CN103932718B - The portable monitoring system of thing is analyzed in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid - Google Patents
The portable monitoring system of thing is analyzed in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid Download PDFInfo
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- CN103932718B CN103932718B CN201310026915.5A CN201310026915A CN103932718B CN 103932718 B CN103932718 B CN 103932718B CN 201310026915 A CN201310026915 A CN 201310026915A CN 103932718 B CN103932718 B CN 103932718B
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Abstract
The present invention discloses the portable monitoring system analyzing thing in a kind of dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid, and it comprises: subsystem next to the skin and compact wearing type electronics.Subsystem next to the skin comprises micropin bodily fluid sampling device, microfluid biochip, micro-fluid pump, close-fitting type electronics and detection calibration room and liquid waste collector; Various piece is interconnected through, a composition complete fluid passage successively by microtubular.Portable monitoring system of the present invention has shorter preheating time, more accurately result, needs less calibration point, during sampling pain reduce, simple to operate; Monitoring system of the present invention is highly sensitive, particularly in hypoglycemia scope.
Description
Technical field
The present invention relates to clinical sample monitoring system, particularly relate to a kind of portable monitoring system detected in real time for material in body fluid.
Background technology
Self-monitoring system (SMBG) such as blood sugar test paper bar and the blood glucose meter of blood glucose are widely used for the detection of blood glucose.Existing SMBG primary limitation is: inconvenient, uncomfortable, intermittent information, and obtains this information and depend on that patient gets the initiative of blood and test; At its best, SMBG provides every day 2,4 or maximum 10 data points, measures maximum number of times like this and reaches 10 times.But the change of blood sugar of diabetes patient is continuously with unpredictable, in the process of a day 24 hours, can up to the change of six times! Therefore, the data of SMBG are discontinuous, only provide a glucose level estimated.But, control the system that blood glucose relates to constantly change.Continuous blood sugar monitoring (CGM) provides patient about the real time information of blood sugar level sequence data in time, and the direction of change of blood sugar, speed and trend.The clinical effectiveness of real-time CGM shows that CGM significantly improves Diabetes Mellitus, as lower HbA1c value, reduce blood glucose fluctuation and hypoglycemic episodes time, reduce the persistent period exceeding hypoglycemia and hyperglycaemic range, and reduce the risk relevant to diabetic complication, improve the quality of life of patient.
At present, the leading products on CGM market implant subcutaneous needle-like electrochemical sensor, such as
pLUS,
rEAL-Time, FreeStyle
can work a couple of days in vivo, after being finished, can be changed by user.But they must calibrate by the data that SMBG detects, to obtain required accurate reading by multiple timing for such as 2,6 hours.
Implant subcutaneous needle-like electrochemical sensor and there is following defect:
● each independent data point lacks accuracy, must repeatedly calibrate by the data that SMBG detects;
● preheating time is longer, is generally greater than 2 hours, and FreeStyle
be 10 hours, make them in initialized warming up period not use, make them be difficult to be applied to hospital emergency rooms and intensive care unit(ICU) (ICU);
● the sensor implanted easily is deposited rapidly/sticks to implant site by substance in vivo, forms thick capsule by scar tissue, the sensor that parcel is implanted, and has a strong impact on its performance, particularly accuracy;
● pain and inconvenience during calibration;
● relate to the operation of pain and inconvenience during implanted sensor: implant the sensor of 13 millimeters long or import, with 45 of difficulty degree of insertions with pain No. 22 pins; Be not easy to take out the sensor implanted;
● about 1 order of magnitude lower than physiological glycemic levels of the oxygen concentration in normal structure, this change that sensor can be caused to respond also reduces the linear upper limit of response.
Another is commercial but be not the CGM of ordinary consumption product be GlucoDay, the principle of application microdialysis, dialyzer about 25mm long ductule Operation subcutaneous tissue will be had, by dialysis solution, the blood glucose in body is taken to external, with the glucose being arranged in external glucose sensor measurement dialysis solution, and the blood sugar concentration in adult that converts.The limitation of this system: Operation dialysis catheter; Local tissue damage and the inflammation of insertion point cause signal drift; Because glucose organizes the balance between dialysis solution to need the time in vivo, cause longer lag time, and this is relevant with dialysate flow.
Some vitro system in addition, are pumped into external glucose sensor by the sub-fraction of the blood extracted in body by multiple, carry out the mensuration of blood glucose; Meanwhile, send back in body after the overwhelming majority of the blood of extraction being cleaned by rinser.Such system is very complicated and dangerous, and expensive, makes it be difficult to be applied in required quick-setting or simple and crude working environment, as family healthcare or emergency room.
For the problems referred to above, the invention provides the portable monitoring system analyzing thing in a kind of dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid, system of the present invention has the following advantages:
● shorter preheating time, such as, use the external CGM of undiluted body fluid;
● result more accurately, such as, uses external CGM sensor, the Sensor Problem do not implanted;
● need less calibration point, such as, use external CGM, only need some calibration;
● painless, even can automatic calibration;
● during sampling pain reduce, simple to operate, such as, during sampling, insertion easy to use and the micropin of taking-up;
● the present invention requires collection of body fluids according to concrete application, then flows through the biosensor embedding biochip by suitable flow velocity continuously or off and on, makes it there is no need extracting solution to return in body;
● the present invention uses the thin film sensor of response fast, can be embedded in the microfluid circulation circuit of a micro-biochip;
● monitoring system of the present invention is highly sensitive, particularly in hypoglycemia scope.
Summary of the invention
In order to solve the above-mentioned deficiency of prior art, the object of the invention is to provide the portable monitoring system analyzing thing in a kind of dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid, and the technical scheme of institute's portable monitoring system is as follows.
Analyze a portable monitoring system for thing in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid, it comprises:
(1). subsystem next to the skin, described subsystem next to the skin comprise by microtubular be interconnected successively through, composition a complete fluid passage following various piece:
1.1 micropin bodily fluid sampling devices, it is made up of micropin, micropin holder and micropin fixing subsides scholar; When sampling, pressing micropin holder with finger strength, promoting fixing micropin and thrusting in skin, and retain in skin, fixed by the micropin be attached on skin fixing subsides scholar; Thrust micropin in skin, can continuous drawing body fluid;
1.2 microfluid biochips, it is assembled by circulation type micro-fluid chip and thin film bio sensor;
1.2.1 circulation type micro-fluid chip comprises: fluid intake, micropore, serpentine channel, sensing chamber, microchannel, and fluid issuing; Various piece is interconnected through successively, forms a complete fluid passage;
1.2.2 thin film bio sensor comprises: working electrode, to electrode, reference electrode, for the contact pad that outer to multiple electrode and microchip instrument is connected, the line of connection 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;
With serial or parallel connection/series and parallel connections form in sensing chamber, embed one or more thin film bio sensors, make the total surface of the thin film bio sensor embedded be and the bioresorbable flowed through monitor the material in body fluid continuously;
1.3 micro-fluid pumps, micro-fluid pump can between micropin bodily fluid sampling device and microfluid biochip, or immediately preceding after microfluid biochip; Controlled power is provided, the body fluid of absorption is flow through microfluid biochip;
1.4 close-fitting type electronics, by sensor interface and micro-fluid pump interface, are connected with microfluid biochip and micro-fluid pump respectively; When the described close-fitting type electronics of startup, drive micro-fluid pump and thin film bio sensor, body fluid will extract continuously or discontinuously from the micropin implanted, and flows through circulation type micro-fluid chip and contacts with the electrode group in the thin film bio sensor embedded, producing the detection signal of test analyte;
1.5 detection calibration room and liquid waste collectors, wherein detection calibration room is fixedly installed in subsystem next to the skin or joins in subsystem next to the skin when calibrating; When analyzing thing in mensuration body fluid, body fluid enters liquid waste collector, and during calibration, body fluid enters detection calibration room; Detection calibration room between micropin bodily fluid sampling device and microfluid biochip, or with liquid waste collector concurrently immediately preceding after micro-fluid pump;
(2). compact wearing type electronics and/or date processing and transmission terminal equipment, described compact wearing type electronics or described date processing and transmission terminal equipment are directly in real time, wireless transmission ground receives detection or the calibrating signal of the test analyte that subsystem next to the skin produces, and then carry out the physiologic result of the storage of data, analyzing and processing and display analysis thing; Or described date processing and transmission terminal equipment receive the physiologic result of the display analysis thing of described compact wearing type electronics by wireless or wire transmission mode.
Date processing and transmission terminal equipment can carry out the longer-term storage of data, the analyzing and processing of result and display.Such as, in one month, blood sugar concentration is schemed over time; Exceed the time of blood glucose threshold value.In addition, date processing and transmission terminal equipment can upload data in individual's " cloud " that the Internet is encrypted, and share, such as doctor, family members, bosom friend with donor, convenient, many-sided, long-term personal health information is provided, is convenient to diagnosis, treatment, disease control.Date processing and transmission terminal equipment can be mobile phone, computer or other portable set.
In one embodiment, described in state micropin holder and be included in bottom there is the projecting plug in hole, at the fluid issuing of side, the fluid passage in micropin holder, and micropin retainer body; Described micropin the fixing scholar of subsides comprise: micropin fixes the recessed socket pasted in scholar's main body, and the hole in recessed socket, at the flange of recessed receptacle periphery, and is attached to the adhesive of medical on flange bottom; The projecting plug of described micropin holder is positioned at the bottom of micropin holder, and the base apertures of described projecting plug is for holding micropin, and micropin is fixed in the base apertures of projecting plug hermetically, and stretches out projecting plug; Described micropin has the hole be communicated with body fluid by the fluid issuing of described micropin holder in micropin body; Described micropin fix paste the hole of scholar and recessed socket respectively with the projecting plug of described micropin and described micropin holder in position, size and geometrically mating.
In one embodiment, the bottom of described micropin holder protrusions plug has the bottom that multiple hole and multiple described micropin are fixed on plug hermetically, described fixing subsides scholar be recessed socket and multiple hole respectively with described projecting plug and multiple micropin in position, size and geometrically mating.
In one embodiment, there is the passage entering into a path for multiple fluid flow path of assembling from multiple micropin in micropin holder.
In one embodiment, bodily fluid sampling device area is less than 5cm
2, be highly less than 10mm.
In one embodiment, the external diameter of described micropin is preferably less than 380um.
In one embodiment, the length that micropin stretches out projecting plug is less than 10mm usually, is preferably less than 5mm, and is more preferably less than 3mm; When miniature bodily fluid sampling device is for sampling blood glucose sample, the length that micropin stretches out projecting plug is preferably less than 5mm.
In one embodiment, control micropin by regulating the length of stretching out holder plug and to implant the degree of depth, sample different body fluid by penetrating the degree of depth different in skin, such as, can sample the mixture of tissue fluid, blood or tissue fluid and blood.
In one embodiment, micropin can with in different angles insertosome, and preferably angle is 90 degree.
In one embodiment, micropin to penetrate in body and stays in the body and samples for a long time, only has Wicresoft or almost noinvasive, considerably reduce health like this to the reaction entering micropin in body to skin and subcutaneous tissue.
In one embodiment, micropin can have the material of mechanical strength to make by any bio-compatibility, such as, be made up of rustless steel, titanium or titanium alloy, silicon and compound thereof, tungsten alloy, plastics, pottery etc.; Micropin can commercially, such as hypodermic needle, Kumetrix ' s silicon micropin etc.
In one embodiment, the fluid passage in micropin holder and the fluid issuing shape in side and size can be selected as required, and preferably their diameters are less than 400um; Fluid path length is less than 20mm.
In one embodiment, to enter for auxiliary micropin and the micropin holder plug fixed in vivo can use any suitable shape and size, be preferably the cone that diameter is less than the protrusion of 8mm.
In one embodiment, micropin holder size is relevant with the quantity of fixing micropin, and when being single micropin, the area of micropin holder is preferably less than 3cm
2.
In one embodiment, micropin holder can be made up of the material that can be used for armarium, such as, be made up of plastics, rubber, metal, pottery etc.Plastics can be PE, PP, POM, PTFE, PES, PSU, PEEK, PC, PU and medical grade PVC etc.; Rubber can be silicone rubber etc.; Metal can be rustless steel, titanium, titanium alloy, aluminum, aluminium alloy etc.
In one embodiment, micropin holder can the method for machining or Making mold manufacture.
In one embodiment, micropin is fixed to paste in scholar and to be entered for auxiliary micropin and the recessed socket fix is in vivo diameter is less than the conical cavity that 10mm is recessed into.
In one embodiment, it is relevant with the quantity of fixing micropin that micropin fixes subsides scholar size, when being single micropin, micropin is fixed the area pasting scholar and is preferably less than 5cm
2.
In one embodiment, micropin is fixed and is pasted the broadside that there is band glue scholar bottom surface, for whole bodily fluid sampling device is fixed on sampling place skin surface, samples for a long time.
In one embodiment, the adhesive of medical be attached on flange bottom is the glue of adhesive bandage formula.
In one embodiment, it is the medical material non-stimulated to skin that micropin fixes the material pasting scholar, such as plastics and rubber, and plastics can be PE, PTFE, PES, PU, medical grade PVC etc.; Rubber can be silicone rubber etc.
In one embodiment, micropin is fixed and is pasted scholar and can the method for machining or Making mold manufacture.
In one embodiment, whole bodily fluid sampling device is fixed on sampling place skin surface, samples for a long time.
In one embodiment, micropin holder fluid issuing can be connected directly to Micropump.
In one embodiment, micropin holder fluid issuing can pass through biochip, is then connected to Micropump.
In one embodiment, between circulation type micro-fluid chip and thin film bio sensor, put into the thin layer double faced adhesive tape had with the pattern perforate of thin film bio sensor matching and assemble; Or shift by method of impressing the liquid glue mated with thin film bio sensor patterns and assemble; Or assemble circulation type micro-fluid chip and thin film bio sensor by the method for ultra-sonic welded or laser weld.
In one embodiment, microtubular is fixed in fluid intake and fluid issuing, is then connected with the bodily fluid sampling device of monitoring continuously in the analytical system of material in body fluid and miniflow pump, makes the dead volume of interface channel minimum.
In one embodiment, circulation type micro-fluid chip comprises plural sensing chamber, has the working electrode matched with sensing chamber quantity in thin film bio sensor; Each working electrode can be prepared into different biosensors, for detecting multiple different analysis thing in real time continuously.
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 glucose, 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 armarium, such as, and plastics, rubber, metal; Plastics can be PE, PTFE, PES, PEEK, PU or medical grade PVC; Rubber can be silicone rubber; Metal can be rustless steel or titanium alloy.Microtubular guides microfluid to lead the place such as sensing chamber that should go, and is connected with off-chip components such as sampler and micro-fluid pump.Microtubular can be rectangle or circle; Size is less than 3000um.
In one embodiment, circulation type micro-fluid chip can be made up of the material for micromachined and bio-compatibility, such as, plastics, silicon, glass, metal or pottery, plastics can be PMMA, PAA, PS, PC, PE, PP, PET or PDMS, and metal can be rustless steel or titanium alloy.
In one embodiment, circulation type micro-fluid chip can pass through the method preparation of laser-induced thermal etching, chemical etching, plasma etching and/or Making mold.Laser-induced thermal etching is suitable for above-mentioned all materials.Available laser: CO
2laser (10.6um), iraser (1064nm), green laser (532nm), UV laser (355nm); Different materials and different machining accuracies, select different laser instrument to process.Chemical etching is suitable for metal, silicon and glass.Making mold is suitable for a large amount of manufacture.
In one embodiment, on plastics, the circulation type micro-fluid chip for the preparation of measuring blood glucose is processed 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 vapour deposition (CVD), plasma gas phase deposition or silk screen printings.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 vapour deposition (CVD), plasma gas phase deposition or electric plating method preparation.
In one embodiment, reference electrode is that size is less than 3mm
2any geometric figure, be preferably the endless belt around working electrode.The material preparing reference electrode can be Ag or Ag/AgCl.Reference electrode can pass through sputtering method, chemical vapour deposition (CVD), plasma gas phase deposition or electric plating method preparation.When the material of reference electrode is Ag, be, by oxidation, Ag is transformed into Ag/AgCl.Such as, in HCl, become Ag/AgCl by constant current oxidation Ag.
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, the film eliminating interference, the film of diffusion control or the film of bio-compatibility on thin film bio sensor.
In one embodiment, can containing for the glucoseoxidase of blood sugar test or glucose dehydrogenase in sensitive membrane, or for the Lactate Oxidase of lactate detection or lactic acid dehydrogenase, bovine serum albumin, perfluorinated sulfonic acid, cellulose; Or comprise medium, such as, for the dimethyl ferrocene of blood sugar test.Be preferably fixing glucose oxidase on the working electrode (s, make the thin film bio sensor detecting blood glucose.
In one embodiment, the film eliminating interference can be cellulose, perfluorinated sulfonic acid, Merlon, polyurethane or electropolymerization phenylenediamine.
In one embodiment, the film that diffusion controls can be perfluorinated sulfonic acid, Merlon, polyurethane or politef.
In one embodiment, the film of bio-compatibility can be perfluorinated sulfonic acid, Merlon, polyurethane, politef, Polyethylene Glycol, poly(ethylene oxide) or heparin.
In one embodiment, perfluorinated sulfonic acid, Merlon, polyurethane or politef can have multi-functional.
In one embodiment, desired position can be placed on accurately with the coating solution that certain volume to be such as less than 1ul by temperature sensitive formula allotter and region needed for covering, such as, only cover the surface of working electrode, form very thin film; Or the enzyme such as GOx needed for the insertion of electricity consumption polymerization; Or other film of non-sensitive film is fixed with 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, such as, be less than 350um.Double faced adhesive tape is processed figuratum perforate, allows 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.Such as, sensing chamber/sensor, communication port can not be blocked by glue; Further, sensing chamber/sensor, communication port location are placed; In addition, can be added other arrange on flow-through microfluid biochip and biofilm sensor, help location assembling.During assembling, between flow-through microfluid biochip 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 that circulation type micro-fluid chip sets.Biofilm sensor is accurately covered on circulation type micro-fluid chip by design; Such as, allow sensing chamber/sensor, communication port locate and place, can be added other at flow-through microfluid biochip and biofilm sensor and arrange, help location assembling.During assembling, pressurization, UV illumination curing UV glue, fixing.
In one embodiment, in assembling circulation type micro-fluid chip and biofilm sensor, use ultrasonic bonding or laser weld, the one side that the method is comparatively suitable at least welding is plastics.Accurately will cover on circulation type micro-fluid chip by design with biofilm sensor.Such as, allow sensing chamber/sensor, communication port locate and place, can be added other at biochip and biosensor and arrange, help location assembling.During assembling, pressurization, applies the ultrasonic frequency be applicable to, fixing.
In one embodiment, the area of micro-fluid pump is less than 5cm
2, be highly less than 10mm, small size, its other component integration that is easy and monitoring system be integrated; This pump dead volume is very little, easily upgrades the body fluid gathered fast.In conjunction with the microfluid flow control circuit of biochip, coutroi velocity, allow body fluid flow through system by suitable flow velocity, such as, flow velocity is less than 10ul/min, and the body fluid gathered in one day 24 hours is less than 14.4ml.In addition, control micro-fluid pump, make the body fluid of collection according to concrete application requirement, flow through the biosensor embedding biochip continuously or off and on, to reach the body fluid to different time points, in mapping time point determining body fluid, analyze the signal of thing, finally reflected the time dependent curve of analyte concentration in real time.Micro-fluid pump can between bodily fluid sampling device and biochip, or immediately preceding after biochip.
In one embodiment, liquid waste collector area is less than 5cm
2, be highly less than 10mm; Include superhigh hydroscopicity material, reduce volume required, such as 5cm
2liquid waste collector can absorb the water of about 27ml or more.Detection calibration room can directly be fixed in subsystem next to the skin; Or can just induce one detection calibration room, the volume of subsystem next to the skin can be reduced like this when calibrating as required.When without the need to calibrating, the switch of liquid waste collector is opened, and the switch of detection calibration room is cut out simultaneously.According to alignment time or the real needs of setting, open the switch of detection calibration room, close the switch of liquid waste collector simultaneously, make the body fluid of collection flow into detection calibration room; After having calibrated, the switch opening liquid waste collector immediately cuts out the switch of detection calibration room simultaneously, when therefore calibrating, without the need to other sampling, achieves painless calibration.When calibrating, there are manual calibration and automatic calibration two kinds of modes, when manual calibration, manually import the detector bar such as blood sugar test paper bar of palpus calibration analyte thing; When automatic calibration, automatically import the detector bar of palpus calibration analyte thing.Such as, when manual calibration, use the conduit being less than 0.5mm diameter, body fluid can be dripped to the check point of blood sugar test paper bar; When automatic calibration, the test strips assembly of BayerBREEZE2 blood sugar test box class can be used.Detection calibration room can between bodily fluid sampling device and biochip, or with liquid waste collector concurrently immediately preceding after micro-fluid pump.
In one embodiment, close-fitting type electronics controls sensor and micro-fluid pump and processes, and transfers signals to Worn type electronics by wireless transmission.Close-fitting type electronics can be battery-powered, and with contact skin part, reply skin is non-stimulated, meet medical standard, and is easy to placement next to the skin.
In one embodiment, compact wearing type electronics carries out signal processing and storage, and wireless or wire transmission signal is to date processing and transmission terminal equipment.Calibration value can be inputted, the concentration of the physiologic result such as blood glucose of display analysis thing in compact wearing type electronics; Predict and the variation tendency of display analysis thing, direction and speed, exceed the warning of setting threshold range; Can be battery-powered.
Use miniature bodily fluid sampling device in the present invention, single needle or spininess penetrate in skin with finger strength by it, from health, extract the body fluid of appropriate amount with proper flow rates, in conjunction with Micropump for analyzing the continuous monitoring of thing in body fluid, the blood glucose be particularly suitable in body fluid is monitored continuously.Bodily fluid sampling device compact conformation of the present invention, easily to use; Bodily fluid sampling device of the present invention uses at atmosheric pressure, and during sampling, on the one hand little, the reliable results of dead volume and accurately, time delay is very short on the other hand, may be used for continuous monitoring, and after sampling does not need the body fluid of extraction to send back in health.
In micro-biochip of the present invention, the size that sensing chamber is different and geometry, position and layout, may be used for the thin film bio sensor embedding various sizes and geometry in parallel or in series; The size that sensing chamber is different and geometry guarantee that the total surface of the biosensor embedded is and the bioresorbable flowed through.The thin film bio sensor being embedded in sensing chamber in microbe chip continuously/intermittently can monitor single in body fluid or multiple analytes simultaneously.
The various geometry of circulation type micro-fluid chip of the present invention and surface, allow body fluid to circulate in microfluid biochip smoothly and dead volume is minimum, bubble-free.The various sizes of microfluidic circuitry and geometry, permission system takes not commensurability body fluid with different speed, adjusts to suitable speed, takes a large amount of body fluid and the breakneck situation of being sent back to by the body fluid taked in body with regard to avoiding.
Circulation type micro-fluid chip of the present invention is of different sizes the entrance and exit passage with geometry, for connecting the device such as sampler and miniflow pump that are connected with micro-biochip, and makes the dead volume of connection minimum.The cumulative volume of circulation type micro-fluid chip of the present invention is very little, such as, is less than 15 microlitres, allows within the short time like this, such as, is less than 15 minutes, with slow speed that is continuous or interval, upgrades all fluids in micro-biochip.Can ensure like this, every a few minutes, measurement data is each time all derive from the detect analytes in the fresh body fluid taked, instead of this analysis thing 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, and the more enzyme of load and protein can be allowed at biosensor surface, produces the more stable biosensor had compared with large-signal.Circular working electrode surface, can more accurately and be fixed on rete in the limited range of electrode surface easily.To work electrode material with peroxide catalyst such as rhodium, detection signal density can be increased and reduce operating potential, reduce/eliminate the uric acid, acetaminophen, ascorbic acid etc. that coexist in body fluid for the interference detected.Use unleachable oxidation catalyst such as rhodium, make the mensuration of hydrogen peroxide, the hydrogen peroxide that such as blood glucose, lactic acid produce through respective oxidase effect, 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 multilamellar, interference can be down to minimum, extend the dynamic range detected, and improves service life and the biocompatibility of biosensor, be suitable for the material of monitoring continuously in body fluid.
Micro-biochip of the present invention is external biological sensor, decreases the problem of sensor anoxia on the one hand, expands sensor responding range; On the other hand, without the response to implanted sensor in body, considerably reduce the problem of sensor performance decay and signal drift, therefore only need less calibration point.
Figure of description
In order to be illustrated more clearly in the technical scheme in the embodiment of the present application, be briefly described to the accompanying drawing used required in embodiment below, apparently, the accompanying drawing that the following describes is only some embodiments recorded in the application, those of ordinary skill in the art are come, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to these accompanying drawings.
Fig. 1 is the portable monitoring systematic schematic diagram analyzing thing in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid;
Fig. 2 is that the monitoring system subsystem parts next to the skin analyzing thing in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid decompose and launch schematic diagram;
Fig. 3 is the monitoring system subsystem assembling parts next to the skin schematic diagram analyzing thing in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid;
Fig. 4 is the monitoring system sensor signal calibration schematic diagram analyzing thing in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid;
Fig. 5 is the split and assembling structural representation of the miniature bodily fluid sampling device of single micropin;
Fig. 6 is the sectional view of split and assembling structural representation along A-A and B-B line of the miniature bodily fluid sampling device of single micropin;
Fig. 7 is the split and assembling structural representation of the miniature bodily fluid sampling device of many micropins;
Fig. 8 is the sectional view of split and assembling structural representation along C-C line of the miniature bodily fluid sampling device of many micropins;
Fig. 9 is the circulation type micro-fluid chip schematic diagram of single sensing chamber;
Figure 10 is the circulation type micro-fluid chip schematic diagram of multiple sensing chamber;
Figure 11 is the electrode group of single-sensor and launches schematic diagram;
Figure 12 is the electrode group of multiple sensor and launches schematic diagram;
The biochip assembling of Figure 13 Shi Dan sensing chamber and single-sensor and expansion schematic diagram;
The biochip assembling of Figure 14 Shi Duo sensing chamber and multisensor and expansion schematic diagram.
Detailed description of the invention
Technical scheme in the application is understood better in order to make art technology art, 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 some embodiments of the present application, instead of whole embodiments.Based on the embodiment in the application, those of ordinary skill in the art are not making other embodiments all obtained under creative work prerequisite, all should belong to the scope of the application's protection.
The portable monitoring system of thing is analyzed in the dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid of embodiment one
1. portable monitoring system
See Fig. 1-3, the portable monitoring system of thing is analyzed for monitoring the various analysis things in body fluid continuously, such as, in blood glucose, lactic acid, sodium ion, calcium ion, magnesium ion, chloride ion, bicarbonate ion and body fluid various protein etc. in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid.It is made up of subsystem 31 next to the skin, compact wearing type electronics 32 and date processing and transmission terminal equipment 33, and date processing and transmission terminal equipment 33 can be mobile phone, computer or other electronic equipment etc.
When the micropin of subsystem 31 next to the skin is placed in skin 15, start after close-fitting type electronics 11 controls micro-fluid pump 8 and thin film bio sensor 4, this monitoring system is started working collection data.After collecting the real time data of analysans, in real time the data wireless of collection is transferred to the physiologic result that compact wearing type electronics 32 carries out the storage of data, analyzing and processing, display analysis thing, the physiologic result analyzing thing can be such as concentration and the variation tendency of blood glucose, and reports to the police to patient to the result exceeding setting threshold range.Then can by result wireless or by line 16 wire transmission to date processing and transmission terminal equipment 33, carry out the longer-term storage of data, the analyzing and processing of result and display.Relevant data and result also can upload in online individual's " cloud " by the Internet by date processing and transmission terminal equipment 33, share such as doctor, family members, bosom friend with the donor of patient, convenient, many-sided, long-term personal health information is provided, is convenient to diagnosis, treatment, disease tracking and management.
2. subsystem next to the skin
See Fig. 2-3, subsystem 31 next to the skin comprises: bodily fluid sampling device micropin holder 1 and fixing micropin 101 and micropin is fixing pastes scholar 2, circulation type micro-fluid chip 3 and thin film bio sensor 4, microtubular 7, micro-fluid pump 8, dichotomous microtubular 9, liquid waste collector 10, the switch 12 of close-fitting type electronics 11 and dichotomous microtubular 9.
When designing and select the parts of subsystem 31 next to the skin, guarantee that the fluid issuing microtubular 103 of micropin holder 1 mates with the fluid intake 301 of microfluid biochip is seamless; The fluid issuing 307 of circulation type micro-fluid chip 3 aligns with the fluid issuing 410 of thin film bio sensor 4, is assembled into biochip 6; The fluid intake 701 of microtubular 7 mates with the fluid issuing 410 of thin film bio sensor 4 is seamless, and the fluid issuing 702 of microtubular 7 mates with the fluid intake 801 of micro-fluid pump 8 is seamless simultaneously; The fluid intake 901 of dichotomous microtubular 9 mates with the fluid issuing 802 of micro-fluid pump 8 is seamless, and the fluid issuing 903 of dichotomous microtubular 9 mates with the fluid intake of liquid waste collector 10 is seamless simultaneously.When assembling subsystem 31 next to the skin, by microtubular fluid issuing 103 and fluid intake 301, fluid issuing 410 and fluid intake 701, fluid issuing 702 and fluid intake 801, fluid issuing 802 and fluid intake 901, the fluid intake of fluid issuing 903 and liquid waste collector 10; Respectively often pair of outlet of mating and entrance are fixed together with glue, ensure that all connection places connect dead volume minimum.The various piece of subsystem 31 is interconnected through successively, forms a complete fluid passage.
When using this monitoring system, first micropin fixing subsides scholar 2 is attached to skin sampling position 15, projecting plug 102 is put into recessed socket 202, and ensure that stretching out micropin 101 aims at the hole place of fixing subsides scholar 2, then with finger strength pressing holder 1, micropin 101 puncture that promotion is fixed enters in skin, and retains in skin, is fixed by the micropin be attached on skin fixing subsides scholar 2.The casting lug thereon 409 of the instrument socket of biochip 6 is inserted the sensor interface 1101 of close-fitting type electronics 11, the casting lug thereon 803 of the instrument socket of micro-fluid pump 8 inserts the miniflow pump interface 1102 of close-fitting type electronics 11, and close-fitting type electronics 11 just can control micro-fluid pump 8 and thin film bio sensor 4.
Start close-fitting type electronics 11, drive micro-fluid pump 8 and thin film bio sensor 4, body fluid will extract, continuously or discontinuously by fluid issuing 103 from the micropin 101 implanted, fluid intake 301, flow through biochip 6 and contact with the electrode group in the thin film bio sensor 4 embedded, producing the detection signal of test analyte, then by fluid issuing 307,410, flow through microtubular 7, micro-fluid pump 8, dichotomous microtubular 9, enters liquid waste collector 10.Within most time, the i.e. non-sensor signal calibration period, switch 12 closes the passage that body fluid enters the fluid issuing 902 of dropper shape, and body fluid finally all can enter the liquid waste collector 10 containing superhigh hydroscopicity material, greatly to reduce the volume of liquid waste collector 10.
This subsystem 31 next to the skin can be used for the test analyte of monitoring continuously in body fluid, after collecting the real time data of test analyte, in real time the data wireless of collection is transferred to compact wearing type electronics 32 and carries out the storage of data, analyzing and processing, display.
3. portable monitoring system calibration
See Fig. 4, detection calibration room is parallel with liquid waste collector 10, containing the disposable test strip 13 of palpus calibration analyte thing and the portable apparatus 14 of test analyte.When carrying out sensor signal calibration, first by disposable must the test strip 13 of calibration analyte thing as the appliance outlet end 1302 of blood sugar test paper bar, insert the socket 1401 of portable apparatus 14 as selftest blood glucose meter of this test analyte; The sample window 1301 of test strip 13 is just in time placed in the below of the fluid issuing 902 of dropper shape, so that the body fluid of effluent fluid outlet 902 just in time drops in sample window 1301; Open portable apparatus 14, switch 12 cuts out body fluid and enters fluid passage 903, can not enter liquid waste collector 10, allows body fluid flow drop in sample window 1301 through the fluid issuing 902 of dropper shape, samples, and detects reading.Read this analysis thing real time readouts of portable apparatus 14, this reading is inputted immediately in compact wearing type electronics 32, carry out the live signal calibration of sensor.After having calibrated, open the passage 903 of liquid waste collector immediately, close fluid issuing 902 switch that body fluid enters dropper shape simultaneously, allow the body fluid gathered enter liquid waste collector 10; Such calibration steps samples in addition without the need to piercing through skin, accomplishes painless calibration.
The miniature bodily fluid sampling device of embodiment two micropin
1. the miniature bodily fluid sampling device of single micropin
See Fig. 5 and Fig. 6, bodily fluid sampling device comprises three primary clusterings: micropin 101, micropin holder 1, and micropin fixing subsides scholar 2.Micropin 101 has passage in micropin body, and this passage has the hole that outlet 103 can be communicated with body fluid.
Micropin holder 1 comprises following four parts: the projecting plug 102 in bottom with hole, at the fluid issuing 103 of side, and the fluid passage 104 in micropin holder 1, and micropin retainer body 105.Projecting plug 102 be positioned at micropin holder 1 bottom and in the base apertures of projecting plug 102 for holding single micropin 101.Micropin 101 is fixed in the base apertures of projecting plug 102 hermetically, and stretches out projecting plug 102 with length-specific, and the length of stretching out projecting plug 102 is less than 10mm usually, is preferably less than 5mm, and is more preferably less than 3mm.Fluid passage 104 connects micropin 101 and outlet 103.
Micropin fixing subsides scholar 2 comprises following four parts: the hole 201 in recessed socket 202, the recessed socket 202 pasted in the middle of scholar's main body 204 is fixed at micropin, flange 203 around recessed socket 202, and the adhesive of medical 205 bottom being attached to flange 203 with liner.Both hole 201 and recessed socket 202 respectively with micropin 101 and projecting plug 102 in position, size and geometrically accurately mating.
When body fluid samples, with ethanol cleaning skin sampling point, peel off the liner of adhesive of medical 205, flange 203 is attached to skin sampling position; Projecting plug 102 is put into recessed socket 202, and ensure that stretching out micropin 101 aims at hole 201 place, then by finger strength pressing retainer body 105, promoting fixing micropin 101 passing hole 201 puncture enters in skin, and retain in skin, fixed by the micropin be attached on skin fixing subsides scholar 2.Thrust the degree of depth of skin by the cut to lengthen stretching out micropin 101, and projecting plug 102 limits penetration depth to ensure safety, no matter the technical ability of user how.Different body fluid can be sampled by penetrating the degree of depth different in skin, such as, can sample the mixture of tissue fluid, blood or tissue fluid and blood.
According to application-specific needs, fluid issuing 103 can be connected directly to Micropump, or first such as, by other device, biochip, is then connected to Micropump.When running the Micropump connected, body fluid extracts continuously or discontinuously from implantation micropin 101, flowing through fluid passage 104 and flows out outlet 103, entering into checkout gear such as, for monitoring the analysis thing of body fluid continuously, the blood glucose in body fluid, lactic acid etc.
When needs are removed, with finger, whole micropin holder 1 and micropin fixing subsides scholar 2 are taken away from skin, then it is abandoned safely.
2. the miniature bodily fluid sampling device of micropin more than
See Fig. 7 and Fig. 8, the main distinction between single micropin miniature bodily fluid sampling device and many micropins miniature bodily fluid sampling device is: in the bottom of multiple hole of the bottom of micropin holder 1 protrusions plug 102 and multiple micropin 101 locking-type plug 102 hermetically.Meanwhile, fixing subsides scholar 2 be recessed socket 202 and multiple hole 201 respectively with projecting plug 102 and multiple micropin 101 in position, size and geometrically accurately mating.In micropin holder 1, other path 10 6 enters into a path for multiple fluid flow path of assembling from multiple micropin, is connected to fluid passage 104 and outlet 103.
When being put in recessed socket 202 by projecting plug 102, guarantee that the multiple micropins 101 stretched out accurately aim at their respective aperture 201 when promoting projecting plug 102 and entering into recessed socket 202.
Other structure, the operation of many micropins miniature bodily fluid sampling device are substantially identical with single micropin miniature bodily fluid sampling device with mode of operation, repeatedly do not illustrate here.
Embodiment three micro-biochip
1. there is the micro-biochip of single sensing chamber and single-sensor
See Fig. 9,11 and 14, there is the biochip 6 of single sensing chamber and single-sensor for monitoring the various analysis things in body fluid continuously, such as, in blood glucose, lactic acid, sodium ion, calcium ion, magnesium ion, chloride ion, bicarbonate ion and body fluid various protein etc. etc.It is assembled by circulation type micro-fluid chip 3 and thin film bio sensor 4.It may be used for the single analysans in continuous detecting body fluid.
1.1 circulation type micro-fluid chips
See Fig. 9, the microfluidic circuitry 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 issuing 307.The various piece of circulation type micro-fluid chip 3 is interconnected through successively, forms a complete fluid passage.Above-mentioned various piece all embeds microfluid biochip main body 3.
Above-mentioned various piece needs can be of different sizes and shape according to difference, and the size of the different sizes of micropore 302 is for regulating back pressure in the flow resistance of microfluid and vitro system or resistance; The different length of serpentine channel 303 and curvature are for regulating back pressure in the flow resistance of microfluid and vitro system or resistance; The size that sensing chamber 310 is different and geometry, position and layout, match with the thin film bio sensor placing the various sizes and geometry that embed sensing chamber 310.
1.2 thin film bio sensors
See Figure 11, thin film bio sensor is made up of following components usually: circular working electrode 401, around the endless belt type of working electrode 401 to electrode 405, reference electrode 406, the contact pad 408 that multiple electrode is connected with instrument, the line 407 of many multiple electrodes of connection and multiple contact pad, for the casting lug thereon 409 of inserting instrument socket, connect the through hole 410 of body fluid, the insulating barrier 420 of electrode, and the insulating layer pattern perforate 421 of mating with multiple electrode.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, reference electrode 406 are mated, and guarantee embed working electrode 401, to electrode 405, reference electrode 406 mate total surface be and the bioresorbable flowed through guarantee the various materials of monitoring continuously in body fluid.The various geometry of the various piece of the microfluidic circuitry of microfluid biochip 3 and surface, also must allow body fluid to circulate in microfluid biochip 3 smoothly and dead volume is minimum, bubble-free.The various sizes of microfluidic circuitry and geometry, in conjunction with miniflow pump, make system with the not commensurability body fluid of different speed collections; Adjust to suitable speed, can be avoided and take a large amount of body fluid, therefore do not need the body fluid taked to send back in body, avoid 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 the working electrode (s, make multiple different biosensor.Such as, fixing glucose oxidase on Rh electrode, can be made into the biosensor detecting blood glucose; Electrode is fixed various ion selective membrane, the ion electrode detecting body fluid intermediate ion concentration can be made; Electrode is fixed various antibody, the electrode detecting various protein concentration in body fluid can be made.By controlling the thickness of fixing film, making thin film bio sensor 4, then can be assembled into biochip 6 with circulation type micro-fluid chip 3, for monitoring the analysis thing in body fluid continuously.
1.3. biochip is assembled
See Figure 13, the circulation type micro-fluid chip 3 being carved with fluid passage is alignd by design with the thin film bio sensor 4 securing required film, and adjusts 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 that fluid bore 307,501,410 is alignd, perforate 502 simultaneously is just in time positioned at above sensing chamber 310.Then pressurization is fixing, obtains the biochip 6 assembled.
Select with fluid intake 301 with export 307 passages at size and the suitable microtubular that geometrically mates, with glue, the microtubular chosen is separately fixed in entrance 301 and outlet 307, then be connected with the bodily fluid sampling device of monitoring continuously in the analytical system of material in body fluid and miniflow pump, and make the dead volume of interface channel minimum.When biochip is by fluid intake 301 and bodily fluid sampling device, after being connected with miniflow pump by fluid issuing 307, start miniflow pump, body fluid will flow through microfluid biochip 3 through bodily fluid sampling device by fluid intake 301, micropore 302, serpentine channel 303, sensing chamber 310, microchannel 306 and fluid issuing 307 in body, flow through miniflow pump, enter liquid waste collector; In sensing chamber 310 body fluid with the working electrode 401 in thin film bio sensor, contact electrode 405, reference electrode 406.
2. there is the biochip of many sensing chamber and multisensor
See Figure 10,12 and 14, there is the biochip 6 of many sensing chamber and multisensor for monitoring the various analysis things in body fluid continuously, such as, in blood glucose, lactic acid, sodium ion, calcium ion, magnesium ion, chloride ion, bicarbonate ion and body fluid various protein etc. etc.It is assembled by circulation type micro-fluid chip 3 and thin film bio sensor 4.It may be used for the multiple analysans simultaneously detected continuously in body fluid.
2.1 circulation type micro-fluid chips
See Figure 10, the microfluidic circuitry 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 issuing 307.Various piece connects through successively.Form a complete fluid passage.Above-mentioned various piece all embeds microfluid biochip main body 3.
2.2 thin film bio sensors
See Figure 12, thin film bio sensor 4 is normally made up of following components: 4 circular working electrodes 401,402,403,404, to electrode 405, reference electrode 406, the contact pad 408 that multiple electrode is connected with instrument, the line 407 of many multiple electrodes of connection and multiple contact pad, for the casting lug thereon 409 of inserting instrument socket, connect the through hole 410 of body fluid, the insulating barrier 420 of electrode, and the insulating layer pattern perforate 421 of mating with multiple electrode.Above-mentioned various piece is all carried in main body 4.
There is the biochip of many sensing chamber and multisensor and there is the micro-biochip difference of single sensing chamber and single-sensor: You Liangge sensing chamber 310,311; The thin film bio working electrode group 401-406 matched comprises 4 working electrodes 401,402,403 and 404, and wherein working electrode 401,402 corresponds to sensing chamber 310, and working electrode 403,404 corresponds to sensing chamber 311.Body fluid is divided inflow sensing chamber 310 and 311 by 2 microchannels 304; Point body fluid of inflow sensing chamber 310 and 311 merges together by 2 microchannels 305.
These 4 different working electrodes can be prepared 4 different biological working electrodes, such as blood glucose, lactic acid, oxygen, pH value biosensor.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, successively can monitor 4 kinds of different analysis things simultaneously.And the sensor parallel of interference mutually may be had to be placed in different sensing chamber, avoid interference.
2.3 assembling biochips
See Figure 14, the circulation type micro-fluid chip 3 carved and the thin film bio sensor 4 securing required film are alignd by design, and adjusts 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 is alignd 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 assembled.
Select with fluid intake 301 and export 307 passages at size and the applicable microtubular that geometrically mates, with glue, the microtubular chosen is separately fixed in entrance 301 and outlet 307, then be connected the continuously analysis system of monitoring in body fluid unite in bodily fluid sampling device and miniflow pump, and make the dead volume of interface channel minimum.When biochip is by fluid intake 301 and bodily fluid sampling device, and after fluid issuing 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 sensing chamber 310 and 311, contact with thin film bio working electrode 401-406 in sensing chamber; Then collect into microchannel 305, microchannel 306, and through fluid issuing 307, flow through miniflow pump, enter liquid waste collector.
Above implementations show 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 detecting more material in body fluid.
Should be understood that the present invention of disclosure is not limited only to specific method, scheme and the material described, because these equal alterable.Will also be understood that terminology used here is only used to describe the object of specific embodiment scheme, instead of 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 specific embodiment of the present invention described in this article.These equivalents also should comprise in the appended claims.
Claims (23)
1. analyze a portable monitoring system for thing in dynamic METHOD FOR CONTINUOUS DETERMINATION body fluid, it comprises:
(1). subsystem next to the skin, described subsystem next to the skin comprise by microtubular be interconnected successively through, composition a complete fluid passage following various piece:
1.1 micropin bodily fluid sampling devices, it is made up of micropin, micropin holder and micropin fixing subsides scholar; When sampling, pressing micropin holder with finger strength, promoting fixing micropin and thrusting in skin, and retain in skin, fixed by the micropin be attached on skin fixing subsides scholar; Thrust micropin in skin, can continuous drawing body fluid;
1.2 microfluid biochips, it is assembled by circulation type micro-fluid chip and thin film bio sensor;
1.2.1 circulation type micro-fluid chip comprises: fluid intake, micropore, serpentine channel, sensing chamber, microchannel, and fluid issuing; Various piece is interconnected through successively, forms a complete fluid passage;
1.2.2 thin film bio sensor comprises: working electrode, to electrode, reference electrode, for the contact pad that outer to each electrode and microchip instrument is connected, connect the line of each 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 each electrode;
With the form of series connection or the form of parallel connection or the form of series and parallel connections in sensing chamber, embed one or more thin film bio sensors, make the total surface of the thin film bio sensor embedded to be and the bioresorbable flowed through, the material continuously in monitoring body fluid;
1.3 micro-fluid pumps, micro-fluid pump can between micropin bodily fluid sampling device and microfluid biochip, or immediately preceding after microfluid biochip; Controlled power is provided, the body fluid of absorption is flow through microfluid biochip;
1.4 close-fitting type electronics, by sensor interface and micro-fluid pump interface, are connected with microfluid biochip and micro-fluid pump respectively; When the described close-fitting type electronics of startup, drive micro-fluid pump and thin film bio sensor, body fluid will extract continuously or discontinuously from the micropin implanted, and flows through circulation type micro-fluid chip and contacts with the electrode group in the thin film bio sensor embedded, producing the detection signal of test analyte;
1.5 detection calibration room and liquid waste collectors, wherein detection calibration room is fixedly installed in subsystem next to the skin or joins in subsystem next to the skin when calibrating; When analyzing thing in mensuration body fluid, body fluid enters liquid waste collector, and during calibration, body fluid enters detection calibration room; Detection calibration room between micropin bodily fluid sampling device and microfluid biochip, or with liquid waste collector concurrently immediately preceding after micro-fluid pump;
(2). compact wearing type electronics and/or date processing and transmission terminal equipment, described compact wearing type electronics or described date processing and transmission terminal equipment are directly in real time, wireless transmission ground receives detection or the calibrating signal of the test analyte that subsystem next to the skin produces, and then carry out the physiologic result of the storage of data, analyzing and processing and display analysis thing; Or described date processing and transmission terminal equipment receive the physiologic result of the display analysis thing of described compact wearing type electronics by wireless or wire transmission mode.
2. portable monitoring system according to claim 1, wherein:
Described micropin holder comprises: the projecting plug in bottom with hole, at the fluid issuing of side, and the fluid passage in micropin holder, and micropin retainer body;
Described micropin the fixing scholar of subsides comprise: micropin fixes the recessed socket pasted in scholar's main body, and the hole in recessed socket, at the flange of recessed receptacle periphery, and is attached to the adhesive of medical on flange bottom;
The projecting plug of described micropin holder is positioned at the bottom of micropin holder, and the base apertures of described projecting plug is for holding micropin, and micropin is fixed in the base apertures of projecting plug hermetically, and stretches out projecting plug;
Described micropin has the hole be communicated with body fluid by the fluid issuing of described micropin holder in micropin body;
Described micropin fix paste the hole of scholar and recessed socket respectively with the projecting plug of described micropin and described micropin holder in position, size and geometrically mating.
3. portable monitoring system according to claim 2, the bottom of wherein said micropin holder protrusions plug has multiple hole, multiple described micropins are fixed on the bottom of projecting plug hermetically, described micropin is fixing paste scholar be recessed socket and multiple hole respectively with described projecting plug and multiple micropin in position, size and geometrically mating.
4. portable monitoring system according to claim 2, has the passage entering into a path for multiple fluid flow path of assembling from multiple micropin in wherein said micropin holder.
5. portable monitoring system according to claim 2, wherein said bodily fluid sampling device area is less than 5cm
2, be highly less than 10mm.
6. portable monitoring system according to claim 2, the length that described micropin stretches out projecting plug is less than 10mm.
7. portable monitoring system according to claim 2, the length that wherein said micropin stretches out projecting plug is less than 5mm.
8. portable monitoring system according to claim 2, wherein said micropin to penetrate in body and stays in the body and samples for a long time, only has Wicresoft or almost noinvasive to skin and subcutaneous tissue.
9. portable monitoring system according to claim 2, wherein said micropin is fixed and is pasted the broadside that there is band glue scholar bottom surface, for whole micropin bodily fluid sampling device is fixed on sampling place skin surface, samples for a long time.
10. portable monitoring system according to claim 2, wherein said micropin bodily fluid sampling device is fixed on sampling place skin surface, samples for a long time.
11. portable monitoring systems according to claim 1, wherein between circulation type micro-fluid chip and thin film bio sensor, put into the thin layer double faced adhesive tape had with the pattern perforate of thin film bio sensor matching and assemble; Or shift by method of impressing the liquid glue mated with thin film bio sensor patterns and assemble; Or assemble circulation type micro-fluid chip and thin film bio sensor by the method for ultra-sonic welded or laser weld.
12. portable monitoring systems according to claim 1, wherein microtubular is fixed in fluid intake and fluid issuing, is then connected with the micropin bodily fluid sampling device of monitoring continuously in the analytical system of material in body fluid and micro-fluid pump.
13. portable monitoring systems according to claim 1, wherein circulation type micro-fluid chip comprises plural sensing chamber, has the working electrode matched with sensing chamber quantity in thin film bio sensor.
14. portable monitoring systems according to claim 1, wherein the area of circulation type micro-fluid chip is less than 5cm
2, be highly less than 2mm.
15. portable monitoring systems according to claim 1, wherein in body fluid, material is blood glucose, lactic acid, oxygen, pH value, hematocrit and/or electrolyte.
16. portable monitoring systems according to claim 15, wherein process the circulation type micro-fluid chip for the preparation of measuring blood glucose by the method for laser-induced thermal etching on plastics.
17. portable monitoring systems 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.
18. portable monitoring systems according to claim 1, wherein reference electrode is that size is less than 3mm
2the endless belt around working electrode; The material preparing reference electrode is that Ag is or/and Ag/AgCl.
19. portable monitoring systems according to claim 1 are 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.
20. portable monitoring systems according to claim 1, wherein the cumulative volume of circulation type micro-fluid chip is less than 15 microlitres, being less than in 15 minutes, with slow speed that is continuous or interval, upgrades all fluids in circulation type micro-fluid chip.
21. portable monitoring systems according to claim 1, wherein the electrode of thin film bio sensor uses the biosensor membranes of multilamellar, the material continuously in monitoring body fluid.
22. portable monitoring systems according to claim 1, with in parallel or series system, the dissimilar working electrode of integrated arrangement on same electrode base board, monitors multiple analytes simultaneously continuously.
23. portable monitoring systems according to claim 1, with in parallel or series system, the multiple working electrode of the same type of integrated arrangement on same electrode base board, monitoring is a kind of continuously simultaneously analyzes thing.
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| PCT/CN2014/070413 WO2014108087A1 (en) | 2013-01-09 | 2014-01-09 | Portable monitoring system for dynamically and continuously measuring analyte in body liquid |
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