CN103913489A - Micro biochip for real-time detection of substances in body fluids - Google Patents
Micro biochip for real-time detection of substances in body fluids Download PDFInfo
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- CN103913489A CN103913489A CN201310007653.8A CN201310007653A CN103913489A CN 103913489 A CN103913489 A CN 103913489A CN 201310007653 A CN201310007653 A CN 201310007653A CN 103913489 A CN103913489 A CN 103913489A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
- G01N33/4915—Blood using flow cells
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0636—Integrated biosensor, microarrays
Abstract
The invention discloses a micro bio-chip for real-time detection of substances in body fluids, the micro bio-chip is assembled by a circulating microfluidic chip and a film biosensor, parts of the circulating microfluidic chip in turn are connected with each other to form a complete fluid pathway, and the film biosensor includes a working electrode, a counter electrode and a reference electrode; in a testing room of the circulating microfluidic chip, one or more film biosensors are embedded in the manner of series connection, or parallel connection/series connection and parallel connection, so that the surfaces of the embedded film biosensors are always contacted with the body fluid flowing by for real-time detection of the substances in the body fluids.
Description
Technical field
The present invention relates to micro-fluid chip field, particularly relate to a kind of micro-biochip detecting in real time for body fluid material.
Background technology
In the clinical detection of body fluid, the Microdialysis sgstem of miniaturization can overcome the dead volume that traditional Microdialysis sgstem is larger, longer shortcoming retardation time.For example, Gaspar has used the multi-sensor chip of circulation type, and in conjunction with Microdialysis sgstem, monitors continuously the glucose in body fluid: realize response speed faster, less dead volume; But in this Microdialysis sgstem, there is no microfluidic control parts, responding range is very narrow, for example, be less than 5mM for the glucose in blood, referring to S Gaspar, X.Wang, H.Suzukib, E.Csoregi, Amperometric biosensor-based flow-through microdetector for microdialysis applications, Analytica Chimica Acta525 (2004) 75 – 82).
Wearable blood sugar table equipment adopts gegenion electroosmosis technology, can by intact skin by glucose specimen collection to gel dish, measure.But in such system, only has biology sensor not containing microfluid biochip.
The biophotonics technology of microminiaturized intrusive mood SpectRx uses laser equipment to produce micropore in the cuticula of skin.By these micropores with by pump collection organization's liquid in diaphragm, measure.In such system, only have biology sensor not use microfluid biochip.
In U.S. Pat 6990849B2, describe a kind of microfluid system that carrys out flow control by microchannel and membrane valve, increased the accuracy of measuring collection of body fluids volume in conjunction with a position transducer, helped Accurate Determining impedance to carry out determination and analysis substrate concentration.This individual system requires to measure accurately microfluid volume, and this system for microfluid, is more difficult.Due to extra position transducer of needs, make this system more complicated.This system is not suitable for the continuous monitoring of body fluid.
Arkal medical skill is used microneedle array that passive tissue fluid taking-up is used for to static measurement, there is no continuous stream, it is said and can be used for continuous coverage; But do not know sample frequency, do not know at particular point in time, measure the retardation time of true blood glucose value in blood glucose value and body.
A kind of system that uses complicated sampling technique and have risk has been described in U.S. Pat 8050729B2; Use optical sensor to measure glucose in body fluid.From its fluid flowing path structure, be more suitable for measuring in batch (-type).But do not know sample frequency, do not know at particular point in time, measure the retardation time of true blood glucose value in blood glucose value and body.
Some vitro system in addition, are pumped into external glucose sensor by a small part of the blood extracting in body by multiple, carry out the mensuration of blood sugar; Meanwhile, after being cleaned by cleaning device, the overwhelming majority of the blood of extraction sends back in body.In such complexity and dangerous system, only have biology sensor not use microfluid biochip.Biology sensor is placed in the runner pipe of body fluid, and this can hinder the proper flow of fluid, also can affect the performance of sensor.In addition, the system that uses disposable blood sugar test paper bar is disclosed in U.S. Patent application 2010/0137778A1.
But in the prior art, lack the micro-biochip that can be advantageously used in material real time continue analysis in body fluid.
Summary of the invention
In order to solve the above-mentioned deficiency of prior art, the object of the invention is to provide a kind of micro-biochip detecting in real time for body fluid material, and the technical scheme of described micro-biochip is as follows.
The micro-biochip detecting in real time for body fluid material, it is assembled by circulation type micro-fluid chip and thin film bio sensor, wherein:
Circulation type micro-fluid chip comprises: fluid intake, micropore, serpentine channel, sensing chamber, microchannel, and fluid egress point; Various piece interconnects perforation successively, forms a complete fluid passage;
Thin film bio sensor comprises: working electrode, to electrode, contrast electrode, for the contact pad that outer to multiple electrodes and microchip instrument is connected, the line of connecting electrode and contact pad, for the casting lug thereon of inserting instrument socket, connect the through hole of body fluid, and there is the electrode dielectric layer of the insulating layer pattern perforate of mating with multiple electrodes;
In sensing chamber, with serial or parallel connection/series and parallel connections form, embed one or more thin film bio sensors, making the total surface of the thin film bio sensor embedding is to contact with the body fluid of flowing through, and monitors continuously the material in body fluid.
In one embodiment, between circulation type micro-fluid chip and thin film bio sensor, put into the thin layer double faced adhesive tape having with the pattern perforate of thin film bio sensor matching and assemble.
In one embodiment, microtubular is fixed in fluid intake and fluid egress point, is then connected with bodily fluid sampling device and miniflow pump in the analytic system of material in continuous monitoring body fluid, makes the dead volume minimum of interface channel.
In one embodiment, circulation type micro-fluid chip comprises plural sensing chamber, has the working electrode matching with sensing chamber quantity in thin film bio sensor; Each working electrode can be prepared into different biology sensors, for detecting in real time continuously multiple different analyte.
In one embodiment, the area of circulation type micro-fluid chip is less than 5cm
2, be highly less than 2mm.
In one embodiment, micropore is less than 400um; When flow velocity is less than 10ul/min flow velocity, micropore is less than 150um.
In one embodiment, serpentine channel width is less than 600um, and length is less than 10mm.
In one embodiment, in body fluid, material can be blood sugar, lactic acid, oxygen, pH value, hematocrit and/or electrolyte.
In one embodiment, microtubular diameter is less than 600um.Microtubular is made up of the material that can be used for Medical Devices, such as, plastics, rubber, metal; Plastics can be PE, PTFE, PES, PEEK, PU or medical grade PVC; Rubber can be silicon rubber; Metal can be stainless steel or titanium alloy.Microtubular guiding microfluid is led the place that should go such as sensing chamber, is connected such as sampling thief and micro-fluid pump with off-chip components.Microtubular can be rectangle or circle; Size is less than 3000um.
In one embodiment, circulation type micro-fluid chip can be by making for the material of micromachined and bio-compatibility, for example, plastics, silicon, glass, metal or pottery, plastics can be PMMA, PAA, PS, PC, PE, PP, PET or PDMS, and metal can be stainless steel or titanium alloy.
In one embodiment, the method preparation that circulation type micro-fluid chip can be manufactured by laser-induced thermal etching, chemical etching, plasma etching and/or mould.Laser-induced thermal etching is suitable for above-mentioned all materials.Available laser: CO
2laser (10.6um), infrared laser (1064nm), green laser (532nm), UV laser (355nm); Different materials and different machining precisioies, select different laser instruments to process.Chemical etching is suitable for metal, silicon and glass.Mould manufacture is suitable for a large amount of manufactures.
In one embodiment, on plastics, process for the preparation of the circulation type micro-fluid chip of measuring blood sugar by the method for laser-induced thermal etching.
In one embodiment, the electrode material of thin film bio sensor can be Au, Pt, Pd, Rh, Ru, Ag, Ni, C etc.Electrode can be prepared by methods such as sputtering method, chemical vapor deposition, plasma gas phase deposition or serigraphys.
The carrier material of thin film bio sensor can be with plastics, silicon, glass, pottery.Plastics can be PI, PEI, PSE, PES, PVC, PET or PP.In thin film bio sensor, insulating layer material can be PMMA, PI, PEI, SU8, SiO
2, or Si
3n
4.
In one embodiment, working electrode is the circular single electrode that diameter is less than 1.5mm, or microelectrode array; The material of preparation work electrode can be Pt, Pd, Rh or Ru, preferably Rh.Working electrode can pass through sputtering method, chemical vapor deposition, plasma gas phase deposition or electric plating method preparation.
In one embodiment, contrast electrode is that size is less than 3mm
2any geometric figure, be preferably the endless belt around working electrode.The material of preparing contrast electrode can be Ag or Ag/AgCl.Contrast electrode can pass through sputtering method, chemical vapor deposition, plasma gas phase deposition or electric plating method preparation.In the time that the material of contrast electrode is Ag, be, by oxidation, Ag is transformed into Ag/AgCl.For example, in HCl, being oxidized Ag by continuous current becomes Ag/AgCl.
In one embodiment, be that size is less than 3mm to electrode
2any geometric figure, be preferably the endless belt around working electrode.Preparation can be Au, Pt, Pd, Rh, Ru or C to the material of electrode.
In one embodiment, multiple bio-sensitive film and other difference in functionality film can be fixed on thin film bio working sensor electrode.Can sensitive membrane on thin film bio sensor, eliminate the film, the film of diffusion control or the film of bio-compatibility that disturb.
In one embodiment, can be containing being useful on glucose oxidase or the glucose dehydrogenase of blood sugar test in sensitive membrane, or for Lactate Oxidase or the lactic dehydrogenase of lactate detection, bovine serum albumin(BSA), perfluorinated sulfonic acid, cellulose; Or comprise medium, for example, for the dimethyl ferrocene of blood sugar test.Preferably fixing glucose oxidase on working electrode, makes the thin film bio sensor that detects blood sugar.
In one embodiment, eliminating the film disturbing can be cellulose, perfluorinated sulfonic acid, polycarbonate, polyurethane or electropolymerization phenylenediamine.
In one embodiment, the film of diffusion control can be perfluorinated sulfonic acid, polycarbonate, polyurethane or teflon.
In one embodiment, the film of bio-compatibility can be perfluorinated sulfonic acid, polycarbonate, polyurethane, teflon, polyglycol, polyethylene oxide or heparin.
In one embodiment, perfluorinated sulfonic acid, polycarbonate, polyurethane or teflon can have multi-functional.
In one embodiment, can be placed on accurately desired position and cover required region with the coating solution that certain volume is for example less than 1ul by temperature sensitive formula divider, for example, only cover the surface of working electrode, form very thin film; Or electricity consumption polymerization inserts such as GOx of required biology enzyme; Or with other film of the fixing non-sensitive film of dip-coating method.
In one embodiment, in assembling circulation type micro-fluid chip and biofilm sensor, use double faced adhesive tape, double faced adhesive tape can be very thin pressure sensitive adhesive, for example, be less than 350um.On double faced adhesive tape, process figuratum perforate, allow some place do not covered by glue; Figuratum double faced adhesive tape is accurately placed between circulation type micro-fluid chip and biofilm sensor by design.For example, sensing chamber/sensor, communication port can not blocked by glue; And place sensing chamber/sensor, communication port location; In addition, can on flow-through micro-fluid chip and biofilm sensor, add other and arrange, help location assembling.When assembling, between flow-through micro-fluid chip and biofilm sensor, add certain pressure or temperature, fixing.
In one embodiment, in assembling circulation type micro-fluid chip and biofilm sensor, use the UV glue of proper viscosity, adopt (stamping) method of impressing, very thin figuratum UV glue is accurately transferred to the position of setting on circulation type micro-fluid chip.Biofilm sensor is accurately covered on circulation type micro-fluid chip by design; For example, allow sensing chamber/sensor, communication port location place, can add other setting at flow-through micro-fluid chip and biofilm sensor, help location assembling.When assembling, pressurization, UV illumination curing UV glue, fixing.
In one embodiment, in assembling circulation type micro-fluid chip and biofilm sensor, use ultrasonic soldering or laser bonding, the one side that the method is suitable at least welding is plastics.To accurately cover on circulation type micro-fluid chip by design with biofilm sensor.For example, allow sensing chamber/sensor, communication port location place, can add other setting at biochip and biology sensor, help location assembling.When assembling, pressurization, applies applicable ultrasonic frequency, fixing.
In micro-biochip of the present invention, the size that sensing chamber is different and geometric configuration, position and layout, can be for embedding the thin film bio sensor of various sizes and geometric configuration in parallel or in series; The different size of sensing chamber guarantees that with geometric configuration the total surface of the biology sensor embedding is to contact with the body fluid of flowing through.The thin film bio sensor that is embedded in sensing chamber in microbe chip can continuously/intermittently be monitored single the kind or multiple analytes in body fluid simultaneously.
Various geometric configuratioies and the surface of circulation type micro-fluid chip of the present invention, allow body fluid in microfluid biochip, to circulate smooth and dead volume is minimum, without bubble.The various sizes of microfluid circuit and geometric configuration, permission system is taked the body fluid of different amounts with different speed, adjust to suitable speed, sends the body fluid of taking back to breakneck situation in body with regard to having avoided taking a large amount of body fluid.
Circulation type micro-fluid chip of the present invention is of different sizes the entrance and exit passage with geometric configuration, for connecting for example sampling thief of device and the miniflow pump that are connected with micro-biochip, and allow connect dead volume minimum.The cumulative volume of circulation type micro-fluid chip of the present invention is very little, for example, is less than 15 microlitres, allows like this within the short time, for example, to be less than 5 minutes, with continuous or slow speed intermittently, upgrades all fluids in micro-biochip.Can guarantee like this, every a few minutes, measurement data is each time all the detection analyte deriving from the fresh body fluid of taking, rather than this analyte in old body fluid.
In micro-biochip of the present invention, be embedded in thin film bio sensor in the microbe chip of circulation type and there is fast response.The electrode of thin film bio sensor is plane and mm size, can allow the more enzyme of load and protein at biosensor surface, produces the more stable biology sensor having compared with large-signal.Circular working electrode surface, can more accurately and be fixed on rete in the limited range of electrode surface easily.With for example rhodium of the peroxide catalyst electrode material of working, can increase detection signal density and reduce operating potential, reduce/eliminate the uric acid that coexists in body fluid, paracetamol, ascorbic acid etc. for the interference detecting.Use such as rhodium of unleachable oxidation catalyst, make the mensuration of hydrogen peroxide, for example blood sugar, lactic acid, through the hydrogen peroxide that oxidase effect produces separately, do not leach material, cause electrode signal more stable, be suitable for simultaneously continuously many kinds of substance in monitoring body fluid.Use the biosensor membranes of multilayer, interference can be down to minimumly, the dynamic range that extends and detect, improves serviceable life and the biocompatibility of biology sensor, is suitable for monitoring continuously the material in body fluid.
Micro-biochip of the present invention is external biological sensor, has reduced on the one hand the problem of sensor anoxic, has expanded sensor responding range; On the other hand, without the response to implanted sensor in body, greatly reduce the problem of sensor performance decay and signal drift, therefore only needed less calibration point.
In micro-biochip of the present invention, with parallel connection or series system, the working electrode of the number of different types of integrated arrangement on same electrode base board, can monitor multiple analytes, such as blood sugar, lactic acid etc. simultaneously continuously; With parallel connection or series system, the working electrode multiple of the same type of integrated arrangement on same electrode base board, can monitor continuously a kind of analyte simultaneously, for example, with two glucose working electrodes detection glucose, the risk losing efficacy to reduce single working electrode, and greatly increase the reliability of measuring; In thin film bio sensor, several working electrodes are shared identical reference electrode and to electrode.
Accompanying drawing explanation
In order to be illustrated more clearly in the technical scheme in the embodiment of the present application, to the accompanying drawing of required use in embodiment be briefly described below, apparently, the accompanying drawing the following describes is only some embodiment that record in the application, come for those of ordinary skills, do not paying under the prerequisite of creative work, can also obtain according to these accompanying drawings other accompanying drawing.
Fig. 1 is the circulation type micro-fluid chip schematic diagram of single sensing chamber;
Fig. 2 is the circulation type micro-fluid chip schematic diagram of multiple sensing chamber;
Fig. 3 is the electrode group of single-sensor and launches schematic diagram;
Fig. 4 is the electrode group of multiple sensors and launches schematic diagram;
The biochip assembling of Tu5Shi Dan sensing chamber and single-sensor and expansion schematic diagram;
The biochip assembling of Tu6Shi Duo sensing chamber and multisensor and expansion schematic diagram.
Embodiment
For the personnel that make art technology field understand the technical scheme in the application better, below in conjunction with the accompanying drawing in the embodiment of the present application, technical scheme in the embodiment of the present application is clearly and completely described, obviously, described embodiment is only the application's part embodiment, rather than whole embodiment.Based on the embodiment in the application, those of ordinary skills are not making all other embodiment that obtain under creative work prerequisite, all should belong to the scope of the application's protection.
Embodiment 1: the micro-biochip with single sensing chamber and single-sensor
Referring to Fig. 1,3 and 5, the biochip 6 with single sensing chamber and single-sensor is for the various analytes of monitoring body fluid continuously, such as, in blood sugar, lactic acid, sodion, calcium ion, magnesium ion, chlorion, bicarbonate ion and body fluid range protein etc. etc.It is assembled by circulation type micro-fluid chip 3 and thin film bio sensor 4.It can be for the single analysans in continuous detecting body fluid.
Circulation type micro-fluid chip
Referring to Fig. 1, the microfluid circuit of circulation type micro-fluid chip 3 is normally made up of following components: fluid intake 301, micropore 302, serpentine channel 303, sensing chamber 310, microchannel 306, and fluid egress point 307.The various piece of circulation type micro-fluid chip 3 interconnects perforation successively, forms a complete fluid passage.Above-mentioned various piece all embeds micro-fluid chip main body 3.
Above-mentioned various piece needs can be of different sizes and shape according to difference, and the size of the difference size of micropore 302 is for regulating the resistance to flow of microfluid and the back pressure of vitro system or resistance; The different length of serpentine channel 303 and curvature are for regulating the resistance to flow of microfluid and the back pressure of vitro system or resistance; The size that sensing chamber 310 is different and geometric configuration, position and layout, embed the various sizes of sensing chamber 310 with placement and the thin film bio sensor of geometric configuration matches.
Thin film bio sensor
Referring to Fig. 3, thin film bio sensor is made up of following components conventionally: circular working electrode 401, around the endless belt type of working electrode 401 to electrode 405, contrast electrode 406, the contact pad 408 that multiple electrodes are connected with instrument, many connect the line 407 of multiple electrodes and multiple contact pads, for the casting lug thereon 409 of inserting instrument socket, connect the through hole 410 of body fluid, the insulation course 420 of electrode, and the insulating layer pattern perforate 421 of mating with multiple electrodes.Described component is all carried in the main body 4 of thin film bio sensor.
Sensing chamber 310 with embed thin film bio sensor working electrode 401, electrode 405, contrast electrode 406 are mated, and guarantee that the working electrode 401 embedding, the total surface that electrode 405, contrast electrode 406 are mated are to contact with the body fluid of flowing through, guarantee to monitor continuously the various materials in body fluid.Various geometric configuratioies and the surface of the various piece of the microfluid circuit of micro-fluid chip 3, also must allow body fluid in micro-fluid chip 3, to circulate smooth and dead volume is minimum, without bubble.The various sizes of microfluid circuit and geometric configuration, in conjunction with miniflow pump, make system gather the body fluid of different amounts with different speed; Adjust to suitable speed, can avoid taking a large amount of body fluid, therefore do not need the body fluid of taking to send back in body, avoided this unfavorable and breakneck situation.
The performance of thin film bio sensor is decided by the film on working sensor electrode.Fixing multiple different bio-sensitive film and other difference in functionality film, on working electrode, are made multiple different biology sensor.For example, fixing glucose oxidase on Rh electrode, can be made into the biology sensor that detects blood sugar; On electrode, fix various ion selective membranes, can make the ion electrode that detects body fluid intermediate ion concentration; On electrode, fix various antibody, can make the electrode that detects range protein concentration in body fluid.By controlling the thickness of fixing film, make thin film bio sensor 4, then can be assembled into biochip 6 with circulation type micro-fluid chip 3, for monitoring continuously the analyte of body fluid.
Assembling biochip
Referring to Fig. 5, the circulation type micro-fluid chip 3 that is carved with fluid passage is alignd by design with the thin film bio sensor 4 of having fixed required film, and adjust thin film bio sensor 4, make bio-sensing rete down.Between circulation type micro-fluid chip 3 and thin film bio sensor 4, put into the thin layer double faced adhesive tape 5 of the pattern perforate of band coupling, alignment; Guarantee fluid bore 307,501,410 alignment, perforate 502 simultaneously is just in time positioned at above sensing chamber 310.Then pressurization is fixing, obtains the biochip 6 of assembling.
Select the suitable microtubular mating with fluid intake 301 and outlet 307 passages in size and geometric configuration, with glue, the microtubular of choosing be separately fixed to entrance 301 and export on 307, then be connected with bodily fluid sampling device and miniflow pump in the analytic system of material in continuous monitoring body fluid, and make the dead volume minimum of interface channel.When biochip is by fluid intake 301 and bodily fluid sampling device, after being connected with miniflow pump with by fluid egress point 307, start miniflow pump, body fluid will flow through micro-fluid chip 3 through bodily fluid sampling device by fluid intake 301, micropore 302, serpentine channel 303, sensing chamber 310, microchannel 306 and fluid egress point 307 in body, the miniflow pump of flowing through, enters liquid waste collector; In sensing chamber 310 body fluid with working electrode 401 in thin film bio sensor, electrode 405, contrast electrode 406 are contacted.
Embodiment 2: the biochip with many sensing chamber and multisensor
Referring to Fig. 2,4 and 6, the biochip 6 with many sensing chamber and multisensor is for the various analytes of monitoring body fluid continuously, such as, in blood sugar, lactic acid, sodion, calcium ion, magnesium ion, chlorion, bicarbonate ion and body fluid range protein etc. etc.It is assembled by circulation type micro-fluid chip 3 and thin film bio sensor 4.It can be for detecting the multiple analysans in body fluid continuously.
Circulation type micro-fluid chip
Referring to Fig. 2, the microfluid circuit of circulation type micro-fluid chip 3 is made up of following components: fluid intake 301, micropore 302, serpentine channel 303, sensing chamber 310 and 311, microchannel 304,305 and 306, and fluid egress point 307.Various piece connects perforation successively.Form a complete fluid passage.Above-mentioned various piece all embeds micro-fluid chip main body 3.
Thin film bio sensor
Referring to Fig. 4, thin film bio sensor 4 is normally made up of following components: 4 circular working electrodes 401,402,403,404, to electrode 405, contrast electrode 406, the contact pad 408 that multiple electrodes are connected with instrument, many connect the line 407 of multiple electrodes and multiple contact pads, for the casting lug thereon 409 of inserting instrument socket, connect the through hole 410 of body fluid, the insulation course 420 of electrode, and the insulating layer pattern perforate 421 of mating with multiple electrodes.Above-mentioned various piece is all carried in main body 4.
The biochip difference of the biochip of embodiment 2 and embodiment 1: You Liangge sensing chamber 310,311; The thin film bio working electrode group 401-406 matching comprises 4 working electrodes 401,402,403 and 404, and wherein working electrode 401,402 is corresponding to sensing chamber 310, and working electrode 403,404 is corresponding to sensing chamber 311.Divide body fluid to flow into sensing chamber 310 and 311 2 microchannels 304; 2 microchannels 305 merge together point body fluid of inflow sensing chamber 310 and 311.
On these 4 different working electrodes, can prepare 4 different biological working electrodes, for example blood sugar, lactic acid, oxygen, pH value biology sensor.Working electrode 401,402 embeds sensing chamber 310 along connection ground, and working electrode 403,404 embeds sensing chamber 311 along connection ground, and working electrode 401,402 and working electrode 403,404 are placed in biochip 6 in parallel simultaneously.Therefore, can successively monitor 4 kinds of different analytes simultaneously.And may have the sensor parallel connection of phase mutual interference to be placed in different sensing chamber, avoid interference.
Assembling biochip
Referring to Fig. 6, the circulation type micro-fluid chip of having carved 3 and the thin film bio sensor 4 of having fixed required film are alignd by design, and adjust thin film bio sensor 4, make bio-sensing rete upward.Between circulation type micro-fluid chip 3 and thin film bio sensor 4, put into the thin layer double faced adhesive tape 5 of the pattern perforate of band coupling, alignment; Guarantee that fluid bore 307,501,410 aligns well, perforate 502 simultaneously is just in time positioned at above sensing chamber 310, and perforate 503 is just in time positioned at above sensing chamber 311.Then pressurization is fixing, just obtains the biochip 6 of assembling.
Select the applicable microtubular mating with fluid intake 301 and outlet 307 passages in size and geometric configuration, with glue, the microtubular of choosing be separately fixed to entrance 301 and export on 307, then with bodily fluid sampling device and miniflow pump in the analyte system being connected continuously in monitoring body fluid, and make the dead volume minimum of interface channel.When biochip is by fluid intake 301 and bodily fluid sampling device, and after fluid egress point 307 is connected with miniflow pump, start miniflow pump, body fluid will pass through fluid intake 301, micropore 302, serpentine channel 303, shunting microchannel 304 through bodily fluid sampling device in body, body fluid is imported respectively to sensing chamber 310 and 311, in sensing chamber, contact with thin film bio working electrode 401-406; Then collect into microchannel 305, microchannel 306, and through fluid egress point 307, the miniflow pump of flowing through, enters liquid waste collector.
Above embodiment shows many sensing chamber biochip structure of 2 sensing chamber and corresponding 4 working electrodes; Those skilled in the art will recognize that as required, biochip of the present invention can have the biochip of more sensing chamber, for detection of more materials in body fluid.
The present invention who should be understood that disclosure is not limited only to specific method, scheme and the material described, because these all can change.Will also be understood that terminology used here is only used to describe the object of specific embodiment scheme, rather than be intended to limit the scope of the invention, scope of the present invention is only limited to appended claim.
Those skilled in the art also will recognize, or can confirm that use is no more than normal experiment, many equivalents of described specific embodiment of the present invention in this article.These equivalents are intended to comprise in the appended claims.
Claims (14)
1. the micro-biochip detecting in real time for body fluid material, it is assembled by circulation type micro-fluid chip and thin film bio sensor, wherein:
Circulation type micro-fluid chip comprises: fluid intake, micropore, serpentine channel, sensing chamber, microchannel, and fluid egress point; Various piece interconnects perforation successively, forms a complete fluid passage;
Thin film bio sensor comprises: working electrode, to electrode, contrast electrode, for the contact pad that outer to multiple electrodes and microchip instrument is connected, the line of connecting electrode and contact pad, for the casting lug thereon of inserting instrument socket, connect the through hole of body fluid, there is the electrode dielectric layer of the insulating layer pattern perforate of mating with electrode;
In sensing chamber, with serial or parallel connection/series and parallel connections form, embed one or more thin film bio sensors, making the total surface of the thin film bio sensor embedding is to contact with the body fluid of flowing through, and monitors continuously the material in body fluid.
2. micro-biochip according to claim 1, wherein between circulation type micro-fluid chip and thin film bio sensor, puts into the thin layer double faced adhesive tape having with the pattern perforate of thin film bio sensor matching and assembles; Or shift by the method for impressing the liquid glue mating with thin film bio sensor patterns and assemble; Or by method assembling circulation type micro-fluid chip and the thin film bio sensor of ultra-sonic welded or laser bonding.
3. micro-biochip according to claim 1, wherein microtubular is fixed in fluid intake and fluid egress point, is then connected with bodily fluid sampling device and miniflow pump in the analytic system of material in continuous monitoring body fluid.
4. micro-biochip according to claim 1, wherein circulation type micro-fluid chip comprises plural sensing chamber, has the working electrode matching with sensing chamber quantity in thin film bio sensor.
5. micro-biochip according to claim 1, wherein the area of circulation type micro-fluid chip is less than 5cm
2, be highly less than 2mm.
6. micro-biochip according to claim 1, wherein in body fluid, material is blood sugar, lactic acid, oxygen, pH value, hematocrit and/or electrolyte.
7. micro-biochip according to claim 5 is wherein processed for the preparation of the circulation type micro-fluid chip of measuring blood sugar by the method for laser-induced thermal etching on plastics.
8. micro-biochip according to claim 1, wherein working electrode is the circular single electrode that diameter is less than 1.5mm, or microelectrode array; The material of preparation work electrode is Pt, Pd, Rh or Ru.
9. micro-biochip according to claim 1, wherein contrast electrode is that size is less than 3mm
2the endless belt around working electrode; The material of preparing contrast electrode is that Ag is or/and Ag/AgCl.
10. micro-biochip according to claim 1 is wherein that size is less than 3mm to electrode
2the endless belt around working electrode; Preparation is Au, Pt, Pd, Rh, Ru or C to the material of electrode.
11. micro-biochips according to claim 1, wherein the cumulative volume of circulation type micro-fluid chip is less than 15 microlitres, is being less than 5 minutes, with continuous or slow speed intermittently, upgrades all fluids in micro-biochip.
12. micro-biochips according to claim 1, wherein the electrode of thin film bio sensor uses the biosensor membranes of multilayer, monitors continuously the material in body fluid.
13. micro-biochips according to claim 1, with parallel connection or series system, the dissimilar working electrode of integrated arrangement on same electrode base board is monitored multiple analytes simultaneously continuously.
14. micro-biochips according to claim 1, with parallel connection or series system, the multiple working electrodes of the same type of integrated arrangement on same electrode base board are monitored a kind of analyte simultaneously continuously.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN103913489B (en) | 2015-06-10 |
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