry method, so as to improve the electrical characteristics of the detection electrode; the biological recognition molecule layer is modified by physical dripping, electrodeposition and adsorption, and the specific type of biological recognition molecule is determined by the target detection object, and in this example, glucose oxidase for detecting glucose and an aptamer for detecting estradiol are specifically selected as the biological recognition molecules. Prussian blue and analogues thereof (PBA) were electrodeposited on the electrode surface for the attachment of the biorecognition molecules prior to immobilization of the biorecognition molecules. After the biological recognition molecules are immobilized, a Nafion layer is spin-coated to be used as a diffusion limiting layer, so that the linearity of the biosensor is expanded to high concentration, and negatively charged interference and biological pollution (such as protein adsorption) are avoided. Wherein, since one biological recognition molecule needs to be modified in each of the two groups of microelectrode arrays, a PDMS film with a specific shape is designed for modifying different biological recognition molecules in a partitioning way in the microelectrode arrays.
FIG. 4 is a schematic diagram of a microelectrode array structure B, which consists of 10 x 10 rectangular pyramids and micro grooves 10 on the back of the microneedle array, wherein the bottom of each pyramid is square with a side length of 500 μm, the height of each pyramid is 800 μm, the distance between the microneedles is 1000 μm, and the thickness of the bottom layer is 1cm; the micropyles are regular rectangular pyramids, and cone vertexes are distributed at the midpoints of the square sides of the bottom surface; the back of the microneedle array is provided with a microgroove 10 which is connected with a hollow structure of the microneedles and has the size of 250 mu m and the length and width of 1.6cm; the microneedle array contains on its back a drug delivery channel 11 matching the syringe needle diameter, in this example a 34G gauge metal needle. The specific preparation process of the microneedle comprises the following steps:
a) Firstly, preparing a master model of a microneedle array structure by utilizing a micro-nano numerical control processing technology, wherein the master model is shown in fig. 5a, the material is stainless steel, the master model consists of 10 x 10 rectangular pyramids, the bottom of each pyramid is square with the side length of 500 mu m, the height of each pyramid is 800 mu m, the distance between the microneedles is 1000 mu m, and the thickness of the bottom layer is 1cm;
b) Selecting a microneedle at the edge in a mould, fixing a needle of an injector aside, pouring solid PLA (polylactic acid) particles into the mould, heating at a high temperature of 200 ℃ in vacuum for 20 minutes until PLA is melted and taken out, pressing by a matched-size tabletting as shown in figure 5b to fill the mould with PLA, standing at room temperature until solidification, and demoulding, wherein the needle of the injector is fixed on the mould to form a drug delivery channel, and pressing the mould by the matched-size tabletting to form a microneedle array back micro-groove structure;
c) Punching on the prepared solid microneedle array by using a laser, controlling the hollow aperture to be 90-110 mu m, and taking out after alcohol cleaning in an ultrasonic cleaning machine for 20min after laser punching.
Finally, aligning and bonding the micro-needle array structure B and the micro-electrode array structure A by using glass cement to form the integrated drug delivery and multi-substance multi-channel detection micro-needle sensor. The micro-needle array is used for extracting subcutaneous interstitial fluid by utilizing capillary force, and the micro-electrode array is used for the subsequent multi-channel electrochemical detection of glucose and estradiol in the liquid to be detected.
Claims (10)
1. A microneedle sensor integrating drug delivery and multi-substance multi-channel detection, characterized by: the microneedle sensor comprises an insulating substrate, a microelectrode array, a reference electrode, a lead, a contact, an insulating layer, a microneedle array, a nanomaterial, a biological recognition molecule layer, a microgroove on the back of the microneedle array and a drug delivery channel;
An insulating substrate on which a microelectrode array is formed, wherein the microelectrode array comprises microelectrodes which are equally divided into a plurality of groups, and each group of microelectrodes is provided with a reference electrode corresponding to the microelectrode array; the surface of the microelectrode array is modified with a biological recognition molecular layer for specifically recognizing a target detection object in interstitial fluid and a nano material for further improving the detection quality of electrochemical signals;
The contacts are distributed around the insulating substrate, and the microelectrode array and the reference electrode are connected to the contacts through leads; wherein, all the surfaces of the leads are covered with an insulating layer;
The micro-needle array is adhered to the micro-electrode array, wherein the micro-needle array consists of a plurality of hollow rectangular pyramids which are distributed at equal intervals and is used for extracting the liquid to be detected, the vertexes of the pyramids are distributed at the center of the side of the square bottom surface, the micro-groove structure at the back of the micro-needle array is used for storing a certain amount of liquid to be detected so as to be in contact with the micro-electrode array for detection, and the back of the micro-needle array is additionally provided with a medicine delivery channel connected with the hollow micro-needles and used for injecting medicine into the liquid to be detected.
2. The integrated drug delivery and multi-substance multi-channel detection microneedle sensor according to claim 1, wherein the microelectrode array is composed of 10-20 circular microelectrodes equally divided into 2-4 groups, wherein the electrode diameter is 150-500 μm, the electrode distance within each group is 500-2500 μm, group-to-group spacing 2250-7250 μm.
3. The integrated drug delivery and multi-substance multi-channel detection microneedle sensor according to claim 1, wherein the number of reference electrodes is matched to the number of microelectrode sets, in a circle with a diameter 1.5-3 times the diameter of the microelectrode, one for each set of microelectrode arrays.
4. The integrated drug delivery and multi-substance multi-channel detection microneedle sensor according to claim 1, wherein the insulating substrate is made of square quartz glass, has a side length of 3-5cm and a thickness of 1-5mm.
5. The integrated drug delivery and multi-substance multi-channel detection microneedle sensor according to claim 1, wherein the microelectrode array is made of conductive thin film material, which is metal with excellent conductivity; the insulating layer is made of inorganic insulating material with good biocompatibility, and is silicon dioxide or silicon nitride.
6. The integrated drug delivery and multi-substance multi-channel detection microneedle sensor of claim 1, wherein said microelectrode array is fabricated using microelectromechanical system micromachining techniques.
7. The integrated drug delivery and multi-substance multi-channel detection microneedle sensor of claim 1, wherein in performing multi-substance detection, different biological recognition molecules are modified by electrodeposition and physical spin coating methods in different groups of microelectrode arrays, thereby realizing specific recognition of different substances in a liquid to be detected; the electrochemical workstation is connected with the microelectrode array, and a three-electrode system is used for giving a certain potential to the working electrode to measure the current when the target substance undergoes oxidation-reduction reaction, so that the concentration of the liquid to be measured is judged.
8. A method of manufacturing a microneedle sensor for integrated drug delivery and multi-substance multi-channel detection according to claims 1-7, wherein the method of manufacturing comprises manufacturing a microneedle array; preparing a microelectrode array;
the preparation of the microneedle array is realized by utilizing a micro-nano numerical control processing technology, a micro-forming reverse mold technology, a 3D printing technology and a laser drilling technology, and specifically comprises the following steps:
step 1) preparing a female die of a microneedle array by utilizing a micro-nano numerical control processing technology, wherein the female die is made of stainless steel and consists of a plurality of rectangular pyramids, the bottoms of the pyramids are square with the side length of 300-600 mu m, the heights of the pyramids are 600-800 mu m, the distance between the microneedles is 600-1000 mu m, and the thickness of the bottom layer is 1-1.5cm; the micropyles are regular rectangular pyramids, and cone vertexes are distributed at the midpoints of the square sides of the bottom surface;
Step 2) selecting a microneedle at the edge in a mould, after fixing a needle head of a syringe, pouring polymer particles comprising one or more of solid polylactic acid PLA, photo-curing resin or acrylic resin PMMA into the mould, heating in vacuum for 20-40 minutes according to the melting temperature of the polymer particles until the polymer melts, taking out, pressing by a tablet with matched size to fill the mould with the polymer, standing at room temperature until the polymer solidifies, and demoulding;
and 3) punching holes on the prepared solid micro-needle array by using a laser, controlling the hollow aperture to be 60-150 mu m, and taking out the solid micro-needle array after alcohol washing in an ultrasonic washing machine for 15-30 minutes after laser punching.
9. The preparation method of claim 8, wherein the specific preparation method of the microelectrode array is as follows:
Step a), spin coating a layer of SPR220 photoresist on the surface of the quartz glass after acid washing, and then carrying out first photoetching;
step b), imaging the microelectrode array, the reference electrode, the lead and the contact on the surface of quartz glass after development;
Step c), sputtering a layer of chromium with the thickness of 30nm serving as a seed layer and 300nm of platinum serving as a conductive layer on the surface of the photoresist pattern by adopting a sputtering process;
Step d), stripping the photoresist-containing part by using an acetone solution and an ethanol solution to leave a conductive layer, and depositing SiO 2 nm or Si 3N4 nm as an insulating layer by adopting plasma chemical vapor deposition;
step e), spin coating a layer of SPR220 photoresist and then carrying out second photoetching;
step f) developing to pattern the lead part and expose the microelectrode array, the reference electrode and the insulating layer above the contact;
Step g) selectively removing the microelectrode array, the reference electrode and the insulating layer above the contact through CHF 3 reactive ion etching;
step h) washing the residual photoresist cleanly by using an acetone solution and an ethanol solution;
Step i) electroplating a layer of multiwall carbon nanotubes on the electrode of the microelectrode array by adopting an electrochemical chronoamperometry; modifying a layer of biological recognition molecule layer on the electrode by adopting physical dripping, electrodeposition and adsorption methods, and spin-coating a modified Nafion layer to serve as a diffusion limiting layer after the biological recognition molecules are fixed.
10. The method of claim 9, wherein the glass cement is coated on the bottom of the microneedle array and aligned with the microelectrode array for adhesion to form a microneedle sensor for integrated drug delivery and multi-substance multi-channel detection, the microneedle array is used for extracting the liquid to be detected and drug delivery, and the microelectrode array is used for subsequent multi-channel electrochemical detection of multiple biomarkers in the liquid to be detected.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410307934.3A CN118203359A (en) | 2024-03-18 | 2024-03-18 | Microneedle sensor integrating drug delivery and multi-substance multi-channel detection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410307934.3A CN118203359A (en) | 2024-03-18 | 2024-03-18 | Microneedle sensor integrating drug delivery and multi-substance multi-channel detection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118203359A true CN118203359A (en) | 2024-06-18 |
Family
ID=91445616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410307934.3A Pending CN118203359A (en) | 2024-03-18 | 2024-03-18 | Microneedle sensor integrating drug delivery and multi-substance multi-channel detection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118203359A (en) |
-
2024
- 2024-03-18 CN CN202410307934.3A patent/CN118203359A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20220151516A1 (en) | Microneedle arrays for biosensing and drug delivery | |
| TWI730504B (en) | Percutaneous microneedle monitoring system | |
| US12097500B2 (en) | Apparatus and methods for monitoring of biomarkers in blood | |
| TWI519781B (en) | Transdermal microneedle array patch | |
| Vasylieva et al. | Silicon/SU8 multi-electrode micro-needle for in vivo neurochemical monitoring | |
| Saifullah et al. | Sampling dermal interstitial fluid using microneedles: a review of recent developments in sampling methods and microneedle‐based biosensors | |
| CN105925480B (en) | Micro-fluidic chip and preparation method for blood-brain barrier drug permeability high flux screening | |
| Takeuchi et al. | Functionalized microneedles for continuous glucose monitoring | |
| US20230111253A1 (en) | Microneedle array sensor patch for continuous multi-analyte detection | |
| Puttaswamy et al. | Nanophotonic-carbohydrate lab-on-a-microneedle for rapid detection of human cystatin C in finger-prick blood | |
| JP2003038467A (en) | Device and method for sampling biological fluid and measuring analyte | |
| Lu et al. | Microneedle-based device for biological analysis | |
| Hu et al. | Microneedle Sensors for Point‐of‐Care Diagnostics | |
| CN1287872C (en) | Air bag controlled micro medicine conveying executor | |
| Zhang et al. | Recent advances in the preparation of microneedle patches for interstitial fluid extraction and analysis | |
| Leanpolchareanchai et al. | Wearable microneedle-based colorimetric and fluorescence sensing for transdermal diagnostics | |
| CN118203359A (en) | Microneedle sensor integrating drug delivery and multi-substance multi-channel detection and preparation method thereof | |
| Zhan et al. | A 3D-printed microneedle extraction system integrated with patterned electrodes for minimally invasive transdermal detection | |
| Schurink | Microfabrication and microfluidics for 3D brain-on-chip | |
| CN113977829A (en) | Preparation method of hollow microneedle array biosensor | |
| JP6213987B2 (en) | Micro glucose sensor | |
| Garg et al. | Recent advancements in the expedition of microneedles: from lab worktops to diagnostic care centers | |
| Wang et al. | Advances in microneedles for transdermal diagnostics and sensing applications | |
| Wang et al. | A novel fabrication method of flexible micro electrode array for neural recording | |
| CN115326891B (en) | Flexible blood glucose concentration sensor and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |