Summary of the invention
Based on this, it is necessary in view of the above-mentioned problems, providing a kind of tissue fluid detection device；The tissue fluid detection device can be realNow to the continuous detection of tissue fluid, precision is high, good reliability, and to the wound very little of human body, can fast implement clinic and answerWith.
A kind of tissue fluid detection device, comprising:
Substrate, the side of the substrate are provided with for being pierced into the micropin for extracting tissue fluid in vivo, and the micropin is provided withFor the duct of tissue fluid circulation, the duct extends through the substrate from the micropin tip to the substrate；
Electrochemical sensor, the electrochemical sensor are set to the side that the substrate deviates from the micropin, and canWith the interstitial fluid contacts for flowing through the micropin, to be detected to the tissue fluid.
The length of the micropin is 100 μm~120 μm in one of the embodiments, and the diameter in the duct is 10 μm~30 μm.
The quantity of the micropin is multiple in one of the embodiments, and multiple micropins form microneedle array.
The area of the microneedle array is 1mm in one of the embodiments,2~9mm2。
The micropin and the electrochemical sensor are to positive setting in one of the embodiments,.
The substrate is provided with the first groove in one of the embodiments, and the electrochemical sensor is set to describedIn first groove.
The micropin and first groove are to positive setting in one of the embodiments, so that the micropin extractedTissue fluid is delivered in first groove by the duct.
Contact angle≤10 ° of the microneedle surface in one of the embodiments,；And/or
Contact angle≤10 ° of first groove surfaces.
The substrate is provided with the fluid channel of indent away from the side of the micropin in one of the embodiments, describedFluid channel includes the second groove and third groove, and second groove is connected to the third groove by link slot, and described theTwo grooves and the micropin are to positive setting, so that by the duct to be delivered to described second recessed for the tissue fluid that extracts of the micropinIn slot, the electrochemical sensor is set in third groove.
Contact angle≤10 ° on the fluid channel surface in one of the embodiments,.
The electrochemical sensor includes working electrode, reference electrode and auxiliary electrode, institute in one of the embodiments,Working electrode, the reference electrode and the auxiliary electrode is stated to be spaced apart from each other.
The tissue fluid detection device further includes cover board in one of the embodiments, the cover board and the substrate shapeAt a cavity, the electrochemical sensor is set in the cavity.
The cavity has opening in one of the embodiments, so that the cavity is connected to outside.
The material of the substrate is high molecular material in one of the embodiments,；And/or
The material of the micropin is high molecular material；And/or
The material of the cover board is high molecular material.
The connection type between the substrate and the cover board is covalent bonding in one of the embodiments,.
Tissue fluid structure of the detecting device of the invention is simple, small in size, easy to carry.When in use, the present invention is organizedLiquid detection device is pasted on the skin, and micropin is pierced into subcutaneously, and under capillarity, tissue fluid enters the duct of micropin, alongDuct conveys and contacts with electrochemical sensor, is detected to tissue fluid by electrochemical sensor to obtain such as blood glucose, swashThe physiologic informations such as element, lactic acid, drug concentration.Especially, electrochemical sensor of the invention is the sensor of three-electrode system, especiallyIt is suitable for the concentration of glucose in detection tissue fluid, further according to concentration of glucose in tissue fluid and the concentration of glucose in bloodRelationship converts to obtain the concentration of glucose in blood.So the present invention make tissue fluid extraction and tissue fluid contained in ingredient connectContinuous detection integration, method is simply, it can be achieved that the real-time detection of Human Physiology information.
Almost without feeling of pain when being pierced into skin due to the micropin that the present invention uses, so this minimally invasive physiologic information inspectionSurvey method can overcome the defect of invasive detection method, realize that physiologic information continuously detects.Moreover, with noninvasive detection methodIt compares, by micropin extracting interstitial fluid, then tissue fluid is detected, can be avoided physical efficiency bioelectricity for measuring signalIt influences, there is higher sensitivity, accuracy and reliability, there is important clinical application value and prospect.
Embodiment 1:
As shown in Figure 1, the tissue fluid detection device of the present embodiment, for detecting human blood glucose concentration, hormone concentration, lactic acidThe physiologic informations such as concentration, drug concentration, so as to monitor the dosage of human body and to the metabolic degree of the drug, withRealize the accurate treatment to disease.
The tissue fluid detection device includes substrate 10, and the side of the substrate 10 is provided with for being pierced into internal extraction groupThe micropin 20 of liquid is knitted, the micropin 20 is provided with the duct 201 for tissue fluid circulation, and the duct 201 is sharp from the micropin 20It holds to the substrate 10 and extends through the substrate 10；
Electrochemical sensor 30, the electrochemical sensor 30 are set to one that the substrate 10 deviates from the micropin 20Side, and can with the interstitial fluid contacts that flow through the micropin 20, to be detected to the tissue fluid.
The present invention is by 20 extracting interstitial fluid of micropin, then in the side away from the micropin 20 of substrate 10 to tissue fluidThe physiologic informations such as concentration of glucose, lactic acid concn, hormone concentration, drug concentration detected, can be avoided physical efficiency bioelectricityInfluence for measuring signal has higher sensitivity, accuracy and reliability.
Specifically, the length of the micropin 20 is 100 μm~120 μm, the diameter in the duct 201 is 10 μm~30 μm.So the wound generated to human body is very small, after the micron-sized micropin 20 is pierced into skin almost without feeling of pain.
In view of the tissue fluid that single micron-sized micropin 20 extracts is limited, it is preferred that the quantity of the micropin 20 is moreA, multiple micropins 20 form microneedle array as shown in Figure 2, area 1mm2~9mm2.So that tissue fluid detection device existsThe volume of the tissue fluid extracted simultaneously when use increases, and meets the requirement of detection.
It is appreciated that the quantity of micropin is unlimited in the microneedle array, and according to testing requirements, the body of the tissue fluid extractedProduct can satisfy detection demand.
It is appreciated that the electrochemical sensor 30 may be disposed at any position in the substrate 10.When electrochemistry passesWhen sensor 30 is located on the extended line in duct 201, the electrochemical sensor 30 is with the micropin 20 to positive setting.Work as electrochemistryWhen sensor 30 and duct 201 form certain displacement, the electrochemical sensor 30 is with the micropin 20 in offset setting.
Preferably, the micropin 20 is with the electrochemical sensor 30 to positive setting.To the tissue fluid that micropin 20 extractsWhen being delivered to side of the substrate 10 away from micropin 20 through duct 201, it can directly be contacted with electrochemical sensor 30, detect tissueThe physiologic informations such as concentration of glucose, lactic acid concn, hormone concentration, drug concentration in liquid, the time is short, high-efficient, accuracy is good.
Specifically, the substrate 10 is provided with the first groove 101, it is recessed that the electrochemical sensor 30 is set to described firstIn slot 101.To which the tissue fluid that the micropin 20 extracts is conveyed by the duct 201 and comes together in first groove 101In, electrochemical sensor 30 can be made to obtain with tissue fluid and preferably contacted.
Again it is preferred to which the micropin 20 is arranged with first groove 101 to positive, so that the tissue that the micropin 20 extractsLiquid is fed directly in first groove 101 by the duct 201, more efficient.
It is appreciated that when the quantity of micropin 20 is multiple and composition microneedle array, the area of first groove 101 >=The area of the microneedle array, and make the microneedle array and first groove 101 to positive setting, so that the duct of micropin 20201 are connected to the first groove 101, so that the tissue fluid for extracting micropin 20 directly comes together in the first groove 101.
Preferably, O can be used2, NO or NO2Corona treatment described in 20 surface of micropin, make its surface and liquidContact angle≤10 °.Preferably, which is water, to make 20 surface of micropin in Superhydrophilic, and then improves the extraction of tissue fluidAnd transfer efficiency.
In view of O2Plasma processing efficiency highest, further, using O2Corona treatment described in 20 table of micropinFace makes 10 ° of contact angle < of its surface and liquid.
Equally, O can be used2, NO or NO2Corona treatment described in 101 surface of the first groove, make described first recessedContact angle≤10 ° on slot 101 surface and liquid, it is preferred to use O2Corona treatment described in 101 surface of the first groove, make institute10 ° of contact angle < for stating 101 surface of the first groove and liquid improve to make 101 surface of the first groove in SuperhydrophilicTransfer efficiency of the tissue fluid in the first groove 101.
The electrochemical sensor 30 is the sensor of three-electrode system, by reacting with ingredient tested in tissue fluidAnd generate the electric signal directly proportional to the constituent concentration.
In conjunction with Fig. 3, the electrochemical sensor 30 includes working electrode 301, reference electrode 302 and auxiliary electrode 303, instituteIt states working electrode 301, the reference electrode 302 and the auxiliary electrode 303 to be spaced apart from each other, and forms three-electrode system.
Wherein, the working electrode 301 includes one of non-enzyme electrode or enzyme electrode.
The enzyme electrode is in the carbon material or metal material surface immobilized enzyme.By introducing carbon material or metalMaterial can increase the load capacity of enzyme, improve electron mobility in electrochemical reaction, enhance tissue fluid detection device sensitivity andDetection accuracy.And the different types of enzyme fixed according to carbon material or metal material surface, it may be implemented to tissue fluid notWith the detection of information.Such as: when detection blood glucose, the enzyme that carbon material or metal material surface are fixed is glucose oxidase；DetectionWhen lactic acid, the enzyme that carbon material or metal material surface are fixed is lactic dehydrogenase.Equally, detect hormone when, carbon material orThe fixed enzyme of metal material surface is to the sensitive enzyme of the hormone response；When detecting antibiotic, carbon material or metal material tableThe fixed enzyme in face is the corresponding enzyme of antibiotic.
The material of the non-enzyme electrode includes at least one of carbon material, metal material, metal oxide materials.It is describedCarbon material includes graphene, carbon nanotube etc., and the metal material includes gold, platinum, copper, tungsten etc., and the metal oxide includesCopper oxide, cobalt sesquioxide, nickel oxide etc..It can be formed in by the method for 3D printing in the substrate 10.
Present invention is particularly suitable for the concentration of glucose in detection tissue fluid, further according to concentration of glucose in tissue fluid and bloodThe relationship of concentration of glucose converts to obtain the concentration of glucose in blood in liquid.
Preferably, using the concentration of glucose in non-enzymatic electrode detection tissue fluid, the working electrode 301 is non-enzymatic electricityPole, including graphene composite layer, the graphene composite layer include 3D graphene and are carried on receiving in the 3D grapheneRice material, contains metallic element in the nano material.
Wherein, 3D graphene is the graphene of three-dimensional structure, with the excellent chemical property of two-dimensional graphene and more greatlySpecific surface area, more nano materials can be loaded, and the network structure charge transfer resistance of 3D graphene is lower, electronics passPass speed faster, thus, sensitivity and detectable limit of the working electrode 301 in glucose detection can be improved.
Meanwhile 3D graphene has the flexibility more more excellent than two-dimensional graphene, distortion, stretching of general level etc. becomeShape will not influence its property and characteristic, so that working electrode 301 be made to have flexibility.It in turn, can by the working electrode 301 satisfactionThe requirement of wearable tissue fluid detection device.
Wherein, the nano material includes at least one of metal, metal oxide, metallic compound, such as gold, platinum, copper,Tungsten, copper oxide, cuprous oxide, cobalt sesquioxide, nickel oxide etc..The present invention is preferably metallic copper, cuprous oxide or copper oxideAt least one of.
Further, Cu2OPO4+It can be realized the catalysis oxidation to glucose, then pass through detection electrochemical sensor electricityThe concentration of glucose, effect are preferable in stream detection tissue fluid.Simultaneously, it is contemplated that specific surface is low after cuprous oxide forms film, urgesChanging effect reduces.Therefore, the nano material is preferably cuprous oxide particle.
The reaction equation of the catalysis oxidation is as follows:
Cu2O+H2PO4-→CuOPO4++2H++e-；
CuOPO4++ glucose → gluconolactone；
Gluconolactone → gluconic acid.
The reference electrode 302 is Ag/AgCl electrode, one layer can be printed in the substrate 10 by the method for 3D printingThen metallic silver carries out chlorination to silver electrode using liquor ferri trichloridi and handles to obtain.
The auxiliary electrode 303 is that perhaps the inert electrodes such as platinum can pass through 3D printing or electrochemical deposition method system to goldIt is standby.
In application, the electrochemical sensor 30 can be realized as the detection to tissue fluid with interstitial fluid contacts, to obtainThe physiologic informations such as concentration of glucose, lactic acid concn, hormone concentration, drug concentration, easy to operate, fast response time, and have moreHigh detection sensitivity and detectable limit.
In view of tissue fluid detection device use environment and use when state, the tissue fluid detection device also wrapsCover board 40 is included, the cover board 40 forms a cavity with the substrate 10, and the electrochemical sensor 30 is located in the cavity.FromAnd the tissue fluid that micropin 20 extracts will not be flowed out along the surface of substrate 10, it is particularly possible to guarantee that tissue fluid detection device is movingEffect when being used under state.
It is appreciated that about 0.1mm~0.5mm will be electrochemical due to the cavity gap very little that cover board 40 and substrate 10 are formedLearning when sensor 30 is set on cover board 40 can also come into full contact with tissue fluid.At this point, can also be by the electrochemical sensor 30It is set on the cover board 40.
Preferably, the cavity has opening, so that the cavity is connected to outside.Thus with the evaporation of tissue fluid,Micropin 20 can constantly extract intracorporal tissue fluid, to realize the purpose of real-time detection.
Specifically, the material of the substrate 10 can be high molecular material, the material of the micropin 20 can be macromoleculeThe material of material, the cover board 40 may be high molecular material.
Preferably, when the material of the substrate 10, the micropin 20 and the cover board 40 is high molecular material, make entireTissue fluid detection device has flexibility, and bending and tensile property are good, can be worn on body surface, realize the reality of physiologic informationWhen detection and continuous detection.
Cause human body uncomfortable in view of the high molecular material of good biocompatibility can be avoided, it is preferred that the macromoleculeMaterial includes one of dimethyl silicone polymer (PDMS), polyurethane (PU), polyvinyl alcohol (PVA).
Preferably, the micropin 20 is an integral molding structure with the substrate 10, and preparation method includes micro- casting method, heatOne of mould pressing method.
Wherein, micro- casting method specifically includes:
(1) mold is provided, the mold includes underlying structure and microneedle configuration；
(2) high molecular material is cast in the mold, isolated integrally formed micropin 20 and substrate 10.
The hot moulding method specifically includes:
(1) mold is provided, the mold includes underlying structure and microneedle configuration；
(2) hot pressing of high molecular material, isolated integrally formed micropin 20 and substrate 10 are carried out with the mold.
It is appreciated that first groove 101 is integrated into substrate 10 when the substrate 10 is provided with the first groove 101Type structure.
Preferably, the connection type between the substrate 10 and the cover board 40 is covalent bonding.That is, the substrate 10 withThe cover board 40 passes through the Covalent bonding together of its own high molecular material.
The application method of the tissue fluid detection device of the present embodiment, comprising the following steps:
S1 provides above-mentioned tissue fluid detection device；
The micropin 20 of the tissue fluid detection device is pierced into vivo by S2, under capillarity, described in tissue fluid entranceThe duct 201 of micropin 20 is simultaneously conveyed along the duct 201, contacts the tissue fluid with the electrochemical sensor 30；
S3 detects the tissue fluid by the electrochemical sensor 30.
Specifically, in step S2 on the skin by tissue fluid detection device patch, micropin 20 is pierced into subcutaneously, it is easy to use,And there is no feeling of pain.
Specifically, can be directly obtained required after step S3 electrochemical sensor 30 detects the tissue fluidPhysiologic information or needs obtain required physiologic information after further converting.Such as: when detection blood glucose, electrochemical sensor 30It detects in tissue fluid after the concentration of glucose, further according to the relationship of concentration of glucose in tissue fluid and the concentration of glucose in bloodConversion obtains the concentration of glucose in blood.Method is simply, it can be achieved that the real-time detection of Human Physiology information.