CN101032403A - Tiny-wound, dynamic and continuous detecting method and system of concentration of sugar in human blood - Google Patents
Tiny-wound, dynamic and continuous detecting method and system of concentration of sugar in human blood Download PDFInfo
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- CN101032403A CN101032403A CN 200610013249 CN200610013249A CN101032403A CN 101032403 A CN101032403 A CN 101032403A CN 200610013249 CN200610013249 CN 200610013249 CN 200610013249 A CN200610013249 A CN 200610013249A CN 101032403 A CN101032403 A CN 101032403A
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Abstract
The present invention proposes method and system for detecting human body blood sugar concentration dynamically and continuously in microtrauma. The detection method includes the first low frequency ultrasonic treatment of skin to increase permeability of skin, the subsequent negative pressure microtraumatic extraction of tissue fluid from skin and conveying the extracted tissue fluid through micro passage to a surface plasma resonance sensor system, measuring the glucose concentration in the tissue fluid through direct measurement of surface plasma resonance refractivity or indirect measurement of protein binding, and final dynamic continuous detection of blood sugar concentration according to the correlativity model between the glucose concentration in blood and the glucose concentration in tissue fluid. The corresponding detection system is also provided. The present invention has excellent clinical application value.
Description
Technical field
The present invention relates to a kind of detection method of human blood glucose concentration, and relate to a kind of human blood glucose concentration detection system that adopts the method, belong to human body physiological parameter detection technique field.
Background technology
Diabetes are common and frequently-occurring diseases of middle-aged and elderly people, raising along with people's living standard, the sickness rate of diabetes also rises day by day, World Health Organization (WHO) is with it and tumor, cardiovascular and cerebrovascular disease is classified worldwide three disaster diseases together as, estimate according to World Health Organization (WHO), at present diabetes patient 1.7 hundred million is arranged approximately in the world and China with regard to nearly diabetes patient 3,000 ten thousand.To be increased to 300,000,000 people by 2025, diabetes are listed in one of Asia top ten killer already, and its popularity degree has surpassed the threat of infectious disease.Active prevention and treatment diabetes are extremely urgent.
What present diabetes detection method mainly relied on is to have wound to measure, promptly need get blood from patient's finger usually, rely on the method for chemistry then, measure the concentration of glucose in the patient blood, there is the wound method in the blood sugar test process, to need consumable goods, each when being carried out blood sugar test, patient all can bring to a certain degree injury to patient, bring misery and the danger of infection is arranged to them, and the shortcoming of this method maximum is exactly the detection of dynamic that can not realize for human blood glucose concentration, the real-time change situation that can't reflect blood sugar concentration in the patient body, do not reach the effect of good auxiliary information, refer to that such as regular getting the hypoglycemia that blood test often can not detect all hypoglycemia incidents and hyperglycemia incident, particularly night does not often detect.According to these problems that the wound blood sugar test is arranged, we have proposed the method for using Wicresoft to detect, to monitoring of the blood sugar concentration dynamic real-time of human body.
Can dynamically real-time monitoring blood sugar level will be the great development in treating diabetes field.Because glucose level and blood sugar level in the tissue fluid have high correlation, so this invasive methods of glucose level of measuring in the tissue fluid receives much attention in recent years.Existing commercialization continuous monitor system---Cygnus Gluco Watch and Mini Med CGMS
TMDeng, the blood sugar monitoring of accurate or every day can not be provided, and need get the finger blood test so that pick off is carried out regular demarcation.The use of Gluco Watch is very convenient, but need to rely on the tissue fluid in the reverse ion electro-osmosis method sampling skin, and the unstability of cutaneous permeability and perspire cause the inexactness of sensor reading, and detect with the method for enzyme electrode, need consumptive material in the use.Mini Med CGMS
TMThe accurate sensor reading is provided, but has been not for daily use designs, it is subcutaneous that it needs trained personnel that glucose sensor is implanted, and therefore can't operate and realize domestic easily.
Except above business-like product, people have also studied other a large amount of Wicresofts or noninvasive blood sugar monitoring method.For example less invasive techniques comprises: spile on skin with laser, and extract blood or tissue fluid by this hole; Only cut epidermis with pocket knife, extract a small amount of tissue fluid then; Remove horny layer, then use the vacuum drawn tissue fluid; Puncture horny layer with microneedle array, and extracting interstitial fluid; Utilize reverse ion electric osmosis principle extracting interstitial fluid; Utilize microdialysis method extracting interstitial fluid etc.These methods are owing to device complexity, operating difficulties, infect, be subjected to shortcomings such as the skin surface environmental aspect influences greatly all to fail to realize clinical practice easily always.Atraumatic technique comprises: a series of optical meanss such as near infrared spectroscopy, mid-infrared light spectrometry, Raman spectroscopy and polarimetry.Because shortcomings such as the accuracy of detection finite sum reliability of noinvasive detection method are lower, also fail to realize clinical practice always, still be in conceptual phase.
Summary of the invention
One of purpose of the present invention is to have wound, noinvasive and Wicresoft to detect the defective and the deficiency of prior art at human blood glucose concentration, propose a kind of do not have pain, nothing infection risk and the high method of certainty of measurement, realize the Wicresoft of human blood glucose concentration, dynamic and continuous detecting.Two of purpose of the present invention is based on this detection method, proposes a kind of the have Wicresoft of the human blood glucose concentration of potential applicability in clinical practice, dynamic, continuous detecting system.
Human body blood sugar concentration of the present invention Wicresoft, dynamically, the technical scheme of continuous detecting method is:
(1) utilizes low frequency ultrasound that skin is carried out pretreatment, improve the permeability of skin;
(2) stable negative pressure of vacuum is acted on the skin that supersound process crosses, transdermal extracts tissue liquid fast;
(3) utilize surface plasma resonance refractive index direct measuring method or utilize escherichia coli GBP protein binding indirect measurement method, measure the concentration of glucose in the tissue liquid that extracts;
(4) set up in the tissue fluid forecast model of concentration of glucose dependency in the concentration of glucose and blood.
(5) forecast model set up of concentration of glucose in the tissue liquid of measuring according to step (3) and step (4) obtains human blood glucose concentration.
Human blood glucose concentration of the present invention Wicresoft, dynamically, continuous detecting method, in the low frequency ultrasound effect, measure skin impedance value in real time, and according to measurement feedback control low frequency ultrasound mechanism.
The present invention is by the surface plasma resonance refractive index direct measuring method or utilize escherichia coli GBP protein binding indirect measurement method to measure concentration of glucose in the tissue fluid, and its concrete steps are:
(1) adopts the multichannel elementary errors to divide measuring method, one of them passage is fed background solution, measure simultaneously and difference is eliminated the influence of environmental factors to certainty of measurement by multichannel;
(2) utilize surface plasma resonance refractive index direct measuring method or escherichia coli GBP protein binding measuring method to measure the glucose solution of concentration known, set up corresponding refractive index mathematical model;
(3), and, realize the measurement and the analysis of concentration of glucose in the tissue fluid in conjunction with corresponding refractive index mathematical model by the variations in refractive index after the measurement feeding tissue fluid to be measured.
Among the present invention when adopting surface plasma resonance refractive index GBP protein binding method measure glucose concentration, employed escherichia coli GBP albumen, can adopt following biotechnology synthetic:
(1) escherichia coli GBP protein coding gene mglB is carried out rite-directed mutagenesis, the site of sudden change is included in the separately sudden change and in E149, A213, three site simultaneous mutations of L238 of E149 site;
(2) make up overexpression escherichia coli wild type GBP albumen and the proteic engineering strain of saltant GBP;
(3) engineered strain is fermented shaking on the bottle, make the GBP albumen can high-caliber stably express;
(4) tunning is carried out the proteic separation and purification of GBP, the purity of target protein reaches more than 95%.
The present invention is in setting up tissue fluid in concentration of glucose and the blood in the forecast model process of concentration of glucose dependency, measurement data points with cutaneous permeability before stable and stable after unusual measurement data points remove, and the skin impedance value of utilizing negative pressure of vacuum tissue fluid extracting process to record in real time revises single-point blood glucose forecast model, with further raising precision of prediction.
The present invention in the human blood glucose concentration Wicresoft that proposes, dynamically, on the basis of continuous detecting method, proposed a kind of Wicresoft of human blood glucose concentration, dynamically, continuous detecting system, this system comprises:
(1) low frequency ultrasound blood processor is used to generate low frequency ultrasound and measures skin impedance value;
(2) negative pressure of vacuum tissue fluid extracting device is used for extracting tissue liquid by stable negative pressure of vacuum;
(3) surface plasma resonance glucose concentration measurement device is used to utilize the surface plasma resonance refractive index direct measuring method or utilizes escherichia coli GBP protein binding indirect measurement method, measures the concentration of glucose of tissue liquid;
(4) control circuit, be used to control low frequency ultrasound blood processor, negative pressure of vacuum tissue fluid extracting device and the co-ordination of surface plasma resonance glucose concentration measurement device, and according to the correlation models of glucose sugar concentration in concentration of glucose and the blood in concentration of glucose in the measured tissue fluid and the tissue fluid, prediction human blood glucose concentration.
The Wicresoft of human body blood sugar concentration of the present invention, dynamic, continuous detecting system, low frequency ultrasound blood processor wherein comprise ultrasonic generator 6, low frequency ultrasound probe 7, ultrasonic coupled cavity 3 and skin impedance measurement electrode 8:
(1) ultrasonic generator 6: be used to produce required low frequency ultrasound and drive signal;
(2) the low frequency ultrasound probe 7: be used for producing low-frequency ultrasonic waves under the driving of ultrasonic generator 6;
(3) ultrasonic coupled cavity 3: be used for holding the couplant 9 of ultrasonication process, on described ultrasonic coupled cavity 3, also be provided with the injection channel 4 and the passing away 5 of couplant 9;
(4) the skin impedance measurement electrode 8: be used to measure skin impedance value.
The Wicresoft of human body blood sugar concentration of the present invention, dynamic, continuous detecting system, negative pressure of vacuum tissue fluid extracting device wherein comprises vacuum pump 12, vacuum chamber 11, catcher 13 and microchannel 14:
(1) vacuum pump 12: be used for producing the stable negative pressure of vacuum of tissue fluid extracting process;
(2) vacuum chamber 11: be used to vacuum pump 12 that an enclosed vacuum suction function space is provided;
(3) catcher 13: be used to hold the tissue liquid 15 that extracts;
(4) microchannel 14: be used to connect vacuum pump 12, vacuum chamber 11 and catcher 13.
The Wicresoft of human body blood sugar concentration of the present invention, dynamic, continuous detecting system, surface plasma resonance glucose concentration measurement device wherein comprises syringe pump 17, injector 16, transfer valve 18 and spr sensor 19:
(1) syringe pump 17: be used to control micro liquid with even flow input spr sensor 19;
(2) injector 16: be used to hold and to spr sensor 19 input micro liquids;
(3) transfer valve 18: the switching that is used for a plurality of fluid passages 23,24,25 of measuring process is selected;
(4) surface plasma resonance sensor 19: the concentration of glucose that is used for measuring tissue fluid.
The Wicresoft of human body blood sugar concentration of the present invention, dynamic, continuous detecting system, except comprising above-mentioned parts, also comprise pump, valve and microchannel element, be used to control the fluid transport between described low frequency ultrasound blood processor, negative pressure of vacuum tissue fluid extracting device and the surface plasma resonance glucose concentration measurement device.
Human body blood sugar concentration of the present invention Wicresoft, dynamically, the main feature of continuous detecting method and detection system is embodied in:
1, the present invention has overcome wound at present, noinvasive and Wicresoft's blood sugar detecting method and detection system are brought wound to patient easily and may cause infection, measurement result is unreliable and shortcoming and defect such as complicated operating process, can realize the Wicresoft of human blood glucose concentration, dynamic, continuous detecting, have good potential applicability in clinical practice;
2, the method for the present invention by low frequency ultrasound and the tissue fluid of negative pressure of vacuum transdermal extraction is a kind of Wicresoft, painless and have a technology of big tissue fluid flow.The low frequency ultrasound processing procedure is very short, and can not cause infection, the transparent performance of handling back skin at low frequency ultrasound kept tens hours, just can extract primary structure liquid fast by vacuum pump every 10-20 minute in during this, for blood sugar concentration dynamically, continuous detecting lays a good foundation;
3, the present invention adopts surface plasma resonance technology to measure concentration of glucose in the tissue fluid, advantage such as have that Measurement Resolution and certainty of measurement are very high, measurement result good reliability, required interstitial fluid volume to be measured are very little, do not need consumptive material in the use or only need very a spot of consumptive material and measuring speed is very fast.
Description of drawings
Fig. 1: based on the human blood glucose concentration Wicresoft detection system structured flowchart of low frequency ultrasound and surface plasma resonance;
Fig. 2: low frequency ultrasound sonde configuration design drawing;
Fig. 3: low frequency ultrasound blood processor structure chart;
Fig. 4: negative pressure of vacuum tissue fluid extracting structure drawing of device;
Fig. 5: based on the blood glucose dynamic measurement device structure chart of surface plasma resonance;
Fig. 6: spr sensor gold membrane superficial tissue figure when the protein binding method is surveyed concentration of glucose.
The specific embodiment
The present invention at first adopts low frequency ultrasound that skin is carried out pretreatment, by the double-layer of lipoid structure in the cavitation destruction keratodermatitis of low frequency ultrasound, increase the permeability of skin, use method extracting interstitial fluid from skin is quick of negative pressure of vacuum then, at last the tissue fluid that extracts is transported to the surface plasma resonance measuring system by the microchannel, adopt surface plasma resonance refractive index direct measuring or protein binding indirect measuring technology method, measure the concentration of glucose in the tissue liquid, according to the dependency prediction model of concentration of glucose in concentration of glucose in the tissue fluid and the blood, realize the dynamic of human blood glucose concentration, detect continuously and in real time.Fig. 1 is the structured flowchart of setting up according to this method based on the human blood glucose concentration Wicresoft detection system of low frequency ultrasound and surface plasma resonance.This method and device have overcome the deficiency that wound, noinvasive and Wicresoft's blood sugar detecting method are arranged, concrete good application prospects.Below according to each accompanying drawing and implementation process to the Wicresoft of human body blood sugar concentration of the present invention, dynamically, continuous detecting method, detection system and experimental procedure be described further:
One, based on tissue liquid abstracting method, device and the step of low frequency ultrasound and negative pressure of vacuum:
The present invention is by the double-layer of lipoid structure in the cavitation destruction keratodermatitis of low frequency ultrasound, thereby the permeability of increase skin is for the negative pressure of vacuum extraction of follow-up tissue fluid provides good condition, and adopting the negative pressure of vacuum technology during tissue fluid extracting mainly is in order further to improve the extraction speed of tissue fluid.
The low frequency ultrasound probe 7, low frequency ultrasound blood processor and the negative pressure of vacuum tissue fluid extracting device that design among the present invention are respectively as Fig. 2, Fig. 3 and shown in Figure 4.Low frequency ultrasound among the present invention probe 7 is made up of sandwich piezoelectric ceramic ultrasonic transducer 1 and horn 2 two parts, as shown in Figure 2, in the design we also on shell integrated the injection channel 4 of coupling liquid, passing away 5 and ultrasonic coupled cavity 3 (being fixed on ultrasonic probe shown in Figure 27 bottom) etc. by screw thread, realized integrated and miniaturization.The low frequency ultrasound blood processor design of Fig. 3 is integrated together low frequency ultrasound probe 7 and skin impedance measurement electrode 8 etc., the miniaturization and the portability of apparatus have been realized, the negative pressure of vacuum tissue fluid extracting device of Fig. 4 obtains negative pressure of vacuum by vacuum pump 12, can realize the injection (by the negative pressure of vacuum effect) of phosphate buffer 10 and the extraction of tissue liquid simultaneously, in catcher 13, obtain the mixed liquid 15 of buffer 10 and tissue fluid.
Tissue fluid extracting step based on low frequency ultrasound and negative pressure of vacuum among the present invention comprises:
(1) skin at tissue fluid extracting position is cleaned and sterilize;
(2) inject couplant 9 in ultrasonic coupled cavity 3, the beginning low frequency ultrasound is handled;
(3) when low frequency ultrasound is handled, adopt skin impedance measurement electrode 8 to measure the skin impedance value (skin impedance value has reflected the situation of cutaneous permeability) at supersound process position, after skin impedance value reaches setting value, stop low frequency ultrasound and handle, and remove the low frequency ultrasound blood processor;
(4) fixing vacuum chamber 11 on the pretreated skin of low frequency ultrasound injects phosphate buffer 10 in vacuum chamber 11, connect and open vacuum pump 12, and control produces stable negative pressure of vacuum and carries out tissue fluid extracting;
(5) adopt microchannel 14 to collect the mixed liquor 15 of vacuum chamber 11 interior buffer 10 and tissue fluid, and be transported to the SPR measuring device, for SPR measuring device measurement concentration of glucose wherein.
Two, based on glucose concentration measurement method, device and the step of surface plasma resonance:
The present invention uses two kinds of methods that the concentration of glucose in the tissue fluid is measured aspect the surface plasma resonance measuring technique, and a kind of is the direct method of measurement, and is a kind of for using escherichia coli GBP albumen binding measuring method.The direct method of measurement is exactly that handle without any modification on the spr sensor surface, utilizes the principle of surface plasma resonance to carry out refractometry to tissue fluid, and the advantage of this method is to measure conveniently, and step is simple, and the sample that needs is few, does not have consumable goods.And the method for using the binding of escherichia coli GBP albumen to measure mainly is to have utilized the specific adsorption ability of this protein for glucose, only the concentration of this material of glucose being measured of exclusiveness, this method is owing to adopted protein with the selective absorption of glucose molecule, effectively strengthened the quality of golden film surface mass, make the better reliability of measurement result, Measurement Resolution and certainty of measurement are higher.
The surface plasma resonance glucose concentration measurement device of the present invention's design partly is made up of micro-injection pump 17, clematis stem road transfer valve 18, microsyringe 16, vacuum Micropump 21, surface plasma resonance sensor 19 etc., as shown in Figure 5.Whole experimental system is applicable to single channel measurement and multichannel difference measurement, provide flow speed stability and flow accurately controlled sample input for system together by micro-injection pump 17 and microsyringe 16, use clematis stem road transfer valve 18 to switch at different sample rooms, also avoid simultaneously importing the interference of the air that may introduce when sample switches, and vacuum Micropump 21 has been positioned in waste liquid pool 20 ends, pressure by in its effect balance whole system of bleeding guarantees that further flow speed stability and pipeline are unobstructed.Whole surface plasma resonance glucose concentration measurement device is by above-mentioned each the functional module coordination of controller 22 controls.Because it is responsive that 19 pairs of air of spr sensor and extraneous veiling glare all compare, so all necessary good seal of whole device each several part, in the pipeline and the air in the sample need be removed in advance, and the measure portion of whole system need be placed in the environment of lucifuge.
The step of two kinds of surface plasma resonance measure glucose concentration is respectively among the present invention:
1, direct measuring method
Measuring process under the lucifuge condition comprises:
(1) human body skin is carried out low frequency ultrasound and handle, the skin after handling from supersound process adopts negative pressure of vacuum technology extracting interstitial fluid, and is transported to the SPR system by the microchannel;
(2) initialization system in air, the background light intensity and the dark current of acquisition spr sensor 19;
(3) in the SPR system, feed deionized water, obtain the stable measuring basis of refractive index (1.333);
(4) wait to feed refractive index curve that deionized water solution obtains and tend towards stability after, feed buffer 10, obtain the background value measured, feed tissue fluid to be measured then;
(5) concentration of coming relative measurement glucose solution by the change value of observation refractive index;
(6) feed deionized water solution once more, excess tissue liquid in the pipeline of removal system.
2, escherichia coli GBP protein binding measuring method
Comprise (tissue fluid is not cushioned under the situation of liquid 10 dilutions) at measuring process under the lucifuge condition:
(1) human body skin is carried out low frequency ultrasound and handle, the skin after handling from supersound process adopts the negative pressure of vacuum technology to extract indirect liquid, and is transported to the SPR system by the microchannel;
(2) initialization system in air, the background light intensity and the dark current of acquisition spr sensor 19;
(3) golden film 27 surfaces to spr sensor 19 activate, and form self assembly molecule layer 28 by Au-S;
(4) on self assembly molecule layer 28 by coupled modes such as amine couplings, with spr sensor 19 gold medal films 27 surfaces of escherichia coli GBP proteinaceous solid after the surface activation process;
(5) feed through tissue fluid to be measured;
(6) computer obtains the signal that CCD collects, and signal is carried out curve fitting, and obtains the corresponding relation between SPR angle and the concentration of glucose;
(7) feed cleaning mixture, the glucose of deproteinising surface adsorption makes protein surface regeneration;
Time about (8) one months, the protein layer approach exhaustion on pick off 19 surfaces is removed the adsorbent on spr sensor 19 surfaces, keeps the cleaning surfaces drying.
Three, the dependency prediction model of concentration of glucose in concentration of glucose and the blood in the tissue liquid
Though concentration of glucose in the tissue fluid and the concentration of glucose in the blood glucose have the dependency of height, but, therefore set up and predict exactly that by the concentration of glucose in the tissue fluid mathematical model of blood sugar concentration is one of committed step of the present invention and key technology as the still blood glucose concentration value of diabetes clinical judgment standard.
The single point correction model of adopt revising among the present invention is predicted blood sugar concentration according to the measured value of concentration of glucose in the tissue fluid: establishing skin to the permeability of glucose is
Wherein Δ t is the vacuum drawn time, V is that (have following problem because directly adopt not adding phosphate buffer in extracting cavity under the situation of negative pressure of vacuum extracting interstitial fluid: the interstitial fluid volume of being extracted out is considerably less, fluid point is not concentrated and foam occurs, and these problems cause the collection of the tissue fluid of extracting out very difficult for the low frequency ultrasound volume of handling the phosphate buffer that injects the back in cavity.), A is that the low frequency ultrasound processing is the skin area of vacuum drawn, CIi (i=1,2,3 ...) be the concentration of the glucose in the mixed liquor of the phosphate buffer that records and tissue fluid, CBi (i=1,2,3 ...) the blood sugar concentration reference value that adopts portable glucose meter to measure during for corresponding each tissue fluid extracting.Calculating K at first during prediction
c=CB
1/ F
1, obtain blood glucose predictive value CB with Fi and Kc then
i'=F
iK
c, calculate blood glucose concentration value and the average relative error of predicting blood glucose concentration value at last, as evaluation means to forecast model.By measuring the variation that the variation of Skin Resistance in negative pressure of vacuum extracting interstitial fluid process comes real-time tracking dermal osmosis coefficient, utilize skin impedance value that the blood glucose forecast model is revised, further improve precision of prediction
Four, the Wicresoft of human blood glucose concentration, dynamic, continuous detecting system
The present invention has proposed corresponding integrated detection system on the basis of proposition based on the human blood glucose concentration Wicresoft detection method of low frequency ultrasound and surface plasma resonance, system structure as shown in Figure 1.By unlatching and the shutoff of controlling each miniature valve, the mobile transmission of all ingredients solution in realizing measuring, move downward by machinery control low frequency ultrasound probe 7 and to enter vacuum chamber 11 near skin surface, under the driving of ultrasonic generator 6 skin being carried out low frequency ultrasound handles, to increase the permeability of skin, move up by machinery control low frequency ultrasound probe 7 then and leave vacuum chamber 11 and set back, bleeding point by the vacuum pump 12 tissue liquid that provides stable negative pressure of vacuum to carry out in the skin extracts afterwards, by the control miniature valve and utilize the pressure impetus of vacuum pump 12 air vents, tissue fluid is transferred to spr sensor 19 detects at last.Control circuit is partly controlled automatically to machinery, miniature valve and spr sensor 19 etc., and comprises collection, processing and the liquid crystal display etc. of test data.Exhausted reagent and useless sample etc. are stored in the waste liquid pool 20, thereby finish automatic successive human blood glucose concentration Wicresoft, dynamically, detect in real time, and this detection system is simple to operate, automaticity is high.
Five, human blood glucose concentration Wicresoft, dynamically, the experimentation of continuous detecting committed step:
Based on the tissue fluid transdermal extraction of low frequency ultrasound and negative pressure of vacuum, to measure concentration of glucose in the tissue fluid and measure concentration of glucose in the tissue fluid based on escherichia coli GBP protein binding method based on the surface plasma resonance refractive index direct measuring method be three committed steps among the present invention, its concrete experimentation is respectively:
1, the experimentation of low frequency ultrasound and negative pressure of vacuum tissue fluid transdermal extraction technology:
In the tissue fluid extracting process, ultrasonic coupled cavity 3 is combined closely with skin, make the unlikely leakage of liquid in the processing procedure.In ultrasonic coupled cavity 3, inject couplant 9 then, couplant 9 is for containing the phosphate buffer 10 of 1% sodium lauryl sulphate, the effect of couplant 9 is the energy attenuation that reduces the ultrasonication process on the one hand, is the surface activity that improves skin by sodium lauryl sulphate on the one hand.Next use 0-30W/cm
2Low frequency ultrasound (20KHz-100KHz) with pulse mode or continuation mode skin is carried out pretreatment, in pretreated impedance of measuring skin simultaneously, when impedance reaches predetermined value, stop preprocessing process.Discharge couplant 9 by the microchannel, injection phosphate buffer 10 flushing skin also dries.Vacuum chamber 11 and skin are combined closely, make the unlikely leakage of gas in the processing procedure, open vacuum pump 12, control stable negative pressure of vacuum extracting interstitial fluid, and tissue fluid is input to surface plasma resonance glucose concentration measurement device by the microchannel.
2, the surface plasma resonance refractive index direct measuring method is measured the experimentation of concentration of glucose in the tissue fluid:
Using SPR directly to measure the method for concentration of glucose in the mixed liquor 15 of tissue fluid and buffer 10, mainly is to come the indirect concentration of extrapolating glucose by the refractive index of measuring solution.Because the amount that tissue fluid extracting goes out is less, need be when extracting tissue fluid by the help of buffer 10 from human body, thereby the artificial overall background that produces tissue fluid is extracted with convenient, in the mixed liquor 15 of tissue fluid and buffer 10, not only contain glucose, the influential material of the refractive index for solution that also contains other simultaneously, refractive index at this solution is the weighted average of the molar concentration of the refractive index of various materials in the solution, when using this method of refractive index of directly measuring mixed liquor 15, need simplify to get rid of in the solution influences less material for refractive index, perhaps gets rid of the metastable material of those content in tissue fluid.Utilize buffer 10 as a comparison solution carry out the refractometry of tissue fluid and buffer 10 mixed liquors 15, this is a kind ofly to compare and measure and relative measurement, by measuring the refractive index of buffer 10, with buffer 10 is benchmark, measure the refractive index of tissue fluid and buffer 10 mixed liquors 15, thereby get rid of the interference of buffer 10, again with the various compositions in the tissue fluid by simplifying or getting rid of, obtain a model of having simplified, model is made up of those materials that can not ignore and simplify in glucose and the tissue fluid, according to of the influence of these materials for refractive index, the final molar concentration of determining glucose, this method goes for the tissue fluid situation that wherein glucose still can be measured after diluted, under the level of our existing system, if in the tissue fluid after diluted the concentration of glucose be not less than 10mg/dl just can be measured.
3, escherichia coli GBP protein binding method is measured the experimentation of concentration of glucose in the tissue fluid:
Experimental provision as shown in Figure 5, wherein first, two, be placed with three kinds of different solution in three fluid passages (23-25) respectively, wherein the solution in the first fluid path 23 is the amine coupling solution that is used for escherichia coli GBP proteinaceous solid is fixed on spr sensor 19 gold medal films 27 surfaces, solution in second fluid passage 24 is escherichia coli GBP protein solution, solution in the 3rd fluid passage 25 is glucose solution to be measured, this solution is that the skin after the ultrasonication extracts by negative pressure of vacuum, first, two, three fluid passages (23-25) feed clematis stem road transfer valve 18 respectively by micro-injection pump 17, because what use is clematis stem road transfer valve 18, so can distinguish as required and feed six kinds of solution successively, clematis stem road transfer valve 18 synchronizations only allow one road solution to feed in the sample cell, form on the surface of surface plasma resonance sensor 19 at last, as the double-decker shown among Fig. 6, wherein 26 is prism, 27 is golden film, 28 is the self assembly molecule layer, 29 is escherichia coli GBP protein, 30 is glucose molecule, measurement is divided into three steps and carries out, at first feed escherichia coli GBP protein, at golden film 27 this kind of surface binding protein 29, feed buffer 10 then, measure the spr signal of buffer 10 this moment, the background signal that obtains measuring.Under the situation that binding protein 29 exists, feed glucose solution again, measure the spr signal of glucose solution, obtain the difference between the spr signal of the spr signal of glucose and buffer 10, draw the corresponding relation of this difference and glucose solution concentration, utilize wavelet transformation to remove noise jamming, utilize the multinomial of high-order that curve is carried out match, obtain the curve of two level and smooth approximate proportional relations.Because temperature has very strong influence for measurement result, so experiment should be carried out under temperature constant state.
The present invention is open and that disclose, and all combinations and method can produce by using for reference this paper disclosure, although combination of the present invention and method are described by detailed implementation process, but those skilled in the art obviously can be spliced method and apparatus as herein described in not breaking away from content of the present invention, spirit and scope or change, or increase and decrease some parts, more particularly, the replacement that all are similar and change apparent to those skilled in the artly, they are regarded as being included among spirit of the present invention, scope and the content.
Claims (10)
- The Wicresoft of a human blood glucose concentration, dynamically, continuous detecting method, it is characterized in that may further comprise the steps:(1) utilizes low frequency ultrasound that skin is carried out pretreatment, improve the permeability of skin;(2) negative pressure of vacuum is acted on the pretreated skin of low frequency ultrasound transdermal extraction tissue liquid;(3) utilize surface plasma resonance (SPR) refractive index direct measuring method or utilize escherichia coli GBP protein binding indirect measurement method, measure the concentration of glucose in the tissue liquid that extracts;(4) set up in the tissue fluid forecast model of concentration of glucose dependency in the concentration of glucose and blood;(5) forecast model set up of concentration of glucose in the tissue liquid of measuring according to step (3) and step (4) obtains human blood glucose concentration.
- The Wicresoft of human blood glucose concentration according to claim 1, dynamically, continuous detecting method, it is characterized in that, in execution in step (1) medium and low frequency ultrasonication, measure skin impedance value in real time, and according to measurement feedback control low frequency ultrasound mechanism.
- 3. human blood glucose concentration according to claim 1 Wicresoft, dynamically, continuous detecting method, it is characterized in that the surface plasma resonance technology that utilizes in the step (3) is measured concentration of glucose in the tissue fluid, concrete steps are:(1) adopts the multichannel elementary errors to divide measuring method, one of them passage is fed background solution, measure simultaneously and difference is eliminated the influence of environmental factors to certainty of measurement by multichannel;(2) utilize surface plasma resonance refractive index direct measuring method or escherichia coli GBP protein binding measuring method to measure the glucose solution of concentration known, set up corresponding refractive index mathematical model;(3), and, realize the measurement and the analysis of concentration of glucose in the tissue fluid in conjunction with corresponding refractive index mathematical model by the variations in refractive index after the measurement feeding tissue fluid to be measured.
- 4. the Wicresoft of human blood glucose concentration according to claim 1, dynamic, continuous detecting method is characterized in that, adopt the proteic concrete steps of using in the biotechnology synthesis step (3) of escherichia coli GBP to be:(1) escherichia coli GBP protein coding gene mglB is carried out rite-directed mutagenesis, the site of sudden change is included in the separately sudden change and in E149, A213, three site simultaneous mutations of L238 of E149 site;(2) make up overexpression escherichia coli wild type GBP albumen and the proteic engineering strain of saltant GBP;(3) engineered strain is fermented shaking on the bottle, make the GBP albumen can high-caliber stably express;(4) tunning is carried out the proteic separation and purification of GBP, the purity of target protein reaches more than 95%.
- The Wicresoft of human blood glucose concentration according to claim 1, dynamically, continuous detecting method, it is characterized in that, in the process of execution in step (4), measurement data points with cutaneous permeability before stable and stable after exceptional data point remove, and the skin impedance value of utilizing negative pressure of vacuum tissue fluid extracting process to record in real time revises single-point blood glucose forecast model, to improve precision of prediction.
- A Wicresoft that adopts the described human blood glucose concentration of claim 1, dynamically, the detection system of continuous detecting method, it is characterized in that described detection system comprises:(1) low frequency ultrasound blood processor is used to generate low frequency ultrasound and measures skin impedance value;(2) negative pressure of vacuum tissue fluid extracting device is used for extracting tissue liquid by negative pressure of vacuum;(3) surface plasma resonance glucose concentration measurement device is used to utilize the surface plasma resonance refractive index direct measuring method or utilizes escherichia coli GBP protein binding indirect measurement method, measures the concentration of glucose of tissue liquid;(4) control circuit, be used to control low frequency ultrasound blood processor, negative pressure of vacuum tissue fluid extracting device and the co-ordination of surface plasma resonance glucose concentration measurement device, and according to the correlation models of glucose sugar concentration in concentration of glucose and the blood in concentration of glucose in the measured tissue fluid and the tissue fluid, prediction human blood glucose concentration.
- 7. detection system according to claim 6 is characterized in that, described low frequency ultrasound blood processor comprises ultrasonic generator (6), low frequency ultrasound probe (7), ultrasonic coupled cavity (3) and skin impedance measurement electrode (8), wherein:(1) ultrasonic generator (6): be used to produce required low frequency ultrasound and drive signal;(2) low frequency ultrasound probe (7): be used under the driving of ultrasonic generator (6), producing low-frequency ultrasonic waves;(3) ultrasonic coupled cavity (3): be used for holding the couplant (9) of ultrasonication process, on described ultrasonic coupled cavity (3), also be provided with the injection channel (4) and the passing away (5) of couplant (9);(4) skin impedance measurement electrode (8): be used to measure skin impedance value.
- 8. detection system according to claim 6 is characterized in that, described negative pressure of vacuum tissue fluid extracting device comprises vacuum pump (12), vacuum chamber (11), catcher (13) and microchannel (14), wherein:(1) vacuum pump (12): be used for producing the stable negative pressure of vacuum of tissue fluid extracting process;(2) vacuum chamber (11): be used to vacuum pump (12) that an enclosed vacuum suction function space is provided;(3) catcher (13): be used to hold the tissue liquid that extracts;(4) microchannel (14): be used to connect vacuum pump (12), vacuum chamber (11) and catcher (13).
- 9. detection system according to claim 6 is characterized in that, described surface plasma resonance glucose concentration measurement device comprises syringe pump (17), injector (16), transfer valve (18) and surface plasma resonance sensor (19), wherein:(1) syringe pump (17): be used to control micro liquid and import spr sensor (19) with even flow;(2) injector (16): be used to hold and to spr sensor (19) input micro liquid;(3) transfer valve (18): the switching that is used for a plurality of fluid passages of measuring process (23-25) is selected;(4) surface plasma resonance sensor (19): the concentration of glucose that is used for measuring tissue fluid.
- 10. detection system according to claim 6, it is characterized in that, also comprise pump, valve and microchannel element, be used to control the fluid transport between described low frequency ultrasound blood processor, negative pressure of vacuum tissue fluid extracting device and the surface plasma resonance glucose concentration measurement device.
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