CN115382088B - Microneedle chip and intelligent injector integrating continuous blood glucose monitoring and insulin injection - Google Patents
Microneedle chip and intelligent injector integrating continuous blood glucose monitoring and insulin injection Download PDFInfo
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- CN115382088B CN115382088B CN202211038631.3A CN202211038631A CN115382088B CN 115382088 B CN115382088 B CN 115382088B CN 202211038631 A CN202211038631 A CN 202211038631A CN 115382088 B CN115382088 B CN 115382088B
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 173
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—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 for measuring glucose, e.g. by tissue impedance measurement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/685—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
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
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- A61M2230/00—Measuring parameters of the user
- A61M2230/20—Blood composition characteristics
- A61M2230/201—Glucose concentration
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Abstract
The invention discloses a microneedle chip and an intelligent injector integrating continuous blood glucose monitoring and insulin injection. The microneedle chip integrating continuous blood glucose monitoring and insulin injection comprises a chip substrate, a microneedle array arranged on the bottom surface of the chip substrate and a chip panel covering the top surface of the chip substrate, wherein the microneedle array comprises a plurality of test microneedles with conductivity and a plurality of infusible injection microneedles, and at least one substance capable of reacting with glucose in blood or tissue fluid and generating a current signal is crosslinked outside the test microneedles. The intelligent injector comprises an adapter, a skin application, CGM, a hose, a controller, an insulin pump and the microneedle chip integrating continuous blood glucose monitoring and insulin injection. The micro-needle chip integrating continuous blood glucose monitoring and insulin injection can be used as a functional device of an artificial pancreas islet closed-loop system to synchronously realize real-time monitoring of glucose concentration in tissue fluid or blood and real-time linkage and intelligent infusion of insulin.
Description
[ Field of technology ]
The invention relates to the technical field of blood glucose control and insulin injection, in particular to the technical field of a microneedle chip and an intelligent injector integrating continuous blood glucose monitoring and insulin injection.
[ Background Art ]
Diabetes is one of the most common chronic diseases in daily life. For type one diabetics and for some type two diabetics, it is necessary to control the glucose (abbreviated as blood glucose) concentration in the blood of the patients depending on daily timing of insulin injection, and the injection amount of each insulin injection depends on the detection of the blood glucose concentration on the day.
Currently, there are three types of blood glucose testers commonly used, namely, a dry POC small instrument-based blood glucose tester, a wet reagent-based biochemical tester, and a continuous blood glucose monitor (Continuous Glucose Monitoring, abbreviated as CGM). Wherein, the blood glucose meter based on the dry POC miniature instrument can only detect the blood glucose value of a patient at a single or a plurality of limited time points and cannot continuously monitor the blood glucose concentration; the biochemical test of blood needs to draw more venous blood, and can only be carried out in a professional medical institution, and the result cannot be obtained in time; the CGM can puncture the monitoring probe subcutaneously and can continuously provide all day blood glucose information. Insulin is typically administered by direct injection of insulin into the blood or interstitial fluid through a needle tip inserted subcutaneously into the human body. The injection mode can be manual injection at fixed time or automatic injection through a mechanical pump (i.e. an insulin pump). In recent years, the industry has invested a great deal of money to develop an automatic closed-loop drug delivery system combining CGM with insulin pump drug delivery to construct an artificial pancreas function, i.e., automatically adjusting the amount of insulin pump injected drug by CGM. Because of limitations in precision, insulin efficacy and the like of the current CGM, in order to ensure safety and effectiveness of the whole intelligent injection process, a so-called insulin administration closed-loop system on the market is usually a semi-closed-loop system, namely, the CGM does not completely guide the operation of an insulin pump, and manual intervention is also needed.
In the existing 'semi' closed loop drug delivery system, the CGM probe and the insulin pump injection needle are required to be respectively installed under the skin through different positions, and a special needle aid is required to implant the needle head, so that the physiological and psychological rejection of patients can be caused inevitably.
[ Invention ]
The invention aims to solve the technical problems of CGM and insulin injection needles in the prior art, and provides a microneedle chip and an intelligent injector integrating continuous blood glucose monitoring and insulin injection, wherein a test microneedle and an injection microneedle can be integrated on the same microneedle chip, so that the microneedle chip can be used as a functional device of an insulin injection closed-loop system to synchronously realize real-time monitoring of glucose concentration in tissue fluid or blood, and real-time linkage and intelligent infusion with an insulin pump.
In order to achieve the above object, the present invention provides a microneedle chip integrating continuous blood glucose monitoring and insulin injection, comprising a chip substrate, a microneedle array arranged on the bottom surface of the chip substrate, and a chip panel covering the top surface of the chip substrate, wherein the microneedle array comprises a plurality of conductive test microneedles and a plurality of infusible injection microneedles, and at least one outer wall of the test microneedles is crosslinked with a substance capable of reacting with glucose in blood or tissue fluid and generating a current signal.
Preferably, the chip substrate comprises an insulating substrate and a metal conductive layer covered on the top surface of the insulating substrate, the metal conductive layer is provided with a plurality of inverted cone parts penetrating out of the insulating substrate downwards so as to be respectively used as test micro needles and injection micro needles and are combined and arranged into a micro needle array, an infusion channel is arranged between the top surface and the bottom surface of the inverted cone parts respectively used as the injection micro needles in a penetrating way, a plurality of micro-pore channels corresponding to the infusion channels respectively used as the injection micro needles are arranged on the chip panel, and a plurality of plate electrode contact points respectively capable of being contacted with the test micro needles are also arranged on the chip panel.
Further, the insulating substrate is made of insulating materials at normal temperature, such as monocrystalline silicon, polycrystalline silicon, silicon nitride or silicon carbide.
Still further, the metallic conductive layer is made of a pure metal, a conductive non-metal or an alloy material.
Furthermore, the chip panel is made of organic materials such as organic glass and the like.
Furthermore, the chip substrate and the chip panel are tightly connected in a hot pressing mode.
Further, each test microneedle is respectively arranged at the outer edge of the bottom surface of the chip substrate, and each injection microneedle is respectively arranged at the middle part of the bottom surface of the chip substrate.
Further, the calculation formula of the number N of the injection microneedles is as follows:
Wherein L is total infusion flux in unit time, L is maximum flux of a single infusion channel in unit time, S is maximum flow rate of liquid of the single infusion channel, d is minimum diameter of the single infusion channel, L and L are both in ml/min, S is in ml/(cm 2 min), and d is in μm.
Further, the top surface of the metal conductive layer is provided with an insulation groove which can isolate each test microneedle from surrounding injection microneedles.
Still further, the shape of the insulation groove may be a straight line shape or a curved line shape.
Still further, the number of insulating grooves outside each of the injection microneedles may be one or more.
Still further, the bottom surface of the chip panel is provided with a plurality of insulation ribs which respectively correspond to the insulation grooves.
Preferably, the substance that can react with glucose in blood or interstitial fluid and generate an electric current signal is glucose oxidase or glucose dehydrogenase. The glucose oxidase or glucose dehydrogenase may be crosslinked with the polymer, with both the polymer and the mediator or with the polymer that has been modified with the mediator.
The intelligent injector comprises an adapter, a skin application, a CGM, a hose, a controller, an insulin pump and a microneedle chip capable of realizing integrated continuous blood glucose monitoring and insulin injection, wherein the microneedle chip for integrated continuous blood glucose monitoring and insulin injection is arranged on the CGM through the adapter, the insulin pump is connected with the CGM through the hose, the CGM is applied on the skin surface of a human body through the skin application, and the controller is respectively electrically connected or in communication with the CGM and the insulin pump. The micro-needle chip, the adapter, the skin application and the hose which can realize integrated continuous blood glucose monitoring and insulin injection jointly form consumable materials of the intelligent insulin injection device, and the consumable materials need to be replaced regularly.
Preferably, the bottom surface of the adapter is provided with a main concave cavity in which a microneedle chip for integrating continuous blood glucose monitoring and insulin injection is embedded, the outer wall of the adapter is respectively provided with a liquid injection connector and a plurality of device electrode contact points, a plurality of micro channels are arranged between the main concave cavity and the liquid injection connector, and one end of each device electrode contact point respectively extends into the main concave cavity and can be communicated with each test microneedle.
Furthermore, the microneedle chip integrating continuous blood glucose monitoring and insulin injection is embedded into the main concave cavity in a hot pressing mode.
Still further, the adapter is made of plexiglas or other organic polymer material.
Furthermore, a micro-cavity is further arranged in the cavity wall of the main cavity, and the outlet of the micro-channel is positioned in the micro-cavity.
The invention has the beneficial effects that:
1) According to the invention, the test micro needle which is externally crosslinked with the test substance capable of reacting with glucose in blood or tissue fluid and generating a current signal is used as a probe of CGM, the injection micro needle with an infusion channel is used as an insulin delivery needle of an insulin pump, and meanwhile, the test micro needle and the injection micro needle are integrated on the same micro needle chip, so that the real-time monitoring of the glucose concentration in tissue fluid or blood and the real-time linkage and intelligent infusion of insulin can be synchronously realized as a functional device of an artificial islet closed-loop system, an implantation indwelling needle is not needed, the use is convenient and almost painless, and a solution is provided for realizing a safe and reliable intelligent artificial islet system;
2) According to the invention, the test microneedles are respectively arranged at the outer edge of the bottom surface of the chip substrate, and whether the microneedle chip is installed flatly or not can be judged by utilizing the signal receiving condition of the test microneedles, so that a user is assisted to realize correction of the installation position of the microneedle chip, and the effectiveness of blood glucose monitoring and insulin infusion is further ensured;
3) Through arranging the insulation grooves and the insulation ribs which can be mutually clamped on the metal conductive layer and the chip panel respectively, each test microneedle can be isolated from surrounding injection microneedles respectively, the structure is simple, the processing is convenient, and the normal work of each test microneedle can be ensured;
4) By additionally arranging the micro-cavity in the main cavity of the adapter, the liquid medicine entering the adapter along each micro-channel is firstly mixed in the micro-cavity, and then is injected subcutaneously along each micro-channel and the infusion channel, so that the uniformity of liquid medicine injection is ensured.
The features and advantages of the present invention will be described in detail by way of example with reference to the accompanying drawings.
[ Description of the drawings ]
FIG. 1 is a schematic perspective view of a microneedle chip integrating continuous blood glucose monitoring and insulin injection;
FIG. 2 is a top view of a microneedle chip integrating continuous blood glucose monitoring and insulin injection, after removal of the chip panel;
FIG. 3 is a cross-sectional view taken along A-A of FIG. 2;
FIG. 4 is a bottom view of a chip panel of a microneedle chip integrating continuous blood glucose monitoring and insulin injection;
FIG. 5 is a B-B cross-sectional view of FIG. 4;
FIG. 6 is a flow chart of the preparation of a microneedle chip integrating continuous blood glucose monitoring and insulin injection;
FIG. 7 is a schematic diagram of the assembly of a microneedle chip and adapter integrating continuous blood glucose monitoring and insulin injection;
FIG. 8 is a bottom view of the adapter;
FIG. 9 is a C-C cross-sectional view of FIG. 8;
FIG. 10 is an exploded schematic view of an intelligent insulin injection device;
In the figure: 1-integrated continuous blood glucose monitoring and insulin injection microneedle chip, 11-microneedle array, 111-test microneedle, 112-injection microneedle, 12-chip base, 121-insulating substrate, 122-metal conductive layer, 1221-insulating groove, 13-chip panel, 131-microporous channel, 132-plate body electrode contact point, 133-insulating bead, 2-adapter, 21-main cavity, 22-microcavity, 23-microchannel, 24-body electrode contact point, 25-infusion connection, 3-skin application, 4-sensor lower shell, 5-data collector, 6-hose, 7-controller, 8-insulin pump.
[ Detailed description ] of the invention
Referring to fig. 1 to 5, the microneedle chip for integrated continuous blood glucose monitoring and insulin injection of the present invention comprises a chip substrate 12, a microneedle array 11 arranged on the bottom surface of the chip substrate 12, and a chip panel 13 covering the top surface of the chip substrate 12, wherein the microneedle array 11 comprises a plurality of conductive test microneedles 111 and a plurality of infusible injection microneedles 112, and at least one outer wall of the test microneedles 111 is crosslinked with a substance capable of reacting with glucose in blood or tissue fluid and generating a current signal. After the microneedle array 11 is inserted subcutaneously into a human body, the test microneedles 111 externally crosslinked with a substance that reacts with glucose in blood or interstitial fluid and generates a current signal may serve as a working electrode, and the remaining test microneedles 111 may serve as a counter electrode or a reference electrode.
The chip substrate 12 includes an insulating substrate 121 and a metal conductive layer 122 covering the top surface of the insulating substrate 121, the metal conductive layer 122 is provided with a plurality of inverted cone portions penetrating out of the insulating substrate 121 downwards so as to be respectively used as the test micro-needles 111 and the injection micro-needles 112 and jointly combined and arranged into the micro-needle array 11, an infusion channel is arranged between the top surface and the bottom surface of each inverted cone portion serving as the injection micro-needles 112 in a penetrating way, a plurality of micro-pore channels 131 corresponding to the infusion channels of each injection micro-needle 112 are arranged on the chip panel 13, and a plurality of plate electrode contact points 132 capable of being respectively contacted with each test micro-needle 111 are also arranged on the chip panel 13. The chip panel 13 protects the microneedle array 11 during dicing, while also increasing the mechanical strength of the chip substrate 12.
Each of the test microneedles 111 is disposed at the outer edge of the bottom surface of the chip substrate 12, and each of the injection microneedles 112 is disposed at the middle of the bottom surface of the chip substrate 12. Each of the test microneedles 111 is disposed at a bottom end corner of the chip substrate 12, respectively. For monitoring blood glucose, only two electrodes (two test microneedles 111) are required at least, and a plurality of electrodes (e.g., four test microneedles 111 disposed at the bottom end corners of the chip substrate 12) distributed at the outer edges of the bottom surface of the chip substrate 12 can simultaneously monitor the state of penetration of the microneedle array 11 into the skin. After a certain voltage is applied to the working electrode under the skin, a current loop can be generated together with the counter electrode which is pricked into the skin, and a signal generated between the two electrodes is received by the instrument. That is, if no signal is generated between the two electrodes, it means that at least the test microneedle is highly likely to not be fully inserted under the skin, and if no signal is generated between all the electrodes (the test microneedle 111), it is highly likely that the entire microneedle array 11 is not inserted into the subcutaneous tissue.
The calculation formula of the number N of the injection microneedles 112 is as follows:
Wherein L is total infusion flux in unit time, L is maximum flux of a single infusion channel in unit time, S is maximum flow rate of liquid of the single infusion channel, d is minimum diameter of the single infusion channel, L and L are both in ml/min, S is in ml/(cm 2 min), and d is in μm. Since the infusion channel of the injection microneedle 112 can be used for the ingress and egress of insulin or the like requiring infusion, the number of injection microneedles 112 is determined by the total infusion flux L per unit time and the maximum flux L per unit time of a single infusion channel. The subcutaneously infused liquid drug may spread radially outward with the injection microneedles 112 and the injection rate cannot be too fast, otherwise the drug solution may not spread outward along the subcutaneous tissue, easily accumulating around the needle tip region of the injection microneedles 112, causing higher pressure, thereby spilling out of the skin or reducing the pressure differential of the infused liquid. N is about 400, based on l being 2ml/min, s being 1 to 6X 10 3ml/(cm2. Mu.m) and d being 10. Mu.m.
The top surface of the metal conductive layer 122 is provided with an insulation groove 1221 for isolating each test microneedle 111 from surrounding injection microneedles 112.
The bottom surface of the chip panel 13 is provided with a plurality of insulation ribs 133 corresponding to the insulation grooves 1221, respectively. Each of the insulation ribs 133 may be respectively filled into each of the insulation grooves 1221 to seal the insulation grooves 1221 when the chip panel 13 and the chip substrate 12 are thermally pressed.
The substance that can react with glucose in blood or interstitial fluid and generate a current signal is glucose oxidase or glucose dehydrogenase.
Referring to fig. 6, the manufacturing method of the microneedle chip 1 capable of integrating continuous blood glucose monitoring and insulin injection includes the steps of:
a) Primary film forming: using chemical vapor deposition technology (Chemical Vapor Deposition, CVD), an inorganic insulating film with a thickness of 10-1000 μm is grown on the top surface of a substrate with a thickness of 500-2000 μm as an insulating substrate 121, the substrate being a silica glass substrate or a silicon material substrate;
b) Opening: according to the arrangement of the microneedle array 11, a plurality of concave parts which do not penetrate through (can also penetrate through) the bottom surface of the substrate are respectively etched on the insulating substrate 121, the concave parts are in an inverted cone shape, the depth of the concave parts is 80-1500 mu m, the opening diameter of the concave parts is 5-500 mu m, and the concave parts are obtained by one or more times of etching by adopting a photoresist etching technology or a maskless etching technology;
The maskless etching technology can be a laser etching technology, and can utilize high-energy-density laser to irradiate the top surface of the substrate, so that the surface material of the irradiated area is subjected to a series of complex physical and even chemical processes such as heating, melting, vaporizing, forming plasma, volatilizing, sputtering and the like, and finally the concave part is formed;
c) And (3) secondary film forming: a base film layer with the thickness of 5-100 mu m is grown on the top surface of the insulating substrate 121 by adopting a chemical vapor deposition technology to serve as a metal conductive layer 122, and part of the base film layer is sunk into each concave part, wherein the base film layer is a pure metal film or an alloy film with conductivity, preferably a pure metal film with the film thickness approaching in all directions, such as a tungsten film or a titanium film, so that the base film layer has good biocompatibility, further realizes long-time stable subcutaneous transfusion and detection, and controls the thickness of the needle base film layer according to actual requirements, and the heights of each test microneedle 111 and injection microneedle 112 of the microneedle array 11 are 50-2000 mu m;
d) Etching: respectively etching to form an insulation groove 1121 and an infusion channel, wherein the diameter of the infusion channel is 1-200 mu m, the width of the insulation groove 123 is 1-100 mu m, and the insulation groove 1121 and the infusion channel are obtained by etching one time or multiple times by adopting an photoresist etching technology or a maskless etching technology;
e) De-lining: selectively removing the substrate by chemical etching while retaining the remaining structure;
f) And (3) film coating: generating a nanoscale metal film coating outside all the test microneedles 111 and the injection microneedles 112 of the microneedle array 11 through physical sputtering or electroplating respectively, and then coating a substance which can react with glucose in blood or tissue fluid and generate a current signal outside at least one test microneedle 111 and performing crosslinking treatment, wherein the metal film coating is preferably a gold film;
g) And (3) packaging: sealing and combining the chip panel 13 etched in advance with the chip substrate 12 by adopting a hot-pressing process, and enabling each test microneedle 111 to be communicated with each plate electrode contact point 132 of the chip panel 13;
h) Cutting: and (3) separating and cutting by adopting a laser cutting machine or a wire cutting machine to obtain a plurality of microneedle chips 1 capable of realizing integrated continuous blood glucose monitoring and insulin injection.
Referring to fig. 7 to 10, the intelligent injector comprises an adapter 2, a skin patch 3, a CGM, a hose 6, a controller 7, an insulin pump 8 and a microneedle chip 1 integrating continuous blood glucose monitoring and insulin injection as described above, wherein the microneedle chip 1 integrating continuous blood glucose monitoring and insulin injection is mounted on the CGM through the adapter 2, the insulin pump 8 is connected with the CGM through the hose 6, the CGM is attached to the skin surface of a human body through the skin patch 3, and the controller 7 is electrically or communicatively connected with the CGM and the insulin pump 8, respectively. Wherein the skin application 3 is effective to prevent the microneedle chip 1 integrating continuous blood glucose monitoring and insulin injection from falling off from the skin of a human body during use, and to avoid invasion of water. The CGM comprises a sensor lower housing 4 and a data collector 5. After insulin is injected into subcutaneous tissue of a human body by using each injection microneedle 112, a real-time change of glucose in the human body is sensed by each test microneedle 111, and an electrochemical signal is converted into a glucose change signal through CGM processing to evaluate the effect of the injected insulin, thereby guiding the next injection amount and frequency of insulin by using each injection microneedle 112. In addition, the glucose change can be fed back continuously through the next insulin injection, so that insulin infusion and CGM linkage are realized.
The skin application is skin hyposensitization application.
The CGM is doctor CGMS-2009 type CGM of Prlingston.
The insulin pump is a doctor insulin pump P-02 of Prlingston, a Bluetooth module can be additionally arranged in the insulin pump, and the Bluetooth module is TTC HY-40R204P of a rising wetting technology or MS50SFA in cloud objects and the like.
The controller is a remote controller.
The bottom surface of the adapter 2 is provided with a main concave cavity 21 in which the microneedle chip 1 for integrated continuous blood glucose monitoring and insulin injection is embedded, the outer wall of the adapter 2 is respectively provided with a liquid injection joint 25 and a plurality of device electrode contact points 24, a plurality of micro channels 23 are arranged between the main concave cavity 21 and the liquid injection joint 25, and one end of each device electrode contact point 24 extends into the main concave cavity 21 and can be communicated with each test microneedle 111. Insulin can enter each micro-channel 23 along the infusion connector 25, pass through the chip panel 13 along each micro-channel 131, and finally be infused subcutaneously through the injection micro-needles 112 through each infusion channel. Each body electrode contact 24 connects each plate electrode contact 132 to the CGM to effect electrical continuity.
A micro-cavity 22 is further arranged in the cavity wall of the main cavity 21, and the outlet of the micro-channel 23 is positioned in the micro-cavity 22. The added micro-cavities 22 can pre-mix insulin flowing along each micro-channel 23 therein, thereby ensuring the injection uniformity of each injection microneedle 112.
The working process of the intelligent insulin injection device comprises the following steps:
The microneedle array 11 of the microneedle chip 1 integrating continuous blood glucose monitoring and insulin injection is smoothly pricked into the skin of a human body at a proper part of the body (usually in the abdomen), the skin patch 3 is attached, and then the insulin pump 8 is fixed in position. The test microneedles 111 crosslinked with glucose oxidase or glucose dehydrogenase can react subcutaneously with glucose in blood or interstitial fluid and generate a current signal that can direct the insulin pump 8 to inject an appropriate amount of insulin through each injection microneedle 112 after conversion to glucose concentration information. After insulin is injected, the glucose concentration in the body can be detected again by using CGM and the response efficiency of the human body to the insulin is recorded, so that the subsequent insulin injection is corrected, the insulin intake suitable for the user is finally obtained, and the function of intelligent pancreas islet is realized.
The above embodiments are illustrative of the present invention, and not limiting, and any simple modifications of the present invention fall within the scope of the present invention.
Claims (8)
1. The microneedle chip integrating continuous blood glucose monitoring and insulin injection is characterized in that: the micro-needle array (11) comprises a chip substrate (12), a micro-needle array (11) arranged on the bottom surface of the chip substrate (12) and a chip panel (13) covered on the top surface of the chip substrate (12), wherein the micro-needle array (11) comprises a plurality of test micro-needles (111) with conductivity and a plurality of infusion micro-needles (112), at least one outer wall of the test micro-needles (111) is crosslinked with substances which can react with glucose in blood or tissue fluid and generate current signals, the chip substrate (12) comprises an insulating substrate (121) and a metal conducting layer (122) covered on the top surface of the insulating substrate (121), the metal conducting layer (122) is provided with a plurality of inverted cone parts which downwards penetrate through the insulating substrate (121) so as to be respectively used as the test micro-needles (111) and the infusion micro-needles (112) and are jointly combined to be arranged into the micro-needle array (11), a plurality of infusion channels are arranged between the top surface and the bottom surface of the inverted cone parts which are respectively used as the infusion micro-needles (112), a plurality of micro-needles (111) are respectively arranged on the chip panel (13) in a penetrating way, a plurality of micro-needle channels (13) which are respectively contacted with the micro-needles (111) of the micro-needles (111) are respectively arranged on the outer edges of the chip substrate (13) respectively, each injection microneedle (112) is respectively arranged in the middle of the bottom surface of the chip substrate (12), the insulating substrate (121) is made of insulating materials such as monocrystalline silicon, polycrystalline silicon, silicon nitride or silicon carbide at normal temperature, and the metal conducting layer (122) is made of pure metal, conductive nonmetal or alloy materials.
2. The integrated continuous blood glucose monitoring and insulin injection microneedle chip according to claim 1, wherein: the number N of the injection microneedles (112) is calculated as follows:
；
Wherein L is total infusion flux in unit time, L is maximum flux of a single infusion channel in unit time, S is maximum flow rate of liquid of the single infusion channel, d is minimum diameter of the single infusion channel, L and L are both in ml/min, S is in ml/(cm 2 min), and d is in μm.
3. The integrated continuous blood glucose monitoring and insulin injection microneedle chip according to claim 1, wherein: the top surface of the metal conductive layer (122) is provided with an insulation groove (1221) which can isolate each test microneedle (111) from surrounding injection microneedles (112).
4. A microneedle chip for integrating continuous blood glucose monitoring and insulin injection according to claim 3, wherein: the bottom surface of the chip panel (13) is provided with a plurality of insulation ribs (133) which respectively correspond to the insulation grooves (1221).
5. The integrated continuous blood glucose monitoring and insulin injection microneedle chip according to claim 1, wherein: the substance that can react with glucose in blood or interstitial fluid and generate a current signal is glucose oxidase or glucose dehydrogenase.
6. Intelligent injector, its characterized in that: the integrated continuous blood glucose monitoring and insulin injection micro-needle chip (1) according to any one of claims 1 to 5, wherein the integrated continuous blood glucose monitoring and insulin injection micro-needle chip (1) is installed on the CGM through the adapter (2), the insulin pump (8) is connected with the CGM through the hose (6), the CGM is attached to the skin surface of a human body through the skin application (3), and the controller (7) is respectively electrically connected or in communication with the CGM and the insulin pump (8).
7. The intelligent syringe of claim 6, wherein: the micro-needle chip (1) embedded main cavity (21) for integrating continuous blood sugar monitoring and insulin injection is arranged on the bottom surface of the adapter (2), a liquid injection connector (25) and a plurality of device body electrode contact points (24) are respectively arranged on the outer wall of the adapter (2), a plurality of micro-channels (23) are arranged between the main cavity (21) and the liquid injection connector (25), and one end of each device body electrode contact point (24) respectively extends into the main cavity (21) and can be communicated with each test micro-needle (111).
8. The intelligent injector of claim 7, wherein: a micro-cavity (22) is further arranged in the cavity wall of the main cavity (21), and an outlet of the micro-channel (23) is positioned in the micro-cavity (22).
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| TWI667016B (en) * | 2017-11-20 | 2019-08-01 | 研能科技股份有限公司 | Blood sugar detecting and controlling system |
| TWI730504B (en) * | 2019-11-19 | 2021-06-11 | 奇異平台股份有限公司 | Percutaneous microneedle monitoring system |
| CN111408034A (en) * | 2020-03-17 | 2020-07-14 | 多感科技(上海)有限公司 | Microneedle drug delivery detection device, microneedle drug delivery system and microneedle drug delivery detection method |
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