A kind of non-invasive continuous blood sugar measuring systemTechnical field
The present invention relates to medical measurement fields, and in particular to a kind of non-invasive continuous blood sugar measuring system.
Background technique
Diabetes have become the serious disease for endangering human health, and according to the statistics of the World Health Organization, 2015 completeBall diabetic has more than 400,000,000 people, will be more than 600,000,000 people to the year two thousand forty.The number of diabetic patients in China occupies the whole world first, has superCross 100,000,000 people's illness.With the increasing living standards of the people with the reasons such as poverty of movement, more and more people's overweight,Obesity, and then induced Diabetic.The age of onset of diabetes is gradually lowered, and more and more young people have suffered from sugar long sinceUrine disease.According to statistics, there is 5 people potential glycosuria with higher in the whole world in every 10 people every about just there is 1 people to suffer from diabetes in 10 peopleSick risk.If the blood glucose level of diabetic cannot be well controlled, can cause eye, oral cavity, angiocarpy,The complication of the multiple organs such as kidney, foot, serious person will lead to death, therefore control blood glucose level in stable range to sugarUrine patient extends the service life and quality of supporting the family is most important.Diabetes can not be cured completely, by keeping on a diet, enhancingPhysical training and the lifelong mode with composite medicine and injection of insulin control blood glucose level.In order to control blood sugar concentration, need to lead toThe mode for crossing medical instrument measurement obtains real-time blood glucose level.The current most common blood sugar measuring method is by puncturing fingerA certain amount of fingerstick capillary blood is drawn, and is detected by blood glucose meter.General diabetic needs to measure 3 within one day~4 times, serious patient needs to measure more times.This measurement method be belong to invasive measurement means, and every time measure when meetingCause the pain of patient, long-term measurement will lead to finger raw cocoon, finger wound bacterium infection, and because of its long-term pain and notIt is suitable, patient compliance can be made psychological, cause the compliance of blood glucose measurement poor.
In addition, the blood glucose level variation of people is a continuous change procedure, diet, movement and the change of physical condition are allIt can cause the fluctuation of blood glucose, the mode of finite number of time blood glucose measurement has certain limitation within mesh the previous day, can not be accurateAt the time of with completely knowing that blood glucose is more than normal value and is lower than normal value.In addition under as people, blood glucose is had significantly in sleepDrop, hypoglycemia can cause fatal as a result, and blood sugar tester measuring method cannot achieve sleep at present for diabeticIn blood glucose measurement.For diabetic, in real time and continuous blood glucose measurement is most effective and safe blood glucose levelMonitoring means, and because continuous measurement needs to measure mass data, therefore it is required that this blood sugar measuring method be it is noninvasive orMinimally invasive, to lower the pain of patient.
For the product that minimally invasive blood glucose continuously measures using brands such as Medtronic, Abbott Laboratories, moral health as representative, method is soft by oneNeedle is inserted into the subcutaneous simultaneously long periods of wear of patient, and the concentration of glucose measured in patient's hypodermis liquid obtains Portugal in continuous tissue fluidGrape sugar concentration value, because concentration of glucose and blood blood sugar concentration are positively correlated in tissue fluid, the measurement of tissue fluid can be with oneDetermine the concentration variation that blood glucose is represented in degree, but this method still falls within invasive measurement method, and patient worn is inconvenient,Long-time service can cause pain, and in addition the particularly relevant relationship of the concentration of glucose of tissue fluid and the concentration of glucose in blood is not trueIt is fixed, and the hysteresis quality with certain time.
The product of Woundless blood sugar measurement is mostly with infrared spectroscopy, Raman spectrum, Skin Resistance, heat metabolism, electromagnetic measurementBased on, the principle of measurement depends on response of the glucose to different environmental stimuli signals, measurement of the principles above to glucosePoor specificity, be easy to be disturbed in the presence of the substances such as hydrone, red blood cell, measurement inaccuracy, therefore can be atFor by medical approval non-invasive continuous blood sugar measuring system.The Woundless blood sugar that unique one kind was once authenticated and sold by FDA is surveyedAmount product glucowatch uses reverse ion permeating method, but this method needs to apply biggish electric current to skinSkin surface detection is rushed to outside glucose for driving in tissue fluid, but for a long time using red swelling of the skin and allergy etc. can be causedReaction, is finally stopped production and selling.There is presently no one kind can really realize that continuous blood sugar that is noninvasive and accurately measuring is surveyedAmount method.
Summary of the invention
For the above problems of the prior art, the invention proposes a kind of non-invasive continuous blood sugar measuring systems.
Non-invasive continuous blood sugar measuring system of the invention includes: regulation and control substance, positive electrode, negative electrode, power supply and skinThe glucose meters on surface；Wherein, positive electrode and negative electrode are individually positioned in skin surface, and are respectively connected to power supply；?The regulation and control substance of setting volume and concentration is placed between positive electrode and skin；Regulation and control substance is the osmotic pressure that can change tissue fluidSubstance, the form of regulation and control substance is paste, gel, condensation shape or sticker shape；The modes of emplacement of regulation and control substance is to be applied toPositive electrode surface is applied to the corresponding skin surface of positive electrode or is pasted onto positive electrode surface；Regulation and control substance has positive electricity；ElectricitySource forms direction perpendicular to the electric field of skin in skin surface by positive electrode, and direction is directed toward in skin, and electro-ionic osmosis is passed throughIt is subcutaneous that mode drives the regulation and control substance with positive electricity to enter；After regulation and control substance enters tissue fluid, the osmotic pressure of tissue fluid is improved,The increase of osmotic pressure causes blood to increase to the filtration pressure of tissue fluid, because filtration pressure is directly proportional to filtrable volume, in bloodFiltration enhancing of the glucose into tissue fluid, eventually lead to glucose filtration blood vessel in the blood actively outer tissue that flows toThe molal weight of liquid increases, and the quality of increased glucose and the incrementss of filtration pressure are directly proportional；Power supply is by negative electrode in skinSkin surface forms direction perpendicular to the electric field of skin, and direction is directed toward outside skin, by tissue fluid in such a way that reverse ion permeatesIn glucose drive to skin surface, form skin surface glucose；Skin is measured by the glucose meters of skin surfaceThe concentration I of skin surface glucose, and according to the Proportional coefficient K demarcated in advance, so that the glucose obtained in the blood of human body is denseSpend C=KI.
Before measuring blood sugar concentration, need first to demarcate proportionality coefficient: the regulation and control substance of setting volume and concentration is placed on skinBetween skin surface and positive electrode, the direction electric field inside perpendicular to skin is applied by positive electrode, drives positively charged modulatorMatter enters tissue fluid, so that the glucose increased in blood penetrates into tissue fluid, applies direction perpendicular to skin by negative electrodeThe outside electric field of skin drives the glucose in tissue fluid to skin surface, measures skin by the glucose meters of skin surfaceThe concentration I of skin surface glucose0, the glucose of blood at this time is obtained using measurement fingerstick capillary blood or venous blood blood measurementConcentration C0, obtain under the regulation and control substance of setting volume and concentration, the concentration I of skin surface glucose0It is dense with the glucose of bloodSpend C0Between Proportional coefficient K: K=C0/I0。
The volumetric concentration of regulation and control substance is set as 0.05%~0.5%；The volume of regulation and control substance is set as 0.33~5000 μL；The volume and concentration of regulation and control substance with calibration proportionality coefficient when volume and concentration it is identical.
Glucose penetrates the infiltration of vascular wall in the source of glucose autoblood of tissue fluid, therefore glucose is dense in tissue fluidThe concentration of glucose of degree and blood has determining proportionate relationship, but medical diagnosis is not fully achieved in the degree of correlation of the twoLevel can cause the error of measurement, more than the allowable error of clinical diagnosis so the proportionate relationship of its concentration is no longer applicable in sometimesRange.The quality of the net outflow into tissue fluid of the glucose in blood is enhanced by regulation and control substance, the Portugal in such tissue fluidThe degree of correlation of the concentration of glucose of grape sugar concentration and blood will greatly improve, can be within the scope of clinical diagnosis toleranceUsing the proportionate relationship of interstitial fluid glucose concentration and blood glucose concentration, reach measurement interstitial fluid glucose concentrationCompare the effect for preparing to be back-calculated to obtain blood glucose concentration.The incipient stage of Woundless blood sugar measurement is carried out by this method, is neededIt to be demarcated and be corrected using measurement fingerstick capillary blood or the result that measures Woundless blood sugar of venous blood blood glucose, for makingUser determines to meet the interstitial fluid glucose concentration of its people's concrete condition and the proportionate relationship of blood glucose concentration, asThe transformational relation of measurement result and blood glucose level.
Regulation and control substance is greater than 1,000,000 one of hyaluronic acid, glycoprotein, amino acid and fatty acid using molecular weight.
Driving time is between 10~30 minutes；The area of positive electrode and negative electrode is in 1~30cm2Between.Power supply is perseverancePotential source or constant-current source；The output voltage of constant pressure source is between 2~5V；The output electric current of constant-current source is 0.5~10mA/cm2, positive electricityCentre distance between pole and negative electrode is 1~5cm.
The shape of positive electrode and negative electrode is round, rectangular or irregular shape；Positive electrode and negative electrode use conductive materialMatter, metal, conducting polymer or conductive oxide semiconductor；Metal example is one of gold, silver, copper, aluminum and zinc；Conduction is poly-Conjunction object is one of polythiophene, polypyrrole, polyethylene dioxythiophene and polyaniline, and conductive oxide semiconductor is indium oxideTin.
The glucose meters of skin surface are using glucose oxidase biosensor, infrared spectrometry instrument, drawingGraceful spectroscopic glucose measuring instrument, micro-fluid chip, the glucose sensor based on field-effect tube, fluorescence reaction glucose sensingOne of device.
Advantages of the present invention:
The present invention is by way of electro-ionic osmosis by importing positively charged regulation and control substance, people in positive electrode subcutaneously tissue fluidIt for the osmotic balance for regulating and controlling blood and tissue fluid, is flowed in tissue fluid so that glucose in blood is actively outer, then by tissueThe glucose of original glucose and blood outflow will be in tissue fluid by negative electrode in such a way that reverse ion permeates in liquidGlucose drives to skin surface driving to skin surface, realizes noninvasive continuous measurement；The present invention is completely noninvasive, will not in measurementThe adverse reaction for causing skin combines with wearable blood glucose measurement device and noninvasive continuous blood sugar monitoring may be implemented；ThisInvention increases the content for the glucose that can be measured to, and mention in such a way that control glucose in blood actively outflowsThe high degree of correlation of measurement object and blood blood glucose, improves the precision of measurement, is suitble to and the blood sugar monitoring of medical grade.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of one embodiment of non-invasive continuous blood sugar measuring system of the invention.
Specific embodiment
With reference to the accompanying drawing, by specific embodiment, the present invention is further explained.
As shown in Figure 1, the non-invasive continuous blood sugar measuring system of the present embodiment includes: regulation and control substance 4, positive electrode 2, negative electrode3, the glucose meters of constant pressure source 1 and skin surface；Wherein, positive electrode 2 and negative electrode 3 are individually positioned in skin surface 5,And it is respectively connected to constant pressure source 1；The regulation and control substance 4 of setting volume and concentration is smeared between positive electrode and skin；Regulation and control substanceWith positive electricity；Constant pressure source 1 forms the electric field perpendicular to skin in skin surface by positive electrode, and direction is directed toward in skin, is passed throughIt is subcutaneous that the mode of electro-ionic osmosis drives the regulation and control substance with positive electricity to enter.
After people takes in sugar, the glucose that food decomposes enters in blood under the digestion and absorption effect of stomach,Whole body is flowed through under the action of systemic blood circulation everywhere, the artery segment from artery blood flow to capillary, and through blood capillaryThe vein end of pipe flows to vein blood vessel.Portugal in capillary region there is the mass exchange of tissue fluid and blood, in bloodGrape sugar penetrates blood vessel in the arterial end of capillary and enters tissue fluid, participates in the metabolic activity of cell, remaining grapeSugar is returned in capillary by the vein end reabsorption of capillary.The intercoursing of blood and tissue fluid be decided by two kinds of liquid itBetween osmotic pressure and liquid pressure it is poor.In normal state, filtration is slightly stronger than reabsorption, is maintained in tissue fluid with thisPossess certain density glucose.The difference of filtration and reabsorption is effective filtration pressure, determines formula are as follows:
NDF=(Pc+πi)-(Pi+πc)
Wherein NDF is effective filtration pressure size, PcFor capillary pressure, πiFor tissue fluid osmotic pressure, PiIt is quiet for tissue fluidHydraulic pressure, πcFor plasma osmolarity.NDF > 0 under normal circumstances.
In the present invention, in the way of electro-ionic osmosis, apply a vertical steady electric field to skin surface to be measured, andA certain amount of regulation and control substance is smeared between positive electrode anode and application on human skin, hyaluronic acid is the main component of tissue liquid,And it is positively charged, it can be entered under the driving of electric field in subcutaneous tissue fluid, according to the formula of tissue fluid osmotic pressure:
πi=iMRT
Wherein, πiFor the size of osmotic pressure, i is permeability, and M is the molar concentration of solute, and R is ideal gas constant, TFor kelvin degree.The osmotic pressure that tissue fluid after the concentration of solute hyaluronic acid, can be improved in tissue fluid is improved, is not being changedUnder the premise of becoming other parameters, such operation will cause the raising of effective filtration pressure, and filtration pressure is directly proportional to filtrable volume, thereforeFiltration of the glucose in blood into tissue fluid at this time is enhanced, and reabsorption is weakened, and is eventually led in bloodGlucose filtration blood vessel enter tissue fluid amount increase.Concentration of glucose at this time in tissue fluid is higher, with blood in bloodThe degree of correlation of sugared concentration variation is also higher.
By the way of electro-ionic osmosis and reverse ion infiltration mode, to skin apply electro-ionic osmosis electric field after modulatorThe volume flow that matter is injected in Skin tissue fluid meets:
Wherein, JvFor volume flow, unit is volume × time-1× area-1, LVEFor electroosmotic flow coefficient,For in skinElectric-force gradient, the regulation and control substance volume of electro-ionic osmosis tissue fluid is volume flow × electro-ionic osmosis time × electro-ionic osmosis electrodeArea.
Enter in subcutaneous tissue using iontophoresis driving regulation and control substance, the volume and volume flow of regulation and control substance are fullSufficient above formula, in typical case, the range of volume flow are 1~600 μ L h-1cm-2Or 1~200 μ L h-1cm-2, 200~400μL h-1cm-2, 400~600 μ L h-1cm-2, 200~400 μ L h-1cm-2, 100~500 μ L h-1cm-2, 200~500 μ L h-1cm-2.At driving time 20 minutes, positive electrode and negative electrode were square, area 2m2In the case of, the modulator of electro-ionic osmosisThe volume of matter is within the scope of 0.33-5000 μ L, and volume range can also be 0.33~100 μ L, 100~1000 μ L, 1000~2500 μ L, 2500~5000 μ L, 100~3000 μ L, 500~2500 μ L etc..
The noninvasive continuous blood sugar measurement method of the present embodiment, comprising the following steps:
1) proportionality coefficient is demarcated before measurement:
Driving volumetric concentration is 0.3%, molecular weight 2,000,000, and volume is that the hyaluronic acid regulation and control substance of 1000 μ L enters groupLiquid is knitted, so that the glucose increased in blood penetrates into tissue fluid, then drives glucose in tissue fluid to skin surface,Using the glucose measuring method of skin surface, the concentration I of skin surface glucose is measured0, utilize measurement fingerstick capillaryBlood or venous blood blood measurement obtain the concentration of glucose C of blood at this time0, it obtains under the regulation and control substance of setting volume and concentration,The concentration I of skin surface glucose0With the concentration of glucose C of blood0Between Proportional coefficient K: C0=KI0。
2) regulation and control substance 4 is smeared in the skin surface of human body, regulation and control substance uses hyaluronic acid.
3) subcutaneous tissue fluid is entered using iontophoresis driving hyaluronic acid:
A) positive electrode 2 is connected with the anode of constant pressure source 1, negative electrode 3 is connected with the cathode of constant pressure source 1；
B) positive electrode 2 and negative electrode 3 are directly attached to the skin surface of human body, and in the centre distance of skin surfaceFor 2cm；
C) start the voltage output of constant pressure source 1, voltage 3V.
4) by the molar concentration of control regulation and control substance, change the osmotic pressure of tissue fluid, increase blood by increasing osmotic pressureFor liquid to the filtration pressure of tissue fluid, filtration pressure is directly proportional to filtrable volume, to enhance mistake of the glucose into tissue fluid in blood 7Filter effect, the osmotic balance of blood and tissue fluid eventually lead to and flow to tissue outside the glucose filtration blood vessel active in bloodLiquid is kept for 20 minutes.
5) under the driving of electric field, in such a way that reverse ion permeates, the glucose in tissue fluid 6 is flowed to by skin 5The surface of negative electrode 3 and skin contact forms skin surface glucose 8.
6) glucose sensor is used, the concentration I of skin surface glucose 8 is measured, by Proportional coefficient K, to obtainConcentration of glucose C=KI in the blood of human body.
It is finally noted that the purpose for publicizing and implementing example is to help to further understand the present invention, but this fieldTechnical staff be understood that without departing from the spirit and scope of the invention and the appended claims, it is various replacement and repairIt is all possible for changing.Therefore, the present invention should not be limited to embodiment disclosure of that, and the scope of protection of present invention is to weighSubject to the range that sharp claim defines.