CN101214152A - Method for micro-wounded dynamically and continuously detecting blood sugar concentration of human body - Google Patents
Method for micro-wounded dynamically and continuously detecting blood sugar concentration of human body Download PDFInfo
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- CN101214152A CN101214152A CNA2008100521342A CN200810052134A CN101214152A CN 101214152 A CN101214152 A CN 101214152A CN A2008100521342 A CNA2008100521342 A CN A2008100521342A CN 200810052134 A CN200810052134 A CN 200810052134A CN 101214152 A CN101214152 A CN 101214152A
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Abstract
A minimally invasive, dynamic and continuous detection method for human blood glucose concentration, including: firstly, using low-frequency ultrasound for the pretreatment on skin; secondly, extracting human tissue fluid from the skin after the low-frequency ultrasound pretreatment under the vacuum negative function; thirdly, detecting the skin impedance/resistance during the permeable skin tissue liquid extraction process; fourthly, measuring the glucose concentration of the extracted human tissue liquid; fifthly, using the skin impedance/resistance to determine the extracted tissue liquid volume and to establish the prediction model of the correlation between the glucose concentration in the tissue liquid and the glucose concentration in blood; sixthly, obtaining the human blood glucose concentration according to the skin impedance/resistance that is measured in the third step, the glucose concentration of the human tissue liquid that is measured in the fourth step and the prediction model that is established in the fifth step. The invention can realize the minimally invasive, dynamic and continuous detection method for the human blood glucose concentration and has the advantages of high measurement resolution and precision, good stability of the measured result, small tissue liquid amount to be measured, rapid measuring speed, etc.
Description
Technical field
The present invention relates to a kind of detection method of human blood glucose concentration.Particularly relate to a kind of Wicresoft of the human blood glucose concentration based on the anti-reflection technology of low frequency ultrasound skin, negative pressure of vacuum extraction technique, Skin Resistance/resistive measurement and surface plasma resonance measuring technique, dynamically, continuous detecting method.
Background technology
Diabetes are common and frequently-occurring diseases of middle-aged and elderly people, and along with the raising of people's living standard, the sickness rate of diabetes also rises day by day, and World Health Organization (WHO) is with it and tumor, and cardiovascular and cerebrovascular disease is classified worldwide three disaster diseases together as.Estimate that according to International Diabetes Federation present global diabetics surpasses 2.4 hundred million, will be increased to 3.5 hundred million to this numeral in 2025; Simultaneously, nearly 4,050 ten thousand according to the total diabetics of the present China of recent statistics, account for about 20% of world patient sum, annual diabetes medical expense reaches 83,300,000,000 yuan.The jumbo growth of the medical expenses that diabetes cause, and bring labour force's massive losses to developing country has been acknowledged as more and more seriously, and is present in the universality public health health problem of whole world All Countries.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, all can be when patient being carried out blood sugar test to patient's generation injury to a certain degree at every turn, bring misery and the danger of infection is arranged to them, and the shortcoming of this method maximum is exactly to realize the detection of dynamic of human blood glucose concentration, the real-time change situation that can't reflect patient's blood sugar concentration, 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.
For realize blood sugar concentration dynamically, continuous detecting, people have attempted several different methods, for example the non-invasive methods of external optical detection, directly measure the implanted method of subcutaneous glucose concentration and the invasive methods that transdermal extraction detects concentration of glucose in the tissue fluid.Because shortcomings such as the accuracy of detection finite sum reliability of non-invasive methods are lower, fail to realize clinical practice always, still be in conceptual phase.The implanted method is not for daily use designs, and it is subcutaneous that it needs trained personnel that glucose sensor is implanted, and therefore can't operate and realize domestic easily.Glucose level and blood sugar level in the tissue fluid have high correlation, and the invasive methods that detects concentration of glucose in the tissue fluid for transdermal extraction provides the detection foundation.In view of invasive methods can alleviate the misery that the patient carries out blood sugar test on the one hand, weaken the danger of infection, can realize dynamic, the continuous detecting of blood sugar concentration on the other hand, invasive methods receives much attention in recent years.
In view of Wicresoft's blood sugar detecting method transdermal extraction tissue fluid sample is subjected to the restriction that skin hangs down permeability, people have proposed the method for multiple raising molecule transdermal transmission, comprise with chemical drugs changing skin texture, utilize the electric field method and utilizing ultrasonic method etc.No matter adopt which kind of method to improve cutaneous permeability, the cutaneous permeability that has increased all can not remain unchanged in the tissue fluid extracting process.The tissue fluid volume that is obtained in certain extraction time by certain abstracting method is determined by cutaneous permeability, and the glucose amount that is contained in the tissue fluid sample is directly related with the volume of tissue fluid sample, this just causes the glucose amount in the tissue fluid sample not only to change with blood sugar concentration, and changes with cutaneous permeability.Existing Wicresoft blood sugar detecting method all is to stablize the blood glucose forecast model of setting up under the constant prerequisite at the hypothesis cutaneous permeability, causes the blood glucose precision of prediction will be subjected to the influence that cutaneous permeability changes.
Though the method for multiple raising cutaneous permeability is arranged at present, but in order to guarantee neither can to cause the damage of irrecoverable property to human body, can realize the Real-time and Dynamic continuous detecting of blood glucose again, so each extraction process obtainable tissue fluid volume all be very little.
Summary of the invention
Technical problem to be solved by this invention is, at the influence of cutaneous permeability variation to the blood glucose precision of prediction, a kind of quantitative tissue fluid volume of extracting out of Skin Resistance/resistance that detects in real time in the tissue fluid extracting process that utilizes is provided, and revise the blood glucose forecast model, improve the Wicresoft of the human blood glucose concentration of precision of prediction, dynamic, continuous detecting method.
Another technical problem to be solved by this invention is, at each extraction process the very little problem of obtainable tissue fluid volume, a kind of employing buffer dilution tissue fluid is provided, utilizes highly sensitive surface plasma resonance protein binding measuring technique to detect the Wicresoft of the human blood glucose concentration of concentration of glucose in the tissue fluid, dynamic, continuous detecting method.
The technical solution adopted in the present invention is: a kind of Wicresoft of human blood glucose concentration, dynamic, continuous detecting method 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) in the process of transdermal extraction tissue fluid, detection of skin impedance/resistance;
(4) utilize surface plasma resonance protein binding measuring method, measure the concentration of glucose that extracts in the tissue liquid;
(5) utilize the quantitative tissue fluid volume of extracting out of Skin Resistance/resistance, set up in the tissue fluid forecast model of concentration of glucose dependency in the concentration of glucose and blood;
(6) Skin Resistance/resistance of measuring according to step (3), the forecast model that concentration of glucose in the tissue liquid that step (4) is measured and step (5) are set up obtains human blood glucose concentration.
Detection of skin impedance/resistance described in the step (3) is to realize by constant voltage excitation, the mode that detects electric current.
Detection of skin impedance/resistance described in the step (3) is to realize by constant current drive, the mode that detects voltage.
Detection of skin impedance/resistance described in the step (3) is to carry out before tissue fluid extracting and afterwards, and the meansigma methods of the Skin Resistance/resistance that measures for twice with front and back is as the pairing Skin Resistance/resistance value of this time tissue fluid extracting process.
Detection of skin impedance/resistance described in the step (3) is the carrying out of constant duration in the tissue fluid extracting process, with the meansigma methods of the Skin Resistance/resistance of all time points in each tissue fluid extracting process as the pairing Skin Resistance/resistance value of this time tissue fluid extracting process.
The surface plasma resonance protein that utilizes described in the step (4) is bound measuring method, measures the concentration of glucose that extracts in the tissue liquid, may further comprise the steps:
(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 escherichia coli GGBP 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.
Escherichia coli GGBP protein described in the step (2) is to adopt biotechnology synthetic, and concrete synthesis step is as follows:
(1) escherichia coli GGBP protein coding gene mglB is carried out rite-directed mutagenesis, carry out simple point mutation in the E149C site;
(2) make up overexpression escherichia coli wild type GGBP albumen and the proteic engineering strain of saltant GGBP;
(3) engineered strain is fermented shaking on the bottle, make the GGBP albumen can high-caliber stably express;
(4) tunning is carried out the proteic separation and purification of GGBP, the purity of target protein is reached more than 95%.In the process of execution in step (5), utilize skin to the infiltration coefficient of glucose and the dependency of Skin Resistance/resistance, by Skin Resistance/resistance the tissue fluid volume of being extracted out is carried out quantitatively.
In the process of execution in step (5), with the forecast model of concentration of glucose dependency in concentration of glucose and the blood in Skin Resistance/resistance introducing tissue fluid, Skin Resistance/resistance, tissue fluid concentration of glucose and the blood sugar concentration of utilizing negative pressure of vacuum tissue fluid extracting process to record are in real time set up the blood glucose forecast model.
The Wicresoft of human blood glucose concentration of the present invention, dynamic, continuous detecting method have following characteristics:
1, overcome the shortcoming that has the wound blood sugar detecting method to bring misery to patient easily at present and may cause infection, and noinvasive and the insecure deficiency of Wicresoft's blood sugar detecting method measurement result, 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 high-permeability of handling back skin at low frequency ultrasound can keep tens hours, just can extract primary structure liquid fast by negative pressure of vacuum every 10 minutes or shorter time in during this, for blood sugar concentration dynamically, continuous detecting lays a good foundation;
3, the present invention adopts surface plasma resonance protein binding measuring technique to measure concentration of glucose in the tissue fluid, has that Measurement Resolution and certainty of measurement are very high, a measurement result good reliability, advantage such as required interstitial fluid volume to be measured is very little and measuring speed is very fast;
4, Skin Resistance/resistance of measuring in the tissue fluid extracting process of utilization of the present invention carries out quantitatively the tissue fluid volume of being extracted out, and revises the blood glucose forecast model, improves precision of prediction.
Description of drawings
Fig. 1 is based on the schematic block diagram of the human blood glucose concentration Wicresoft detection system of low frequency ultrasound and surface plasma resonance;
Fig. 2 is a low frequency ultrasound blood processor structural representation;
Fig. 3 is a negative pressure of vacuum tissue fluid extracting apparatus structure sketch map;
The sketch map on surface plasma resonance sensor gold film surface when Fig. 4 is protein binding method survey concentration of glucose.
Wherein:
1: ultrasonic generator 2: ultrasonic probe
3: reference electrode 4: ultrasonic coupled cavity
5: couplant 6: buffer
7: vacuum chamber 8: vacuum pump
9: catcher 10: microchannel
11: the mixed liquor 12 of buffer and tissue fluid: measurement electrode
13: reference electrode 14: correcting electrode
15: surface plasma resonance sensing 16: golden film
17: self assembly molecule layer 18:GGBP protein
19: glucose 20: skin
21: epidermal area 22: skin corium
A, b, c: little valve A: ultrasonic generator
B: ultrasonic probe C: liquid crystal display
D: control circuit E: vacuum pump
F: vacuum chamber G:SPR
H: waste liquid pool L: reagent
The specific embodiment
The Wicresoft of human blood glucose concentration of the present invention, dynamically, continuous detecting method, be on application number is 200810052117.9 the disclosed micro-flow liquid comprehensive processing system of patent application, to realize.At first adopt 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 quick extracting interstitial fluid from skin of negative pressure of vacuum then, and in the tissue fluid extracting process detection of skin impedance/resistance, then the tissue fluid that extracts is transported to the surface plasma resonance measuring system by the microchannel, adopt surface plasma resonance protein binding measuring technique, measure the concentration of glucose in the tissue liquid, utilize the quantitative tissue fluid volume of extracting out of Skin Resistance/resistance that detection obtains in the tissue fluid extracting process at last, and be introduced in the tissue fluid dependency prediction model of concentration of glucose in the concentration of glucose and blood, realize human blood glucose concentration dynamically, continuously, real-time and high accuracy detects.
Fig. 1 is the structural representation block diagram based on the human blood glucose concentration Wicresoft detection system of low frequency ultrasound and surface plasma resonance that the method according to this invention is set up; Fig. 2 is a low frequency ultrasound blood processor structural representation; Fig. 3 is a negative pressure of vacuum tissue fluid extracting apparatus structure sketch map; Surface plasma resonance sensor gold membrane superficial tissue sketch map when Fig. 4 is protein binding method survey concentration of glucose.Below in conjunction with drawings and Examples to the Wicresoft of human blood glucose concentration of the present invention, dynamically, continuous detecting method makes a detailed description.
The Wicresoft of human blood glucose concentration of the present invention, dynamic, continuous detecting method 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;
In conjunction with Fig. 2, shown in Figure 3, the tissue fluid extracting step based on low frequency ultrasound and negative pressure of vacuum in above-mentioned two steps specifically includes:
(1) skin at tissue fluid extracting position is cleaned and sterilize;
(2) inject couplant 5 in ultrasonic coupled cavity 4, ultrasonic generator 1 output ultrasonic signal begins that skin is carried out low frequency ultrasound and handles;
(3) when low frequency ultrasound is handled, two electrode systems that adopt ultrasonic probe 2 and reference electrode 3 to form are measured the skin impedance value (skin impedance value has reflected the situation of cutaneous permeability) at supersound process position, after resistance value reaches setting value, stop low frequency ultrasound and handle, and remove the low frequency ultrasound blood processor;
(4) fixing vacuum chamber 7 on the pretreated skin of low frequency ultrasound injects phosphate buffer 6 in vacuum chamber 7, connect and open vacuum pump 8, and control produces stable negative pressure of vacuum, carries out tissue fluid extracting;
(5) adopt microchannel 10 to collect the mixed liquor 11 of vacuum chamber 7 interior buffer and tissue fluid, and be transported to surface plasma resonance measurement mechanism, for surface plasma resonance measurement mechanism measurement concentration of glucose wherein.
(3) in the process of transdermal extraction tissue fluid, detection of skin impedance/resistance; The mode that described detection of skin impedance/resistance could encourage, detect electric current by constant voltage realizes, or realizes by the mode of constant current drive, detection voltage.
And described detection of skin impedance/resistance is to carry out before tissue fluid extracting and afterwards, and the meansigma methods of the Skin Resistance/resistance that measures for twice with front and back is as the pairing Skin Resistance/resistance value of this time tissue fluid extracting process.
Perhaps, described detection of skin impedance/resistance can also be the carrying out of constant duration in the tissue fluid extracting process, with the meansigma methods of the Skin Resistance/resistance of all time points in each tissue fluid extracting process as the pairing Skin Resistance/resistance value of this time tissue fluid extracting process.
The electrode system that measurement Skin Resistance/resistance is used is made up of measurement electrode, reference electrode and correcting electrode.Measurement electrode 12 is fixed in the vacuum chamber 7, by the skin-communication signal of telecommunication of mixed liquor 11 after low frequency ultrasound is handled of buffer and tissue fluid.Guaranteeing that measurement electrode 12 neither influences the negative pressure of vacuum tissue fluid extracting, again under the prerequisite that can fully contact with the mixed liquor 11 of buffer and tissue fluid, measurement electrode 12 can adopt multiple shape and structure to be fixed in the vacuum chamber 8, cylinder annular electrode 12 as shown in fig. 1 and the disc type electrode 12 shown in Fig. 3.Reference electrode 13 and correcting electrode 14 are fixed near the skin site after low frequency ultrasound is handled.Measurement electrode 12 and reference electrode 13 are used for measuring Skin Resistance/resistance after low frequency ultrasound is handled at the instantaneous value of tissue fluid extracting process, and correcting electrode 14 combines the interference that is used to deduct reference electrode 13 and 14 times Skin Resistance/resistance variations of correcting electrode with measurement electrode 12 and reference electrode 13.With before the tissue fluid extracting and the meansigma methods of the meansigma methods of the Skin Resistance/resistance that measures afterwards or a plurality of Skin Resistance/resistance of obtaining in the medium time interval measurement of tissue fluid extracting process as the Skin Resistance/resistance value of tissue fluid extracting process correspondence at every turn.
The present invention measures Skin Resistance/resistance in the tissue fluid extracting process step comprises:
(1) constant pressure source/constant-current source provides the signal of telecommunication to measurement electrode 12 and reference electrode 13;
(2) measurement is by the current/voltage of electrode;
(3) constant pressure source/constant-current source provides the signal of telecommunication to correcting electrode 14 and reference electrode 13;
(4) measurement is by the current/voltage of electrode;
(5) constant pressure source/constant-current source provides the signal of telecommunication to correcting electrode 14 and measurement electrode 12;
(6) measurement is by the current/voltage of electrode;
(7) calculate Skin Resistance/resistance, the interference of deduction reference electrode 13 and 14 times Skin Resistance/resistance variations of correcting electrode;
Repeating step (1) calculates repeatedly the meansigma methods of Skin Resistance/resistance to (7).
(4) utilize surface plasma resonance protein binding measuring method, measure the concentration of glucose that extracts in the tissue liquid;
The present invention adopts surface plasma resonance escherichia coli GGBP (D-galactose/D-glucose BindingProtein; That is: D-galactose/D-glucose is conjugated protein) albumen binding measuring technique measures the concentration of glucose in the tissue fluid.This method is utilized the specific adsorption ability of GGBP protein to glucose, only the concentration of this material of glucose being measured of exclusiveness.Owing to adopted protein with the selective absorption of glucose molecule as ligand, effectively strengthened the quality of surface plasma resonance sensor gold film surface mass, make the measurement result reliability higher, Measurement Resolution and certainty of measurement are higher.The present invention is under the lucifuge condition, utilizes the surface plasma resonance measure glucose concentration, may further comprise the steps:
(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 escherichia coli GGBP protein binding measuring method to measure the glucose solution of concentration known, set up corresponding refractive index mathematical model, this step specifically:
(a) utilize escherichia coli GGBP protein binding measuring method to measure the glucose solution 1 of concentration known, obtain the refractive index of glucose solution 1 correspondence;
(b) utilize escherichia coli GGBP protein binding measuring method to measure the glucose solution 2 of concentration known, obtain the refractive index of glucose solution 2 correspondences;
(c) utilize step (a) and (b) in the concentration value of glucose solution and corresponding refractive index value set up the 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.
At surface plasma resonance sensor surface binding escherichia coli GGBP protein, realize that the step of structure as shown in Figure 4 is as follows:
(1) golden film 16 surfaces to surface plasma resonance sensor 15 activate, and form self assembly molecule layer 17 by the Au-S key;
(2) on self assembly molecule layer 17 by coupled modes such as amine couplings, escherichia coli GGBP protein 18 is fixed in surface plasma resonance sensor gold film 16 surfaces after the surface activation process, makes surface plasma resonance sensor pass through GGBP protein 18 and combine with glucose 19 molecular specificities.
In above-mentioned step, employed escherichia coli GGBP protein is to adopt biotechnology synthetic, and concrete synthesis step is as follows:
(a) escherichia coli GGBP protein coding gene mglB is carried out rite-directed mutagenesis, carry out simple point mutation in the E149C site;
(b) make up overexpression escherichia coli wild type GGBP albumen and the proteic engineering strain of saltant GGBP;
(c) engineered strain is fermented shaking on the bottle, make the GGBP albumen can high-caliber stably express;
(d) tunning is carried out the proteic separation and purification of GGBP, the purity of target protein is reached more than 95%.
Behind the GGBP protein of surface plasma resonance sensor binding simple point mutation, have very high concentration of glucose detection sensitivity, can detect concentration through glucose in the tissue fluid of buffer dilution.
(5) utilize the quantitative tissue fluid volume of extracting out of Skin Resistance/resistance, set up in the tissue fluid forecast model of concentration of glucose dependency in the concentration of glucose and blood;
In execution in step (fives') process, need utilize skin to the infiltration coefficient of glucose and the dependency of Skin Resistance/resistance, by Skin Resistance/resistance the tissue fluid volume of being extracted out is carried out quantitatively;
In execution in step (fives') process, also need the forecast model with concentration of glucose dependency in concentration of glucose and the blood in Skin Resistance/resistance introducing tissue fluid, Skin Resistance/resistance, tissue fluid concentration of glucose and the blood sugar concentration of utilizing negative pressure of vacuum tissue fluid extracting process to record are in real time set up the blood glucose forecast model.
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.
Adopt two point calibration models blood sugar concentration to be predicted among the present invention: to suppose that the human blood glucose concentration Wicresoft among the present invention, negative pressure of vacuum extraction time dynamic, that continuous detecting method adopts are Δ t according to the Skin Resistance/resistance that records in real time in the negative pressure of vacuum tissue fluid extracting process, tissue fluid concentration of glucose, it is that the skin area that negative pressure of vacuum extracts is A that low frequency ultrasound is handled, it is V that each negative pressure of vacuum extracts the volume that injects phosphate buffer in the forward direction vacuum chamber, and the Skin Resistance/resistance that measures in negative pressure of vacuum tissue fluid extracting process is R
i(i=1,2,3 ...), the concentration of glucose of the buffer that the surface plasma resonance systematic survey obtains and the mixed liquor of tissue fluid is CS
i(i=1,2,3 ...), the blood sugar concentration that adopts clinical method to measure when the 1st time and the 2nd tissue fluid extracting is respectively CB
1And CB
2Skin is to the infiltration coefficient P of glucose
i, i.e. tissue fluid volume that contains glucose and skin conductivity coefficient r by the unit skin area in the unit interval
iRelation in direct ratio, can represent with following formula:
P
i＝C
1r
i+C
2 (1)
Wherein, C
1And C
2Be the constant coefficient that will determine in the model, skin conductivity coefficient r
iCan calculate by following formula by Skin Resistance/resistance:
The volume v of the tissue fluid that the employing negative pressure of vacuum is extracted out
iCan represent with following formula:
v
i＝P
i·A·Δt (3)
Simultaneous (1), (2) and (3) formula, the relational expression that obtains tissue fluid volume and Skin Resistance/resistance is
See by formula (4), can realize the quantitative of tissue fluid volume by measuring Skin Resistance/resistance.
The present invention's (on an empty stomach or 2 hours after the meal) under the state of glucostasis begins to measure, and measures 2 blood sugar concentration CB in the phase in glucostasis
1And CB
2When glucostasis, tissue fluid concentration of glucose and blood sugar concentration are approximate identical, and the glucose amount that adopts negative pressure of vacuum to extract out should equal the glucose amount in the vacuum chamber, so obtain the following relationship formula:
CB
1·v
1＝(V+v
1)·CS
1(5)
CB
2·v
2＝(V+v
2)·CS
2(6)
Because CB
1, CB
2, CS
1, CS
2, R
1, R
2, Δ t, V and A be known quantity, so simultaneous (5), (6), (7) and (8) formula can solve constant coefficient C
1And C
2With C
1And C
2The dependency prediction model of substitution tissue fluid concentration of glucose and blood sugar concentration
Just the high-precision forecast of blood sugar concentration can have been realized.
(6) Skin Resistance/resistance of measuring according to step (three), the forecast model that concentration of glucose in the tissue liquid that step (four) is measured and step (five) are set up obtains human blood glucose concentration.
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 (9)
1. the Wicresoft of a human blood glucose concentration, dynamic, continuous detecting method 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) in the process of transdermal extraction tissue fluid, detection of skin impedance/resistance;
(4) utilize surface plasma resonance protein binding measuring method, measure the concentration of glucose that extracts in the tissue liquid;
(5) utilize the quantitative tissue fluid volume of extracting out of Skin Resistance/resistance, set up in the tissue fluid forecast model of concentration of glucose dependency in the concentration of glucose and blood;
(6) Skin Resistance/resistance of measuring according to step (3), the forecast model that concentration of glucose in the tissue liquid that step (4) is measured and step (5) are set up 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 the detection of skin impedance/resistance described in the step (3) is to realize by constant voltage excitation, the mode that detects electric current.
The Wicresoft of human blood glucose concentration according to claim 1, dynamically, continuous detecting method, it is characterized in that the detection of skin impedance/resistance described in the step (3) is to realize by constant current drive, the mode that detects voltage.
The Wicresoft of human blood glucose concentration according to claim 1, dynamically, continuous detecting method, it is characterized in that, detection of skin impedance/resistance described in the step (3) is to carry out before tissue fluid extracting and afterwards, and the meansigma methods of the Skin Resistance/resistance that measures for twice with front and back is as the pairing Skin Resistance/resistance value of this time tissue fluid extracting process.
The Wicresoft of human blood glucose concentration according to claim 1, dynamically, continuous detecting method, it is characterized in that, detection of skin impedance/resistance described in the step (3) is the carrying out of constant duration in the tissue fluid extracting process, with the meansigma methods of the Skin Resistance/resistance of all time points in each tissue fluid extracting process as the pairing Skin Resistance/resistance value of this time tissue fluid extracting process.
The Wicresoft of human blood glucose concentration according to claim 1, dynamically, continuous detecting method, it is characterized in that, the surface plasma resonance protein that utilizes described in the step (4) is bound measuring method, measures the concentration of glucose that extracts in the tissue liquid, may further comprise the steps:
(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 escherichia coli GGBP 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.
7. the Wicresoft of human blood glucose concentration according to claim 6, dynamic, continuous detecting method is characterized in that, the escherichia coli GGBP protein described in the step (2) is to adopt biotechnology synthetic, and concrete synthesis step is as follows:
(1) escherichia coli GGBP protein coding gene mglB is carried out rite-directed mutagenesis, carry out simple point mutation in the E149C site;
(2) make up overexpression escherichia coli wild type GGBP albumen and the proteic engineering strain of saltant GGBP;
(3) engineered strain is fermented shaking on the bottle, make the GGBP albumen can high-caliber stably express;
(4) tunning is carried out the proteic separation and purification of GGBP, the purity of target protein is reached 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 (5), utilize skin to the infiltration coefficient of glucose and the dependency of Skin Resistance/resistance, the tissue fluid volume of being extracted out is carried out quantitatively by Skin Resistance/resistance.
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 (5), with the forecast model of concentration of glucose dependency in concentration of glucose and the blood in Skin Resistance/resistance introducing tissue fluid, Skin Resistance/resistance, tissue fluid concentration of glucose and the blood sugar concentration of utilizing negative pressure of vacuum tissue fluid extracting process to record are in real time set up the blood glucose forecast model.
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|---|---|---|---|---|
| CN102687008A (en) * | 2010-01-08 | 2012-09-19 | 霍夫曼-拉罗奇有限公司 | Sample characterization based on AC measurement methods |
| CN102687008B (en) * | 2010-01-08 | 2015-01-28 | 霍夫曼-拉罗奇有限公司 | Sample characterization based on AC measurement methods |
| CN101779971B (en) * | 2010-01-14 | 2012-07-18 | 天津大学 | Micro-scale and dynamically-controllable tissue fluid transdermal extraction and collection device |
| CN103210310A (en) * | 2010-06-07 | 2013-07-17 | 拜尔健康护理有限责任公司 | Slope-based compensation including secondary output signals |
| CN103210310B (en) * | 2010-06-07 | 2015-03-18 | 拜尔健康护理有限责任公司 | Slope-based compensation including secondary output signals |
| CN108095734A (en) * | 2017-12-12 | 2018-06-01 | 天津大学 | A kind of microwave spectrum Woundless blood sugar Concentration Testing method based on Ear lobe blood liquid layer |
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