CN1700884A - Systems for extracting bodily fluid and monitoring an analyte therein - Google Patents
Systems for extracting bodily fluid and monitoring an analyte therein Download PDFInfo
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- CN1700884A CN1700884A CN 200480001020 CN200480001020A CN1700884A CN 1700884 A CN1700884 A CN 1700884A CN 200480001020 CN200480001020 CN 200480001020 CN 200480001020 A CN200480001020 A CN 200480001020A CN 1700884 A CN1700884 A CN 1700884A
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Abstract
A system for extracting a bodily fluid sample (e.g., an interstitial fluid [ISF] sample) and monitoring an analyte therein includes a disposable cartridge and a local controller module. The disposable cartridge includes a sampling module adapted to extract a bodily fluid sample and an analysis module adapted to measure an analyte (e.g., glucose) in the bodily fluid sample. The local controller module is in electronic communication with the disposable cartridge and is adapted to receive and store measurement data from the analysis module. An ISF extraction device includes a penetration member configured for penetrating and residing in a target site of a user's skin layer and, subsequently, extracting an ISF sample therefrom. The device also includes a pressure ring(s) adapted for applying pressure to the user's skin layer in the vicinity of the target site. The device is configured such that the pressure ring(s) is capable of applying pressure in an oscillating manner whereby an ISF glucose lag of the ISF sample extracted by the penetration member is mitigated. A method for extracting ISF includes providing an ISF fluid extraction device with a penetration member and a pressure ring(s). Next, a user's skin layer is contacted by the pressure ring(s) and penetrated by the penetration member. An ISF sample is then extracted from the user's skin layer while pressure is being applied in an oscillating manner by the pressure ring(s). The oscillating pressure mitigates an ISF glucose lag of the extracted ISF sample.
Description
Technical field
The present invention relates generally to the method that armarium is relevant with it, especially for the equipment, the system and method that extract body fluid and monitoring analyte wherein.
Background technology
In recent years, be used to (for example to monitor body fluid, blood or tissue fluid) middle analyte is (for example, glucose) equipment and the method that reduces user discomfort and/or pain in development concentrated in the effort on the armarium on, and simplification monitoring method and development allow on the equipment and method of continuous or semicontinuous monitoring.The simplification of monitoring method makes that user can be at home or do not need caring person's help from these analytes of monitoring in other place.In order often to encourage and the use of rule, in equipment that is designed to domestic and method, reduce the discomfort and/or the pain particular importance of user.It is generally acknowledged that if blood sugar monitoring equipment and correlation technique thereof are painless relatively, user will be more frequent than other situation and its blood sugar level of monitoring of rule.
In context, the favourable part of blood sugar monitoring, continuous or semicontinuous monitoring equipment and method is that they improve the influence to blood sugar concentration of blood sugar concentration trend, food and medicine, and the understanding of the whole glycemic control of user.Yet in fact, continuous and semicontinuous monitoring equipment has shortcoming.For example, extracting in the process of tissue fluid (ISF) sample from target site (for example, the target site of user cortex), the ISF flow velocity may reduce in time.In addition, after many hours continuous ISF extract, the pain of user and/discomfort may significantly increase, and may produce permanent cicatrix at target site.
Therefore, this area still needs be a kind of analyte that is used for monitoring body fluid (for example ISF) (for example, glucose) equipment and correlation technique thereof, it uses simple, less relatively to discomfort and/or pain that user produces, and be convenient to continuous or semicontinuous monitoring and can excessively do not increase the pain of user or produce permanent cicatrix.
Summary of the invention
The system that is used to extract humoral sample and monitoring analyte wherein according to embodiment of the present invention, it uses simple, less relatively to pain and/or discomfort that user produces, and be convenient to continuous and semicontinuous monitoring and can excessively do not increase the pain of user or produce permanent cicatrix.In addition, it is also less relatively to pain and/or discomfort that user produces to extract equipment according to the ISF of embodiment of the present invention, and is convenient to continuous and semicontinuous monitoring and can excessively increase the pain of user or produce permanent cicatrix.In addition, the method according to this invention is convenient to continuous and semicontinuous monitoring and can not excessively be increased the pain of user or produce permanent cicatrix.
The system that is used to extract humoral sample and monitor analyte wherein according to exemplary embodiment of the invention comprises cartridge case (for example, disposable cartridge case) and local controller module.This cartridge case comprises the sampling module and the analysis module that is suitable for measuring analyte in the humoral sample that is suitable for extracting from health humoral sample (for example, ISF sample).In addition, electronic communication between this local controller module and this disposable cartridge case, and be applicable to from this analysis module reception and storage of measurement data (for example, current signal).
Sampling module according to the system of embodiment of the present invention comprises that optionally configuration is used to thrust user cortex target site, and reside in the user cortex subsequently and therefrom extract the ISF sample thrust part.Selectable, sampling module can use trace to ooze watchman's clapper, Ultrafiltration, laser, antiparticle electric osmose therapy, and electroporation and/or ultrasonic technique are extracted sample (for example, ISF sample) with the target site from user.
This sampling module also optionally comprises at least one when thrusting part and reside in the user cortex, is used for pressure is applied near the pressure rings of the user cortex target site.In addition, if desired, this sampling module can dispose and make into pressure rings and can pressure be applied to the cortex of user with mode of vibration, thereby is postponed to be alleviated by the ISF glucose that thrusts in the ISF sample that part extracts.
Except the pressure rings that can exert pressure with mode of vibration (perhaps interchangeable), also can adopt other ISF glucose to postpone mitigation technique in embodiments of the present invention.These ISF glucoses postpone mitigation techniques and comprise, use to postpone to alleviate chemical substance, use hot, ultrasonic, non-vibration mechanically actuated, vacuum, electrode potential and their combination to adopt and alleviate the delay of ISF glucose.
The discardable characteristic of disposable cartridge case makes the system according to embodiment of the present invention use simple.In addition, when pressure rings is operated with mode of vibration according to the present invention, make things convenient for continuous or semicontinuous monitoring, minimized the generation of the pain and the permanent cicatrix of user simultaneously.
The system that is used for monitoring user ISF analyte (for example glucose) according to embodiment of the present invention comprises, cartridge case and with the local controller module of this cartridge case electronic communication.This cartridge case comprises that the analysis module and the configuration that are used for the Measurement and analysis thing are used for from the local controller module of this analysis module reception and storage of measurement data.In addition, this analysis module comprises that configuration is used for being inserted into the analyte sensor (for example, glucose sensor) of user target site and at least one to small part and is applicable to pressure is applied near this target site pressure rings.In addition, analysis module is configured to make pressure rings to exert pressure with mode of vibration, postpones thereby alleviate the ISF glucose.
Tissue fluid (ISF) extraction equipment according to embodiment of the present invention comprises, configuration is used to thrust user cortex target site, and reside in the user cortex subsequently and therefrom extract the ISF sample thrust part (for example, the foraminous thin-walled pin of tool).This ISF extracts equipment and comprises that also at least one is applicable to when thrusting part and reside in the user cortex, and pressure is applied near the user cortex target site pressure rings (for example, the pressure rings of three concentric arrangement).This ISF extraction equipment is configured to make pressure rings to exert pressure with mode of vibration, postpones thereby alleviate by the ISF glucose in the ISF sample that thrusts the part extraction.
Because extract penetrating into part and can residing in the user cortex of equipment according to the ISF of embodiment of the present invention in ISF sample extraction process, this ISF extraction equipment uses simple.In addition, because ISF extraction equipment is configured to exert pressure with mode of vibration, when minimizing user pain and producing permanent cicatrix, be convenient to continuous or semicontinuous monitoring.By pressure rings with near exert pressure blood flow can also the optimization aim site of mode of vibration, thereby make the ISF glucose postpone to be minimized.
Tissue fluid (ISF) extracting method according to embodiment of the present invention comprises, provides to have the ISF stream extraction equipment that thrusts part and at least one pressure rings.Then, pressure rings contacts and thrusts the cortex that part thrusts user with the cortex of user.When the working pressure ring was applied to the user cortex with mode of vibration with pressure, the ISF sample extracted from the user cortex via thrusting part thus.Pressure applies applied this mode of vibration, the ISF glucose that is used to alleviate by the ISF sample that thrusts the part extraction postpones, and/or be used for being convenient to continuous or semicontinuous extraction ISF sample in interval time (for example, interval time of extending in the scope in 1 to 24 hour) one section extension.
Description of drawings
By with reference to following that illustrate, the illustrated embodiment of having utilized the principle of the invention with and the detailed description of accompanying drawing will obtain better understanding to the features and advantages of the present invention, in the accompanying drawings:
Fig. 1 is the system of analyte was wherein extracted and monitored in indication according to the humoral sample of exemplary embodiment of the invention a simplified block diagram;
Fig. 2 according to exemplary embodiment of the invention, be applied to the simplification schematic diagram of the ISF sampling module of user cortex, dotted arrow is represented mechanism, solid arrow represents that ISF flows, and perhaps when with element 28 associatings, represents applied pressure;
Fig. 3 is the simplified block diagram according to the analysis module of exemplary embodiment of the invention and local controller module;
Fig. 4 is the simplified block diagram of analysis module, local controller module and remote controllers module according to exemplary embodiment of the invention;
Fig. 5 is according to the simplified block diagram of the remote controllers module of exemplary embodiment of the invention;
Fig. 6 is according to the disposable cartridge case of exemplary embodiment of the invention and the top perspective of local controller module;
Fig. 7 is the bottom perspective view of disposable cartridge case and local controller module among Fig. 6;
Fig. 8 is the perspective view of the system of another illustrative embodiments according to the present invention, and disposable cartridge case and local controller module are attached on the user arm;
Fig. 9 is the simplification cross-sectional side view according to the extraction equipment of exemplary embodiment of the invention;
Figure 10 is the extraction environment division perspective view according to the another illustrative embodiments of the present invention of shaking;
Figure 11 is the simplification cross-sectional side view that extracts equipment among Figure 10;
Figure 12 is as the curve chart of time function with perfusion in the test of extraction equipment enforcement among Fig. 9;
Figure 13 is the flow chart of order of steps in the process of representing according to one exemplary embodiment;
Figure 14 is that the part of the extraction equipment of another embodiment according to the present invention is simplified cross-sectional side view;
Figure 15 is the time graph that concentration of glucose was compared with the time, the glucose distribution curve that expression is determined from finger capillary blood, contrast ISF sample and test I SF sample;
Figure 16 A and 16B represent to contrast ISF glucose and finger capillary blood glucose, test I SF glucose and finger capillary blood glucose respectively and are superimposed upon the regression line on the Clarke Error Grids;
Figure 17 is the test I SF curve chart that skew is compared with relative time with contrast ISF glucose measurement percentage ratio;
Figure 18 is that test I SF glucose and finger capillary blood glucose are superimposed upon the regression line on the clarke error grid (Clarke Error Grids) after the bias correction; And
Figure 19 A is respectively that contrast ISF compares with time delay as %RMS (CV) with test I SF error with 19B.
The specific embodiment
A kind of according to exemplary embodiment of the invention be used to (for example extract humoral sample, the ISF sample) and the monitoring wherein analyte (for example, glucose) system 10, as shown in Figure 1, it comprises disposable cartridge case 12 (being included in the frame of broken lines), local controller module 14 and remote controllers module 16.
In system 10, disposable cartridge case 12 comprises and is used for extracting the sampling module 18 of humoral sample (ISF sample just) and the analysis module 20 that is used for measuring the analyte (glucose just) of this body fluid from health (B for example is not to use person's cortex).Sampling module 18 and analysis module 20 can be those any suitable sampling well known in the art and analysis modules.Should be noted that they all are configured to disposable because the sampling module 18 and the analysis module 20 of system 10 all are the assemblies of disposable cartridge case 12.Yet, should also be noted that according to the embodiment of system of the present invention and can select to use non-once cartridge case (just, opposite, only be " cartridge case ") with " disposable cartridge case ".
Two kinds can be extracted humoral sample for the sampling module (comprising sampling module 18) of embodiment of the present invention being used to of using (for example, technology ISF) is micro-dialysis and ultra-filtration method.For example, micro-dialysis and ultra-filtration law technology can adopt the tubulose semipermeable membrane with first end, second end and micropore, it allows low-molecular-weight chemical compound (for example, glucose) by this semipermeable membrane diffusion, perhaps otherwise through this semipermeable membrane migration.Yet the size of this micropore and/or geometry are predetermined, to prevent that high-molecular weight chemical compound (such as, protein) is by this semipermeable membrane diffusion or migration.
The semi-permeable membrane materials that is fit to includes, but not limited to polyacrylonitrile, cuprophan, regenerated cellulose, Merlon and polysulfones.In use, this tubulose semipermeable membrane is, for example, is implanted under the cortex skin of user health.
In micro-dialysis, primer solution (perfusion solution) pumps into this first end, thereby this primer solution is by the flows inside of this pipe, and the chemical compound of various small-molecular weights (for example glucose) is just moved in this primer solution by this semipermeable membrane diffusion or through this semipermeable membrane.This primer solution flows to this second end.The chemical compound of this primer solution and various small-molecular weights can be transferred to analysis module 20 then, and analyzed module 20 is analyzed.
In the ultra-filtration method, relatively low (just, " bearing ") pressure is applied to this first end and second end, causes that body fluid (for example, ISF) passes through the filtering migration of this semipermeable membrane, and flows to first and second ends of this pipe.The ultrafiltrate that obtains (for example, the ISF ultrafiltrate) can be transferred to analysis module 20 then, and analyzed module 20 is analyzed.
If desired, this tubulose semipermeable membrane can be fused to conduit or sleeve pipe and thinks and insert and operation is provided convenience.In U.S. Patent No. 5,002, in 054,5,706,806 and 5,174,291, they all here are incorporated herein by reference about the further details of micro-dialysis and ultra-filtration method.
Can utilize the another kind of technology to extract ISF by sampling module 18 is laser.Use laser to have a lot of benefits, comprise the local erosion that can produce little acanthopore or skin, and can not follow the pain of big degree.For example, the laser of narrow focusing is suitable for removing the cortex of user, thereby forms micropore therein, and the ISF that produces is extracted.Because use laser can control the degree of depth of this excision closely, the process of extracting ISF can be painless in theory, thereby this ISF is a depletion of blood basically.The power level of laser, wave-length coverage, optical characteristics (optics) and pulse frequency can be adjusted, so that increase the efficient of ablating.Can be about the more details of when gathering ISF, using laser in U.S. Patent No. 5,165,418 and international open No.WO97/07734 in find, they all are incorporated herein by reference.
By using counter ion electro-osmosis method technology, the ISF sample of iontophoresis (iontophoresed) can extract by using sampling module 18.This technology depends on by the mode that applies current potential or electric current and makes the motion of ISF and glucose through the user cortex.For example, ionotherapy comprises the electrode (it is coated with hydrogel) of cortex that is installed to user and a pair of iontophoresis of arranging from a distance.Between two electrodes, apply for example about 0.01 to about 0.5mA/cm then
2Electric current density.Usually, the polarity of the electric current that is applied was switched once to increase the flux (flux) through the iontophoresis ISF sample of user cortex in per 10 minutes.Applying electric current causes iontophoresis ISF to extract from the cortex of user owing to electric osmose power.Near this iontophoresis electrode, be useful on the liquid storage tank of gathering this iontophoresis ISF sample, thereby they can be analyzed subsequently by analysis module 20.Can be about the more details of counter ion electro-osmosis method in U.S. Patent No. 6,233, to find in 471 and 6,272,364, they here all are incorporated herein by reference.
Can use the another kind of technology to extract ISF for sampling module 18 is electroporation.Electroporation comprises that at first the cortex by user forms the micropore of at least one desired depth.The method that is used to form this at least one micropore can be to use laser or hot wire (heated wire).Then, and the electrode that is coupled of this micropore electricity and another electrode that is spaced between apply voltage.
By being applied voltage at user by the cortex that micropore staves, the electroporation effect can aim at the following organizational structure in surface, capillary tube for example, thereby very big enhancing the withdrawal of biofluid.Can be provided for collecting and shifting the device of ISF, thereby can analyze by analysis module 20 subsequently by the ISF sample that electroporation extracts.Can be about the more details of electroporation in U.S. Patent No. 6,022, find in 316, it here all is incorporated herein by reference.
It is ultrasonic can using another technology to extract ISF for sampling module 18.This technology focuses on ultrasonic beam on the user cortex fritter area.Reduce along with using reducing of area in the ultrasonic quantity that applies the nociceptor in the position.Therefore, on small size very, apply and ultrasonicly will produce less sensation, and will make ultrasonic and/or its local effect under higher-strength, carry out and have pain seldom or uncomfortable.Can locally produce bigger power, cause cavitation, the mechanical vibration in skin self, and near the big local shear forces the skin surface.Ultrasonic probe can also produce acoustic streaming, and this relates to the big convection current by ultrasonic generation.It seems that this help to increase the speed that ISF extracts.Can be about ultransonic more details in U.S. Patent No. 6,234, find in 990, it here all is incorporated herein by reference.
Yet, as shown in Figure 2, the particular sample module 18 of system 10 be comprise the target site (TS) that thrusts health B and extract the ISF sample thrust part 22, the ISF sample block of emission (launching) mechanism 24 and at least one pressure rings 28.ISF sample block 18 is suitable for providing successive or semi-continuous ISF to flow with monitoring (for example, measurement of concetration) analyte (such as glucose) in the ISF sample to analysis module 20.
In the use of system 10, thrust the operation of part 22 by trigger mechanism 24 and be inserted in the target site and (just, thrust this target site).Be used for when the cortex of user extracts the ISF sample, thrust part 22 and for example can be inserted into 1.5mm in the insertion depth scope of 3mm maximum.In addition, thrust part 22 and can dispose the ISF sample extraction that is used for the continuous or semicontinuous mode of optimization.In this, thrusting part 22 can comprise, for example, 25 standard sizes (gauge) have the thin-wall stainless steel pin (not illustrating) of elbow in Fig. 1 or Fig. 2, and wherein the fulcrum of this syringe needle bending is arranged between needle point and the pin heel.Be applicable to that the pin that thrusts part according to the present invention describes (Application No. No.10/185,605) in U.S. Patent Application Publication No.2003/0060784 A1.
Trigger mechanism centers on the wheel hub (hub) (not illustrating) that thrusts part 22 24 selectable comprising in Fig. 1 or Fig. 2.This wheel hub configuration is used to control the degree of depth of thrusting part 22 insertion target sites.In extracting ISF sample process, the control insertion depth by prevent to cut unintentionally be positioned at the user cortex relatively darker blood capillary have benefit, its eliminated thus the ISF sample of the extraction that causes by blood pollution, penetrate into the obstruction of part or the obstruction of analysis module.The control insertion depth also is used for making in the use of system 10 pain and/or the uncomfortable minimum of user experience.
Except the control insertion depth, this wheel hub can lock onto on the pressure rings after thrusting the part emission and (combine with pressure rings), and serves as the additament of pressure rings thus.Selectable, this wheel hub itself can be configured to not only serve as the insertion depth control device but also serve as the pressure rings of thrusting after part is launched.
Although the trigger mechanism shown in Fig. 2 24 is included in the sampling module 18, trigger mechanism 24 selectable being included in the disposable cartridge case 12 are perhaps in the local controller module 14 of system 10.In addition, in order to simplify the use of user to system 10, sampling module 18 can be made the integral part of analysis module 20.
(for example, ISF), thrusting part 22 can concentric placement at least one pressure rings 28 to extract body fluid from target site for convenience.Pressure rings 28 can be any suitable shape, includes but not limited to annular.In addition, pressure rings 28 configuration is used for applying the mechanical force (pressure just) of vibration near target site when thrusting the cortex that part resides in user.This vibration can be by using biased element (not illustrating) realization, for example spring or locating piece in Fig. 1 or Fig. 2.26S Proteasome Structure and Function according to the pressure rings in the sampling module of the present invention (and ISF extraction element) will be below in conjunction with Fig. 9-12 more detailed description.
In the use of system 10, pressure rings 28 is applied to before penetrating into target site near the target site TS thrusting part 22, with the cortex of tension user.Thrusting the cortex that is used for fixing user in the process and preventing protuberance of part thrust in this tension.Selectable, thrusting before part penetrates into, the fixing of user cortex can be realized by the degree of depth control element (not shown) that thrusts that is included in the sampling module 18.This thrust that degree of depth control element rests or " floating over " user cortical surface on, and thrust the limiter (being also referred to as insertion depth) of the degree of depth as control.Thrust the embodiment of degree of depth control element and it is applied in U.S. Patent application No.10/690, describe in 083, it all is incorporated herein by reference at this.If desired, this penetrates into part can launch when pressure rings is applied to the user cortex, thereby simplifies trigger mechanism.
Be launched away and thrust target site TS in case penetrate into part 22, the pin (not illustrating in Fig. 1 or Fig. 2) that thrusts part 22 for example will reside in below the user target site cortical surface in the about 1.5mm insertion depth in the 3mm scope.Pressure rings 28 is being exerted pressure on the cortex of user (representing with arrow under pointing in Fig. 2), and this is near the ISF supercharging the target site.Subepidermal (sub-dermal) barometric gradient that is caused by pressure rings 28 makes ISF flow on the pin, and arrives analysis module (shown in the arrow that arc among Fig. 2 is upwards indicated) by this sampling module.
The ISF of the pin by penetrating into part flows and is subjected to passing in time the influence of the potential decay that produces, and potential decay is because near the ISF loss this target site and because the cortex of the user under the pressure rings 28 relaxes causes.Yet, in system according to the present invention, when this thrusts part and resides in the user cortex, the cortex that pressure rings 28 can be applied to user in the mode of vibration (for example, have predetermined pressure rings circulation (cycling) program or via the pressure rings cyclic program of ISF flow-speed measurement and feedback control), to minimize the ISF decay of flowing.In addition, in the process of exerting pressure, can be arranged one period here under mode of vibration, wherein be changed by the pressure rings applied pressure, perhaps local pressure gradient is removed and is eliminated from the ISF of user cortex net outflow.
In addition, near user cortex target site, alternately apply a plurality of pressure rings and can be used for controlling flowing of ISF by sampling and analysis module, and restriction user cortex is arbitrarily to the time of certain portions under pressure.Recover by the cortex that allows user, exert pressure with mode of vibration and also can reduce the painful and/or uncomfortable of cicatrix on patient skin and patient.With the mode of vibration ring 28 other benefits of exerting pressure is that the ISF glucose postpones (difference between concentration of glucose in user ISF and the concentration of glucose in user blood just) and reduces.
In case learned present disclosure, those of ordinary skills can design the pressure rings cyclic program of the various permanent cicatrixs that are used to reduce the pain/discomfort of glucose delay, user and/or produce on skin.For example, pressure rings 28 can be launched (just, making pressure be applied to cortex around the user target site places like that) one from 30 seconds to 3 hours interval, and can withdraw subsequently (just, making pressure not be applied to the user cortex places like that) interval from 30 seconds to 3 hours scopes.In addition, determine, when applying (just of pressure, at least one pressure rings unfolded interval time) about 30 seconds in about 10 minutes scope and the release of pressure (just, interval time of this at least one pressure rings withdrawal) in the time of in about 5 minutes to 10 minutes scope, the ISF glucose postpones and the pain/discomfort of user can reduce significantly.The circulation of particularly preferred pressure rings comprises exerted pressure 1 minute and release pressure 10 minutes.Owing to use different time quantums, this circulation to be called the circulation of differential pressure ring to applying of pressure with discharging.
The pressure rings cyclic program can be designed so that following relationship is equilibrated (balanced): (i) pressure rings is launched one period that is enough to extract the body fluid of requirement; (ii) comprise and alleviate the physiological reaction that the ISF glucose postpones; And the permanent cicatrix that does not accommodate generation of user is minimized.In addition, the pressure rings cyclic program can also be designed for provides the measurement that produced semicontinuous analyte once in for example per 15 minutes.
Pressure rings 28 can be made by the known suitable materials of those of ordinary skills.For example, pressure rings 28 can comprise the material of relative stiffness, includes but not limited to acrylonitrile butadiene styrene plastic material, injection plastic material, polystyrene material, metal or their combination.Pressure rings 28 also can comprise the material of relative resilient distortion, includes but not limited to elastomeric material, polymeric material, polyurethane, latex material, silicone material or their combination.
The inside opening that is limited by pressure rings 28 can be any suitable shape, includes, but are not limited to, and circle, square, triangle, C shape, U-shaped, hexagon, octagonal and zigzag shape.
Flow through the ISF of sampling and analysis module when pressure rings 28 is used to minimize flow decay and/or control of ISF,, thrust part 22 and in the target site of user cortex, keep expansion (just, resident) when pressure rings 28 in use the time.Yet when pressure rings 28 was used to alleviate the delay of ISF glucose, this thrust part 22 and can intermittently reside in the cortex of user.This interrupted resident generation of thrusting part 22 can be exerted pressure with pressure rings 28, and be consistent also can be inconsistent.
Except working pressure ring 28 with alleviate the ISF glucose postpone outer (perhaps as an alternative), different embodiments according to the present invention can use other device to postpone to alleviate the ISF glucose, for example, and for instance, chemical devices (just, postpone to alleviate chemicals), ultrasonic, machinery, heat, vacuum, electromotive force, perhaps its combination.It is usually, this that to be used to alleviate device that the ISF glucose postpones be supposition increases hemoperfusion and/or ISF around being used to alleviate the device that the ISF glucose postpones.By increasing the local circulation of body fluid, can increase the balancing speed of the glucose between blood and the ISF.
Chemical devices can be used to alleviate glucose and postpone.This chemical devices applies to target site (for example, the skin layer of user) and postpones to alleviate chemical substance and strengthen circulation.The chemical compound that can carry out the exemplary and indefiniteness of this function is a capsaicin, histamine, natural bile salts, sodium cholate, sodium lauryl sulphate, NaTDC, sodium taurodeoxycholate, sodium glycocholate, perhaps its combination.In addition, in U.S. Patent No. 6,251, (it is hereby incorporated by) describes and all skin penetration enhancers and the combination thereof mentioned also are suitable spares in 083 and 5,139,023.This chemical devices can be sneaked into Emulsion or gel so that the use of this chemical devices is simple and directly.In addition, adsorbing material for example Pilus Caprae seu Ovis can be used to promote the amount of the chemical devices that applies.
Being used to alleviate the another kind of device that the ISF glucose postpones is to use ultrasonic.Ultrasonic delay mitigation technique comprises by applying ultrasonic to target site near the placement ultrasonic probe target site (for example, the cortex of user).Ultrasonicly cause local pyrexia to what target site applied first scheduled volume, this helps to alleviate the ISF glucose and postpones.In specific implementations, after alleviating the glucose delay, ultrasonic probe can apply the ultrasonic of second scheduled volume bigger than first scheduled volume then, so that ISF extracts.In this embodiment, ultrasonic probe is not only carried out the function that alleviates the glucose delay but also is carried out the function of extracting ISF.In U.S. Patent No. 5,231, open in 975 and 5,458,140, it all is hereby incorporated by about the further details of ultrasonic technique.
Being used to alleviate the another kind of device (technology) that glucose postpones is non-vibrating machine operation.This mechanically actuated can comprise draws or crowded target site, by drawing the bonding agent that causes target site distortion, and the equipment (piezoelectric transducer just) that awards the vibration of user cortex.The machinery that is used for the Action Target site is in U.S. Patent No. 6,332, and open in 871 and 6,319,210, it all is hereby incorporated by.
Being used to alleviate the another kind of mode that glucose postpones is heat.In this device, heated probe (for example, resistance heater) is applied to target site (for example skin of user) to strengthen the circulation of body fluid.Selectable, can use infrared ray (IR) source as heating source.In this embodiment, can serviceability temperature popping one's head in and determine to be applied to the heat of user cortex, is comfortable thereby make this treatment to user, and the interval of thermotherapy is short relatively interval (just, less than 5 minutes).Usually, the heat that applies must be than 37 ℃ high, but can not be too high otherwise cortex user can burn.About details from heat to target site that apply in US Patent No 6,240, record in 306 and 6,155,992, it all is hereby incorporated by.
Be used to alleviate the another kind of mode that glucose postpones and be to use vacuum.For example, vacuum can help to stretch target site (for example cortex of user), and this can help to alleviate the delay of ISF glucose.In addition, vacuum provides the negative pressure source of being convenient to extract from target site ISF.Use vacuum in U.S. Patent No. 6,155 at target site, describe in 992, it all is hereby incorporated by.
Be used to alleviate the another kind of mode that glucose postpones and be to use electromotive force.In this case, for example use pair of electrodes to apply electric current to target site (for example skin of user).This electric current is to strengthen circulation and to reduce mode that the ISF glucose postpones excite nerve cell and tissue.
With reference to figure 3, the analysis module 20 of system 10 comprises distribution ring 302, and a plurality of micro fluidic network 304 are connected 306 with a plurality of electronics.Each micro fluidic network 302 all comprises first passive valve 308, glucose sensor 310, waste liquid pool 312, the second passive valve 314 and relief valve 316.Micro fluidic network 304 comprises that a plurality of sectional dimensions are at for example 30 to 500 microns passage.In order to monitor the glucose in (for example, measuring) the ISF sample that flows, a plurality of (n) substantially the same micro fluidic network 304 (being also referred to as sensor branch 304) can be included in the analysis module 20.Distribute ring 302, the first passive valve 308, waste liquid pool 312, the second passive valve 314 and relief valve 316 configurations are used to control the ISF that flows through analysis module 20.
In analysis module according to the present invention, can use any suitable glucose sensor known to a person of ordinary skill in the art.Glucose sensor 310 can comprise, for example comprises the redox reaction system of enzyme and redox active chemical compound or mediator.Various mediator has been well known in the art, the iron cyanide for example, azophenlyene ethyl-sulfate, phenazine methosulfate, phenylenediamine, 1-methoxyl group-phenazine methosulfate, 2,6-dimethyl-1,4 benzoquinone, 2,5-two chloro-1,4-benzoquinone, ferrocene derivatives, osmium bipyridyl coordination compound, and ruthenium complex.The enzyme that is applicable to the glucose in the quantitative analysis whole blood includes, but is not limited to glucoseoxidase and dehydrogenase (all being based on NAD and PQQ).Other material that may reside in the redox reaction system comprises buffer agent (for example, citraconate, citrate, malic acid, maleic acid, and phosphate buffer); Bivalent cation (for example, calcium chloride and magnesium chloride); Surfactant (for example, three whistles base toluene, Macol, Tetronic, Silwet, Zonyl, and Pluronic); And stabilizing agent (for example, albumin, sucrose, trehalose, mannitol and lactose).
Be based at glucose sensor 310 under the situation of electrochemical sensor of glucose, glucose sensor 310 can respond the glucose that occurs in the ISF sample and produce current signal.Local controller module 14 can receive this current signal (connecting 306 via electronics) then and convert thereof into the ISF concentration of glucose.
Use identical glucose sensor (each all used interval time of qualification, such as hour) to make continuous or semi-continuous glucose measurement become possibility continuously.The execution of using identical glucose sensor continuously can be to switch to another glucose sensor by guiding the ISF that flows into from sampling module to flow to glucose sensor 310 in interval a period of time, block then the ISF that flows to this pick off also this ISF to be flowed.Till the continuous use of this glucose sensor can constantly repeat each pick off in being included in analysis module and all was used.
The mobile continuous glucose sensor that switches to of ISF can be realized by for example following process.After analysis module 20 initialization, be assigned to " n " individual sensor branch 304 through distributing ring 302 from the ISF sample of sampling module 18.Yet the arrival end that is flowing in each sensor branch of ISF is interrupted by first passive valve 308 of each sensor branch.In order to begin the measurement of glucose, selected sensor branch activates by the relief valve 316 of opening this sensor branch.The process of the relief valve that unlatching is chosen can be electronically controlled by local controller module 14, and it connects 306 via electronics and communicates by letter with analysis module 20.When opening relief valve 316, the gas (for example air) that is present at first in the sensor branch 304 (it seals) overflows from the port of export of sensor branch 304, thereby ISF can flow into this sensor branch 304.Because the relief valve 316 of another sensor branch 304 still keeps cutting out, ISF is only fluence to go into selected sensor branch 304.
The pressure of ISF is enough greatly opening first passive valve 308, so it will flow to glucose sensor 310.Produce measuring-signal and connect 306 electronics by glucose sensor 310 subsequently and send local controller module 14 (shown in dotted arrow among Fig. 3) to through electronics.ISF continuous-flow also enters waste liquid pool 312, and the capacity of waste liquid pool is scheduled to, and this makes it can be kept at glucose sensor needs the ISF that flows through in the life-span amount.For example, mean flow rate is that about per minute 50 is received liter, and the glucose sensor life-span be one hour, the volume of waste liquid pool 312 should be about 3 microlitres.Second passive valve is positioned at waste liquid pool 312 ends.314 configurations of second passive valve are used to stop to flow of ISF.
Continue to carry out this process by the relief valve 316 of opening another sensor branch 304 then.When optionally opening this relief valve 316 (it can be finished via communication by local controller module 14), ISF will flow into corresponding sensor branch 304 opening first passive valve, 308 backs that are arranged in this sensor branch.Thereafter, the glucose sensor 310 of this sensor branch will provide measuring-signal to analysis module 20.
Till the continuous all the sensors branch 304 that repeats in analysis module 20 of this process all was used.For the system that about eight hours continuous glucose monitorings are provided, need about eight sensor branch 304 in the analysis module 20.Yet, it should be understood by one skilled in the art that, the analysis module 20 of disposable cartridge case 12 is not limited to eight sensor branch, and therefore, and this system can be designed to measure the ISF glucose level in longer than eight hours (the perhaps even shorter) time.
Should be noted that thus this analysis module 18 outside health B has been carried out further description.In optional embodiment, do not use sampling module according to system of the present invention.Yet the part of analysis module 18 (it comprises for example glucose sensor) to being inserted among the health B of small part (for example, is inserted into the hypodermic layer of health B).Suitable continuous glucose sensor is included in U.S. Patent No. 6,514,718; 6,329,161; Those pick offs of describing in 6,702,857 and 6,558,321, it all is incorporated herein by reference at this.
This glucose sensor can use enzyme, and for example glucoseoxidase or glucose dehydrogenase are fixed on the working electrode with the osmium redox polymers.Cross-linking reagent with two kinds of difference in functionalitys can be used for enzyme and polymer together are fixed to the surface of this electrode such as epoxide or aziridine.This glucose sensor does not need additional any reagent that freely spreads with regard to the energy measurement glucose, and converts concentration of glucose to proportional levels of current or electric charge.
Other glucose sensor can use the enzyme that is fixed to working electrode, for example glucoseoxidase.Common, use cross-linking reagent example enzyme to be fixed to working electrode such as glutaraldehyde with two kinds of difference in functionalitys.In this glucose sensor, oxygen is converted into hydrogen peroxide, thereby the concentration of the concentration of this hydrogen peroxide and this glucose is proportional.This hydrogen peroxide is in the working electrode oxidation then, thereby can find out the size of electric current, to determine the glucose level among the present ISF.
Also have another kind of glucose sensor use can be inserted into the magnetic bead (for example emulsifying pearl (latex bead)) of the transformation of hypodermic layer, and this glucose sensor use the FRET (fluorescence resonance energy transfer) technology to come monitoring glucose.At U.S. Patent application No.6, in 232,130 and 6,040,194, it all is hereby incorporated by about other details of this glucose monitor.
Configuration local controller module 14 makes it can electronics and be mechanical coupling to disposable cartridge case 12.This mechanical couplings make disposable cartridge case 12 removable be connected (for example, being inserted in the local controller module 14) with local controller module 14.The configuration of local controller module 14 and disposable cartridge case 12 makes them to be connected with the skin of user in the mode that the combination of guaranteeing disposable cartridge case 12 and local controller module 14 is fixed on the user skin by using rubber plaster for example.
In the use of system 10, the measurement of first electronic controller, 404 control analysis modules 20 circulation, as mentioned above.Communication between local controller module 14 and the disposable cartridge case 12 connects 306 realizations (referring to Fig. 3) via the electronics of analysis module 20.Electronics connects 306 can connect (referring to Fig. 7) by the brace 708 of local controller module 14.For example, the signal of telecommunication sends to analysis module 20 with selectively unlocking relief valve 316 by local controller module 14.The signal of telecommunication of the concentration of glucose of expression ISF sample then sends to the local controller module by analysis module.First electric controller 404 is explained these signals by using local controller algorithm 408, and goes up the demonstration measurement data at first data display equipment 406 (it can be read by user).In addition, measurement data (for example, ISF concentration of glucose data) can store in first data storage elements 409.
Before using, be inserted in the local controller module 14 without the disposable cartridge case 12 that uses.This is inserted between disposable cartridge case 12 and the local controller module 14 telecommunication is provided.Mechanical control device 402 in this local controller module 14 should keep in place by disposable cartridge case 12 in the use of system 10 safely.
After on the skin of the user that is connected of local controller module and disposable cartridge case, and when user receives triggering signal, measure circulation and start by first electronic controller 404.When this startup, thrust part 22 and be transmitted into the cortex of user with beginning ISF sampling.This emission both can have been started by first electric controller 404 and also can have been started by mechanical interaction by user.
Fig. 5 illustrates the simplified block diagram of the remote controllers module 16 of expression system 10.Remote controllers module 16 comprises second electronic controller, 502, the second radio link, 504, the second data-storing elements 506, second data display equipment 508, prediction algorithm 510, alarm 512, blood sugar measuring system (being suitable for utilizing blood glucose bar 516 measuring blood) and data are transported element 518.
Second electronic controller 502 is suitable for controlling the various thin part of remote controllers module 16.504 configurations of second radio link are used for and 14 two-way communications of local controller module (for example, second radio frequency connection 504 can receive the data relevant with the ISF concentration of glucose from local controller module 14).Can be via the data that second radio link 504 receives by 502 checking and the verifications of second electric controller.In addition, the data of Jie Shouing also can be handled and be analyzed by second electric controller 502 like this, and store in second data storage elements 506 (for example, the further data retrieval by user carries out perhaps is used for prediction algorithm 510) for future use into.Second data display equipment 508 of remote controllers module 16 can be for example dispose be used for concerning user easily form show measurement data and be used to show the graphical LCD display of easy-to-use interface data management when further.
Measure the blood sugar level in the blood sample (BS) for convenience, blood sugar measuring system 514 partly provides as a whole with remote controllers module 16.These blood glucose measurement measuring system 514 usefulness blood glucose bars 516 are measured, and blood sampling (for example, bleeding) is placed on this blood glucose bar.The result of this blood glucose measurement that produces can compare with the dextrose equivalent that is calculated by prediction algorithm 510.
Data are transported element 518 and can be provided with disposable cartridge case 12, and can comprise that disposable cartridge case produces detailed data in batches, for example nominal data and batch ID number.Remote controllers module 16 can read and be included in data and transport data on the element 518, and this data can be used to explain the ISF glucose data that receives from local controller module 14.Selectable, the data that data are transported on the element 518 can send local controller module 14 to via second radio link 504, and can be used in the data analysis of being carried out by local controller module 14.
Second electronic controller, 502 configurations of remote controllers module 16 are used for decryption, and carry out various algorithms.A particular algorithm is that prediction algorithm 510 is estimated the glucose level of (in 0.5-1 hour) in the recent period.Because life period poor (" time delay ") between the corresponding variation of the variation of the glucose that in user blood, is comprised and the glucose that user ISF is comprised, prediction algorithm 510 uses the measurement data of a series of mathematics algorithm storages to operate, to consider the user special parameter of reflection individual time delay of relation.The output result of prediction algorithm 510 is based on the blood sugar level that the ISF glucose level is estimated.If prediction algorithm 510 is estimated the LG level, can send the physiological event that signal and alarm 512 activate to remind user to estimate, for example danger of hypoglycemia or stupor.This area is common to be carried the art personnel and should be appreciated that alarm 512 can comprise any appropriate signal, comprises audition, and vision or vibration signal are with the caring person of direct prompting user or this user.Owing to can remind sleeping user to meet with the hypoglycemia incident, so audible signal is preferred.
ISF dextrose equivalent and the difference between the blood glucose value (concentration) at synchronization at any given time are called the delay of ISF glucose.The ISF glucose postpones can be regarded as the reason owing to physiology and machinery.The physiology's reason that postpones in the ISF glucose relates to glucose and spreads the needed time between blood and user cortex gap.The mechanical reason that postpones relates to the method and apparatus that is used to obtain the ISF sample.
Thereby alleviated (reduce or minimize) owing to the ISF glucose of physiology's reason postpones by applying the blood flow that increases the target site that flows to the user cortex with release pressure at the cortex of user with mode of vibration according to the embodiment of device of the present invention, system and method.Comprise that the ISF extraction element according to pressure rings of the present invention (being discussed in more detail below) applies and release pressure by this way.Be used to solve the another kind of method that the ISF glucose postpones and be to use the algorithm (for example, prediction algorithm 510) of estimating blood sugar concentration according to the ISF concentration of glucose of measuring.
Prediction algorithm 510 can have general formula, for example
Estimate blood glucose=f (ISF
k i, rate
j, ma
nRate
m p, mutual)
Wherein
I is the integer value between 0 to 3;
J, n and m are the integer values between 1 to 3;
K and p are that value is 1 or 2 integer;
ISF
iBe the ISF dextrose equivalent of measuring, which ISF value what its subscript (i) expression related to is, just, and 0=currency, the previous value of 1=; The previous again value of 2=, etc.;
Rate
jBe meant the speed of the variation between the adjacent ISF value, subscript (i) refers to which adjacent ISF value is used for computation rate, just, speed between 1=current I SF value and the last ISF value, speed between the former ISF value of the 2=ISF value before value and two values for current I SF value, etc.; And
Ma
nRate
mBe the rolling average speed between the meansigma methods of adjacent many groups ISF value, subscript (n) and (m) expression be included in the quantity (n) of the ISF value in the moving average and with respect to the time location (m) of the mobile adjacent meansigma methods of currency.
The common form of prediction algorithm is all linear sets that allow and may cross term, and the coefficient of these and these cross terms is the regression analyses of the blood glucose value by to the ISF value measured and acquisition ISF sample time the and definite.About being applicable to that other details according to the prediction algorithm of system of the present invention is included in U.S. Patent application No.10/652, in 464, it all is hereby incorporated by.
Those of ordinary skills be also to be understood that the output result of this prediction algorithm can be used to control armarium, for example insulin dispensing (delivery) pump.Can be the amount that gives patient's insulin pill at particular point in time according to the exemplary embodiments of the definite parameter of algorithm output.
The combination of local controller module 14 and disposable cartridge case 12 can be disposed on the skin that is used to be worn on user to simplify the sampling and the monitoring (referring to Fig. 6-8) of extracting ISF from the user cortex.
In the use of system embodiment shown in Fig. 1-10, disposable cartridge case 12 is positioned at local controller module 14 and by its control.In addition, the combination of disposable cartridge case 12 and local controller module 14 is arranged to by user wears, and preferably is worn on user arm top or forearm.The electronic communication of local controller module 14 and disposable cartridge case 12 is so that control survey and receive measurement data from analysis module.
With reference to figure 6, local controller module 14 comprises that first data display equipment 406 and a pair of being used for are attached to belt 602 on the user arm to local controller module 14.Fig. 6 also is illustrated in the disposable cartridge case 12 before being inserted in the local controller module 14.
Shown in Fig. 7 is the upward view of the local controller module 14 before disposable cartridge case 12 is inserted into insertion cavity 704 in the local controller module 14.Disposable cartridge case 12 and local controller module 14 are configured to make disposable cartridge case 12 to be fixed on by mechanical force and insert in the cavity 704.In addition, local controller module 14 and disposable cartridge case 12 are via a series of molded brace 706 electronic communications on the disposable cartridge case 12.When disposable cartridge case is inserted into when inserting in the cavity 704, a series of braces 708 on the insertion cavity 704 of these molded braces 706 and local controller module 14 are aimed at.
Fig. 8 illustrates disposable cartridge case 12 and is inserted into the later local controller module 14 of local controller module 14, and the combination of this disposable cartridge case and local controller module is attached to the arm of user.Fig. 8 also illustrates the remote controllers module 16 that is positioned at local controller 14 radio communication scopes.
Fig. 9 is the sectional view of tissue fluid (ISF) the extraction equipment 900 according to exemplary embodiment of the invention.ISF extracts equipment 900 and comprises and thrust part 902, pressure rings 904, the first bias pieces 906 (first spring just) and second bias piece 908 (second spring just).
Thrusting part 902 configurations is used for thrusting the cortex of user and being used for therefrom extracting subsequently ISF at target site.Thrusting part 902 also disposes and is used for during therefrom extracting ISF keeping (resident) cortex at user.For example, thrust in the cortex that part 902 can be retained in user and surpass one hour, thereby allow continuous or semi-continuous ISF to extract.In case know the disclosure, those of ordinary skills just will appreciate that to be thrust time expand of reaching 8 hours in the cortex that part can reside in user or more.
Pressure rings 904 is configured to vibrate between deployed condition and retracted mode.When pressure rings 904 during in deployed condition, it is in that to penetrate into part resident in the user cortex, pressure is applied to user target site cortex on every side, thereby (i) provide convenience, and (ii) control as mentioned above and extract equipment 900 by ISF and flow to for example ISF of analysis module for extracting ISF from the user cortex.When pressure rings 904 during at retracted mode, the pressure that it will be very little or pressure can be applied to cortex around the user target site.Because pressure rings 904 can vibrate between deployed condition and retracted mode, can control that the user cortex is any gives the time of certain portions under pressure, thereby the user cortex is recovered and reduce pain and cicatrix.
Pressure rings 904 has the overall diameter in 0.08 inch to 0.56 inch scope for example usually, and the wall thickness in 0.02 inch to 0.04 inch scope (in Fig. 9 by size " A " expression).
Thrust part 902 and can be configured to independently move with pressure rings 904, perhaps fixing with respect to pressure rings 904.Thrust part 902 with respect to pressure rings 904 fixed situations under, thrusting part 902 will move together in company with pressure rings 904.Yet, the target site part (for example, the skin of target site) and the frictional force that penetrates between the part 902 can make target site present " tent " structure, although and make and to thrust part 902 along with the withdrawal of pressure rings is moved, thrust part and still be retained in the target site.In this, make and thrust part and be its simplicity of design with respect to the fixed benefit of pressure rings.
906 configurations of first biased element are used to promote the cortex (just, pressure rings 904 being placed into deployed condition) and the pressure rings 904 that is used to withdraw that pressure rings 904 is pressed onto user.The configuration of second biased element 908 is used for emission and thrusts part 902 and thrust target site so that thrust part.
Can be for example in the scope of about 1 to 150 pound per square inch (PSI is calculated by the power on every pressure rings cross-sectional area) by pressure rings to the cortex applied pressure (power) of user.In this, minimize the pain/discomfort of user simultaneously in order to provide enough ISF to flow, approximately the pressure of 50PSI is considered to useful.
In the embodiment of Fig. 9, penetrate in the groove of pressure rings 904 that part 902 parts are placed on vibration, the degree of depth of groove is thrust degree of depth decision by the maximum of thrusting part 902.Although clearly do not illustrate in Fig. 9, the pressure rings 904 of thrusting part 902 and vibration can relative to each other move and be applied to independently of one another the cortex of user.
Extract in the use of equipment 900 at ISF, the pressure rings 904 of vibration can be launched with regular user's cortex and make target site zone isolation and supercharging, and provides clean malleation to flow by thrusting part 902 to promote ISF thus.
If desired, ISF extracts equipment 900 and can comprise and thrust degree of depth control element (not shown) with restriction be controlled at the degree of depth that is needled in the emission process.Suitable thrust degree of depth control element with and the embodiment that uses at U.S. Patent application No.10/690, open in 083, it all is incorporated herein by reference at this.
Extract in the use of equipment 900 at ISF, it is staggered relatively to comprise that ISF extracts the skin of the system of equipment 900 and user, pressure rings 904 towards skin (referring to, for example, Fig. 8).Pressure rings 904 promotes skin to produce projection.This projection is thrust (for example, injecting) by thrusting part 902 then.Thrusting the whole or part of part 902 when remaining in the skin, the ISF sample is extracted from this projection accurately.
The flow velocity of the ISF sample that extracts is quite fast at the beginning, but usually can be along with the time slows down.One section 3 seconds to 3 hours between after date, pressure rings can be withdrawn to allow skin to recover an about interval of 3 seconds to 3 hours.Pressure rings 904 can launch again then one about 3 seconds to about 3 hours interval, withdrew then about 3 seconds to 3 hours.The process of expansion and withdrawal pressure rings 904 continues to carry out to extract termination up to ISF.The circulation of this expansion and withdrawal is preferably uneven, therein each is recycled the different time interval.
As described herein, the pressure rings (for example, the pressure rings among Fig. 9 904) that is used for embodiment of the present invention can be used to alleviate (just, reducing) ISF glucose and postpone.Suppose that (and being not limited thereto) this alleviating is to increase ISF sample extraction point or analysis module near the dabbling result site of small part insertion.If desired, other increases perfusion and therefore alleviates the appropriate device that ISF postpones and can combine with pressure rings.For example, can heat to increase perfusion the pressure rings among Fig. 9 904.This heating can realize by the resistance material of embedment pressure ring 904 or the cavity circulation that heating liquid is passed through in the pressure rings 904 by for example making electric current.The device that increases perfusion (and therefore reducing the delay of ISF glucose) based on being applicable to of chemistry comprises, for example, applies local vascular dilation agent (for example, histamine) at ISF sample extraction point or analysis module near the site that small part is inserted.In addition, that configuration is used to increase is dabbling, can combine with pressure rings 904 based on the equipment of ultrasonic probe, and/or configuration be used to increase dabbling, can combine with pressure rings 904 based on the equipment of electricity irritation.
Figure 10 and Figure 11 are respectively cross-sectional view and the perspective views that the ISF of another illustrative embodiments according to the present invention extracts equipment 950.ISF extracts equipment 950 and comprises pressure rings 954A, 954B and the 954C that thrusts part 952 and a plurality of annular array.ISF extracts equipment 950 and also comprises a plurality of first biased element 956A, 956B and 956C, with respectively towards promoting pressure rings 954A, 954B and 954C with cortex facing to user; Second biased element 958 thrusts part 952 with emission; And, thrust degree of depth control element 960.If desired, thrusting degree of depth control element 960 can combine with pressure rings 954C, to form the whole degree of depth and the pressure rings element of thrusting.
In use, place ISF extraction element 950 so that pressure rings 954A, 954B and 954C towards the user cortex.This can realize by for example using ISF in the sampling module extract humoral system as mentioned above to extract equipment 950 and this system being placed on the cortex of user.
Therefore pressure rings 954A is pushed to the cortex of user by biased element 956A, thereby produces projection at the cortex of user, thrusts part 952 subsequently and injects (just, thrusting) this projection.When pressure rings 954A when user mode (just, launch), pressure rings 954B and pressure rings 954C can maintain retracted position by biased element 956B and 956C respectively.
When thrusting that part 952 is all or part of to be resided in the user cortex, extract in the projection that ISF can form from the user cortex.After about 3 seconds to 3 hours, pressure rings 954A withdrawal recovers interval time of about 3 seconds to 3 hours to allow the user cortex.After withdrawal pressure rings 954A, pressure rings 954B can launch to exert pressure with the cortex to user.When pressure rings 954B was in user mode (just, launching), pressure rings 954A and pressure rings 954C can remain on retracted position by biased element 956A and 956C respectively.After date between about 3 seconds to 3 hours time, pressure rings 954B can be withdrawn a scope 3 seconds to 3 hours interval, and pressure rings 954C launches then.The time interval of pressure rings 954C in 3 seconds to 3 hours scopes, keep-up pressure interval time in 3 seconds to the 3 hours scope of withdrawing then on the cortex at user.When pressure rings 954C when user mode (just, launch), pressure rings 954A and pressure rings 954B remain on retracted position by biased element 956A and 956B respectively.Pressure rings 954A, 954B and 954C launch and the cyclic process of withdrawal continues to carry out finishing up to liquid extraction.Embodiment shown in the image pattern 9 is such, a plurality of pressure rings shown in Figure 10 and 11 launch and withdrawal circulation embodiment preferably uneven, therein each is recycled the different time interval.
Those of ordinary skills be also to be understood that can be with any sequential deployment according to a plurality of pressure rings in the ISF extraction equipment of the present invention, and the top expansion of an indefiniteness and the order of withdrawal discussed.For example, can working pressure ring 954B or the 954C order of before pressure rings 954A, exerting pressure.In addition, can launch more than one pressure rings simultaneously.For example, can launch whole three pressure rings simultaneously by the embodiment shown in Figure 10 and 11, thereby the function of these pressure rings is the same with single pressure rings.
For at the embodiment shown in Figure 10 and 11, the pressure that is applied on the user skin can be in 0.1 to 150 pound per square inch (PSI) scope for example in a plurality of pressure rings each.In addition, it should be understood by one skilled in the art that, can use in operating process the pressure rings that constant force (for example, about 2 pounds power) or constant pressure (for example, the pressure of 20 to 30 pound per square inches) is applied to target site according to the embodiment of the present invention.Selectable, this power or pressure among pressure applies circulation or between can change.For example, pressure can change from the 20-30 pound in 1 minute extraction circulation.
Pressure rings 954A, 954B and 954C for example can have the overall diameter in 0.08 to 0.560 inch, 0.1 to 0.9 inch and 0.16 to 0.96 inch scope respectively.The wall thickness of each pressure rings can be in 0.02 to 0.04 inch scope for example.
If desired, can be flat (referring to Figure 14) according to innermost pressure rings in the extraction equipment of alternative embodiment of the present invention, its objective is when applying insignificant pressure pin to be remained in the cortex of user when keeping blood flow to this zone.Shown in Figure 14 is the partial cross sectional view of tissue fluid (ISF) the extraction equipment 970 of the optional illustrative embodiments according to the present invention.ISF extracts equipment 970 and comprises and thrust part 972, pressure rings 974, and flat pressure rings 975 is used for first bias piece 976 (just, first spring) of bias pressure ring 974 and is used for second bias piece 978 (being also referred to as second spring) of the flat pressure rings of bias voltage.
In this optional embodiment, this flat pressure rings is round pin (just, thrusting part 972) and comprise the hole that its size enough allows pin just in time therefrom to pass.This flat pressure rings preferably has 0.02 to 0.56 inch diameter.
Comprise that in extraction equipment according to the present invention at least one pressure rings has a lot of benefits.The first, the vibration pressure ring is used to alleviate the delay of (just, reducing) ISF glucose between expansion and retracted mode.When pressure rings was withdrawn, the pressure on the user cortex discharged, and the health of user reacts by the hemoperfusion that increases to target site.This phenomenon is called as reactive hyperemia, and supposition to be the ISF that makes at target site by mechanism obtain useful replenishing by the vibration of pressure rings.ISF this is supplemented with the delay that helps reduce between ISF glucose and whole blood blood glucose value.
Another benefit of extracting equipment according to ISF of the present invention is that the vibration of pressure rings allows the skin it under to recover, so has alleviated the pain of user, do not accommodate the generation of permanent cicatrix.
In addition, extraction equipment with a plurality of pressure rings (for example, embodiment among Figure 10 and 11) can have at least one permanent unfolded pressure rings so that ISF gathers, other pressure rings is vibrated between expansion and retracted mode simultaneously, thereby the zones of different power of the cortex of user is exerted oneself down at any given time.This combination of the pressure rings of permanent unfolded pressure rings and vibration further helps to alleviate the pain/discomfort of user.
Another benefit that has according to the ISF extraction equipment of embodiment of the present invention is, this pressure rings can be used to control the condition that the ISF sample glucose measurement of extraction carries out.For example, if the flow velocity of this glucose sensor of ISF sample process is constant or constant, the electrochemical glucose pick off can be more accurately with accurate.Extracting the pressure rings of equipment according to ISF of the present invention provides the control of flow velocity can for the ISF sample that extracts.For example, the withdrawal of pressure rings can stop flowing of ISF sample 0.1 second to 60 minutes clock time in interval, to allow to carry out glucose concentration measurement.In case glucose concentration measurement is finished, one or more pressure rings can heavily be launched to extract to continue ISF.Can realize semi-continuous ISF sample extraction by this way.
In case known present disclosure, one one of skill in the art will recognize that extracting equipment according to ISF of the present invention can be used for various systems, includes but are not limited to the system of extraction humoral sample as described above and monitoring analyte wherein.For example, ISF extraction equipment can use in the sampling module of this system.
With reference to Figure 13, the method 1000 of collecting the ISF sample continuously from the user cortex according to exemplary embodiment of the invention comprises: provide ISF fluid extraction equipment, shown in step 1010.This ISF fluid extraction device that provides has the part of thrusting and at least one pressure rings (for example, a pressure rings or three concentric pressure rings).This thrusts part and pressure rings can be to thrust part and pressure rings about as described above according to what ISF of the present invention extracted equipment and system.
Then, as setting forth in step 1020 like that, near the cortex of pressure rings and user target site contact (for example, finger tip skin histology target site, the limbs target site, abdomen target site or other are from wherein extracting the target site of ISF sample).Pressure rings can use any suitable technique to contact with the cortex of user, comprises, for example, about above-described embodiment according to system of the present invention and equipment.
As illustrating in step 1030, the target site of user cortex thrusts by thrusting part then.Then, as illustrating in step 1040, pressure is applied to the user cortex and postpones with the ISF of the ISF that alleviates extraction with mode of vibration when, from the cortex of user, extract ISF by thrusting part.In the method according to the invention, pressure applies the various mode of vibrations that adopted and is described about Fig. 1-12 in the above.
The following examples are used to illustrate the useful aspect according to the embodiment of various device of the present invention, system and method.
Embodiment 1: the influence on the hemoperfusion of the pressure rings of vibration in the pressure rings zone of vibration.
Laser-Doppler imaging data perfusion is collected with half canonical interval in the inboard paracentral 0.25 square centimeter of zone of the pressure rings that is connected with person under inspection's forearm.The overall diameter of pressure rings is 0.53 inch, and its wall thickness is 0.03 inch.Launching to collect base-line data before the pressure rings facing to person under inspection's cortex.Pressure rings was launched 10 minutes facing to cortex, and had 0.5 pound elastic force, from cortex withdrawal 30 minutes, repeated this expansion and withdrawal circulation then.Pressure rings was launched 5 hours facing to cortex subsequently, improved 1 hour, and launched 10 minutes facing to skin at last.Shown in the curve that on average is poured in Figure 12 in 0.25 square centimeter of measured zone.
As in the curve of Figure 12 as can be seen, compare with the baseline hemoperfusion, pressure rings is launched to have reduced by the hemoperfusion in the pressure rings region surrounded (just, along with applying of pressure, hemoperfusion reduces).Yet, removes this pressure rings (just, release pressure) and not only reversed this effect, and hemoperfusion exceeds baseline and actual increasing.
Embodiment 2: the influence that the pressure rings of vibration postpones the ISF glucose
Study to determine that use is according to the influence of blood flow on the ISF dextrose equivalent during the vibration pressure ring of exemplary embodiment of the invention.20 persons under inspection that suffer from diabetes have experienced the process of measuring the baseline hemoperfusion in the palmar hand and the back side portion of its forearm.These persons under inspection participate in a test then, its middle finger blood sample, and collect once at contrast ISF sample and treated ISF sample per 15 minutes intervals in 3 to 6 hour interval.Contrast ISF sample obtains from the forearm that the person under inspection does not carry out any cortex operation, and treated ISF sample is obtained by the cortex of the pressure rings operation of vibration from the person under inspection.Interim between 3 to 6 hours test, the diabetes medicament that blood glucose is subjected to absorbing microwave food and comprising insulin and oral hypoglycemic influences, thereby most of person under inspection's blood glucose has experienced rising and descended.
This treated ISF sample produces as follows: apply 150 pounds pressure approximately per square inch by not sampling in 30 seconds by pressure rings, the wait interval that is 5 minutes then, is to allow hemoperfusion to this sampled targets site.(Devon UK) directly carries out by mole laser instrument doppler imaging device before obtaining contrast and treated ISF sample in the hemoperfusion measurement.It is to carry out on 2 square centimeters the zone at center that laser-Doppler is imaged on ISF sample target site.
The ISF glucose measurement is by the OneTouch of change
Ultra
Glucose meter and test strip system carry out.The ISF sample of about 1 μ L is extracted and deposits to automatically the measured zone of test strip from person under inspection's cortex by pin.Geng Gai OneTouch not
Ulra
Glucose meter and test strip system are used for determining the whole blood blood glucose value from pointing.
Each person under inspection in minute time delay and perfusion measure and in table 1, to provide.
Table 1
| Person under inspection's numbering | Control zone average blood perfusion unit | Treated zone leveling hemoperfusion unit | Treated with the contrast hemoperfusion ratio | Contrast ISF total delay (branch) | Treated ISF total delay (branch) | Total delay alleviates (branch) |
| ????8 | ??97.1 | ??212.9 | ??2.19 | ????30 | ????10 | ????20 |
| ????9 | ??65.3 | ??170.3 | ??2.61 | ????21 | ????5 | ????16 |
| ????10 | ??84.0 | ??187.6 | ??2.23 | ????26 | ????4 | ????22 |
| ????11 | ??50.2 | ??117.3 | ??2.34 | ????22 | ????-5 | ????27 |
| ????12 | ??68.4 | ??223.5 | ??3.27 | ????12 | ????-2 | ????14 |
| ????13 | ??95.4 | ??295.2 | ??3.09 | ????30 | ????15 | ????15 |
| ????14 | ??62.0 | ??150.3 | ??2.42 | ????47 | ????12 | ????35 |
| ????15 | ??51.7 | ??92.8 | ??1.80 | ????50 | ????10 | ????40 |
| ????16 | ??80.0 | ??80.9 | ??1.01 | ????41 | ????24 | ????17 |
| ????17 | ??64.6 | ??107.9 | ??1.67 | ????46 | ????12 | ????34 |
| ????18 | ??101.2 | ??244.4 | ??2.41 | ????50 | ????11 | ????39 |
| ????19 | ??86.2 | ??142.4 | ??1.65 | ????27 | ????16 | ????11 |
| ????20 | ??114.8 | ??256.9 | ??2.24 | ????42 | ????16 | ????26 |
| ????21 | ??118.6 | ??198.3 | ??1.67 | ????13 | ????5 | ????8 |
| ????22 | ??73.2 | ??156.2 | ??2.13 | ????25 | ????8 | ????17 |
| ????23 | ??114.7 | ??278.2 | ??2.43 | ????30 | ????8 | ????22 |
| ????24 | ??94.4 | ??253.6 | ??2.69 | ????15 | ????8 | ????7 |
| ????25 | ??161.2 | ??482.0 | ??2.99 | ????8 | ????-2 | ????10 |
| ????26 | ??58.7 | ??151.7 | ??2.59 | ????42 | ????9 | ????33 |
| ????27 | ??114.6 | ??363.3 | ??3.17 | ????29 | ????8 | ????21 |
| ????28 | ??56.3 | ??117.0 | ??2.08 | ????31 | ????10 | ????21 |
| Meansigma methods: | 86.3 | ?203.9 | ?2.32 | ?30.3 | ?8.7 | ?21.7 |
| ?SD： | 28.1 | ?97.2 | ?0.6 | ?12.8 | ?6.6 | ?9.9 |
Data representation ISF glucose in the table 1 postpones on average to have alleviated 21.7 minutes, for example drops to 8.7 minutes (6.6SD) by the pressure rings of using vibration from average 30.3 minutes (12.8SD).Alleviating by realizing to cause that local blood perfusion lifting mode applies with release pressure on person under inspection's cortex of this delay on average improved 2.3 times (0.6SD) with respect to its hemoperfusion in the ISF sample area of contrast sample area.
Embodiment 3: the assessment of scaling method and the influence on ISF glucose sensor degree of accuracy thereof
Various scaling methods and they have been carried out the research assessment to the influence of system's degree of accuracy.The person under inspection who suffers from diabetes experiences this research, wherein above every interval parallel collection in 15 minutes in 5.5 hours interval it is being carried out three kinds of sample types of glucose measurement (just measuring circulation).In research process, impel the glucose skew by oral 75g glucose solution.
Three kinds of sample types that are used for glucose measurement of collecting are for referring to blood sample, contrast ISF sample and treated ISF sample.Refer to blood sample, be also referred to as finger capillary blood (FCB), collect by the finger puncture of standard.The ISF sample (CISF) of contrast is not collected through the arm of any cortex operation from the person under inspection's, and treated ISF sample (TISF) is collected through the another arm of the pressure rings cortex operation of vibration from user.The time that all samples is collected, the data that produce each sample type were to (just, measuring loop No. and concentration of glucose) by computer time stamp record.The concentration of glucose of FCB is abbreviated as [G]
FCB, it is by using two One Touch
Ultra blood-glucose meter and test strip (LifeScan, Milpitas, CA) bipartite measurement.Record value is the meansigma methods of two meter readings of each sample.
Being collected on the method for these two ISF sample types is different.CISF collects in the mode of forearm dorsal part different loci sampling with each interval from person under inspection's a arm.Its sampling module that adopts comprises pressure rings, and the pin of little standard unit is with the adapter that is used for contacting with glucose test strip.The ISF of about 1 microlitre collects by being needled in the about 2 millimeters skin depth of cortex of 30 standard units.Pressure rings by the 5.5mm diameter applies about 15 newton's power so that the collection of CISF (intermediate value of acquisition time is 3.0 seconds) on skin, this CISF is at the OneTouch of change
The measurement zone deposition of Ultra glucose test strip.This entrance area is physically changed contacting with the adapter of sampling module, thereby CISF can directly deposit in this measurement zone.
TISF collects in sampling module, and this sampling module and CISF are employed slightly different.This sampling module is installed in person under inspection's forearm dorsal surface.Particularly, the arm that is used to collect TISF is not the arm that is used to collect CISF.Compare with the collection of CISF, each interval of TISF is collected from same loci.The sticking sampling module that is posted on the arm of this use medical rubber cream comprises the pin that is used to thrust 25 dark standard units of skin 2mm, also comprises the pressure rings around this pin, and this pressure rings is pressed to skin to collect TISF.This sampling module also comprises the liquid storage tank that is used to build up TISF.In this test, this liquid storage tank is that (Drummond Scientific, Broomall PA), wherein collect the capacity of 320nL, and the swept volume of this and pin is complementary for the capillary glass tube of 0.5 μ L.In case collect required volumetrical ISF, this capillary tube is removed, TISF transfers to the One Touch of dissimilar changes
On the Ultra glucose measurement bar.Change this second and consider that direct capillary tube extracts TISF to measurement zone, this measurement zone makes the volumetric ratio that must measure be used for bar little of CISF.In this second change, only use a working electrode (two working electrodes are opposite with using), and the area of work and reference electrode reduces to hold relative low sample size.Only it is noted that and in the collection process of 320nL sample, exert pressure that these normally about 85 seconds.After collecting required volume, pressure rings is transformed into retracted mode, and pin continues to reside in the skin under this state.Do not apply other pressure at these equilibrated 15 minutes in the interval.
Table 2 expression is measured three kinds of sample type data of collecting the circulation from the person under inspection who suffers from diabetes at 22.The result of FCB sampling is with concentration of glucose (just, [G]
FCB) expression, its result's unit is mg/dL.The result of CISF and TISF is represented that by electric current its unit is a nanoampere, and is abbreviated as i respectively
CISFAnd i
TISFFor the form of reducible data, because the difference of electrode area and to i
CISFAnd i
TISFCarry out standardization, thereby they can directly compare and be used for identical calibration formula.In addition, use precalculated calibration formula with i
CISFAnd i
TISFValue converts a series of concentration of glucose to.The concentration of glucose of CISF and TISF is abbreviated as [G] respectively
CISF[G]
TISF, and represent with the mg/dL of unit.
Table 2
| Measure circulation | ?[G] FCB?(mg/dL ?) | ?i CISF?(nA) | ??i TISF??(nA) | ?[G] CISF?(mg/dL ?) | ??[G] TISF??(mg/dL) |
| ????1 | ??107 | ??241 | ??65 | ||
| ????2 | ??104 | ??436 | ??361 | ??124 | ????101 |
| ????3 | ??110 | ??428 | ??401 | ??121 | ????113 |
| ????4 | ??200 | ??422 | ??644 | ??119 | ????186 |
| ????5 | ??311 | ??505 | ??1008 | ??144 | ????296 |
| ????6 | ??362 | ??804 | ??1171 | ??234 | ????345 |
| ????7 | ??369 | ??908 | ??1272 | ??265 | ????375 |
| ????8 | ??338 | ??916 | ??1182 | ??268 | ????348 |
| ????9 | ??354 | ??916 | ??1275 | ??268 | ????376 |
| ??10 | ??345 | ??1011 | ??1109 | ??296 | ????326 |
| ??11 | ??354 | ??958 | ??1387 | ??281 | ????410 |
| ??12 | ??348 | ??1122 | ??1229 | ??330 | ????362 |
| ??13 | ??334 | ??1007 | ??1229 | ??295 | ????362 |
| ??14 | ??310 | ??1106 | ??1096 | ??325 | ????322 |
| ??15 | ??291 | ??1216 | ??1126 | ??358 | ????331 |
| ??16 | ??268 | ??1053 | ??1012 | ??309 | ????297 |
| ??17 | ??251 | ??1047 | ??1025 | ??315 | ????301 |
| ??18 | ??238 | ??995 | ??905 | ??292 | ????265 |
| ??19 | ??222 | ??997 | ??740 | ??292 | ????215 |
| ??20 | ??211 | ??974 | ??812 | ??285 | ????237 |
| ??21 | ??195 | ??845 | ??743 | ??247 | ????216 |
| ??22 | ??175 | ??793 | ??708 | ??231 | ????205 |
For CISF and TISF glucose measurement, its measurement bar of changing separately all uses the ISF succedaneum to demarcate, and this makes can determine real concentration of glucose in CISF and TISF.The ISF succedaneum is the fluid from blood plasma, is used to imitate ISF.In calibration process, use the ISF succedaneum to be because the ISF of relatively large volume (just, about 1 milliliter) is not easy to collect.This calibration process needs relatively large volumetrical fluid to be because must prepare a plurality of demarcation things (normally six).Use is prepared the ISF succedaneum by the blood plasma (500 microlitres+500 microlitres) of isotonic saline solution dilution in 1: 2.Suitably volumetrical 1 mole of glucose solution splash into the ISF succedaneum with prepare concentration of glucose be 2.5,5,10,20 and six parts of 30mM demarcate things.Demarcate the thing concentration of glucose for each, repeat at least 5 times, and in 5 seconds, calculate average current value.Use conventional linear regression, calculate the slope and the intercept that are used for reduction formula, it becomes concentration of glucose with current conversion.Owing to the reason of electrode area to i
CISFAnd i
TISF. carried out standardization, be used for calculating [G]
CISF[G]
TISFReduction formula similar, it is represented with equation .1A and equation .1B below:
Equation .1A [G]
CISF=0.3 * i
CISF-7.6nA
Equation .1B [G]
TISF=0.3 * i
TISF-7.6nA
Should be noted that this demarcation type undertaken by the manufacturer of this test strip probably.
To discuss now and use, be used for accurately measuring the calibration process (calibration procedure) of different modes of the glucose of ISF according to the semicontinuous or continuous glucose sensor in the system of the present invention.This demarcation mode is undertaken by the user of semicontinuous or continuous glucose sensor probably.For example, demarcation only can be used one to the glucose measurement of FCB with use the glucose measurement bar such as One Touch separately
Ultra glucose measurement bar carries out.In this case, can calculate a simple ratio with estimation [G] with FCB
CISF, it is abbreviated as [G]
CISF, FCBAs arbitrary time span, measure circulation 6 according to FCB and be used to carry out single-point calibration.Should be noted that and measure a kind of state of circulation 6 expressions, in this state [G]
FCBAlong with the time increases, and, still express the possible interval that user can be selected even so owing to lack to postpone to alleviate and to demonstrate problematic demarcations at interval.Use simple ratio, reduction formula can be represented by equation .2
Equation .2
In equation .2, [G]
FCB, 6Be illustrated in the 6th concentration of glucose of measuring finger capillary blood in the circulation, and i
CISF, 6Be illustrated in the 6th electric current of measuring the CISF sample of circulation measurement.Because the concentration of glucose in ISF tends to postpone backward than the concentration of glucose among the FCB, use FCB to demarcate and effectively predicted following ISF concentration of glucose.
In order to simplify the only analysis of the part of description list 2 in present embodiment and next embodiment.To further analyze measuring circulation 5,12 and 21, and be called " rising ", " stablizing " and " decline " hereinafter.Table 3 illustrates previously mentioned three and measures circulation [G]
CISF, FCB[G]
CISFComparison.These data are pointed out the bigger absolute error of existence between the producer of the ISF glucose sensor measurement of using single-point FCB demarcation CISF and use 6ISF succedaneum demarcation thing demarcates.
Table 3.Comparison between single-point FCB demarcation and use CISF sample producer demarcate
| Measure circulation | [G] CISF，FCB(mg/dL) | ?[G] CISF?(mg/dL) | Absolute error |
| Rise | ????227 | ????144 | ????83 |
| Stable | ????505 | ????330 | ????175 |
| Descend | ????380 | ????247 | ????134 |
Except CISF, TISF also can use single-point FCB to demarcate and analyze its concentration of glucose.For this situation, can derive equation .3 to use the concentration of glucose of FCB prediction TISF, it is abbreviated as [G]
TISF, FCB
Equation .3
.2 is similar to equation, and equation .3 also uses measurement circulation 6 to carry out FCB and demarcates.Table 4 illustrates [G]
TISF FCB[G] with
CISFThree comparisons of measuring in the circulation.Absolute error (83 to 175mg/dL) between the producer that the ISF glucose sensor that uses single-point FCB to demarcate is measured TISF and used the 6ISF succedaneum to demarcate thing demarcates is littler than all absolute errors (14-18mg/dL) shown in the table 3.Therefore, table 3 and table 4 have proved that when using FCB to demarcate the ISF glucose sensor with further prediction ISF concentration of glucose ISF glucose postpones the effectiveness that alleviates.
Comparison between table 4. single-point FCB demarcation and use TISF sample producer demarcate
| Measure circulation | ??[G] TISF，FCB??(mg/dL) | ?[G] TISF?(mg/dL) | Absolute error |
| Rise | ????311 | ????296 | ????16 |
| Stable | ????380 | ????362 | ????18 |
| Descend | ????230 | ????216 | ????14 |
The ISF glucose concentration measurement can be used for predicting the concentration of FCB glucose.Usually, the internist prefers using the concentration of glucose conduct among the FCB to determine that suitably treatment is with the basis of control disease state, because this is the way that adopts in history.Yet, commercialization or just mainly using ISF but not blood the successive of commercial significant proportion and the glucose sensor that minimizes intrusion.Therefore, there is the demand of using concentration of glucose in the continuous or semicontinuous ISF glucose sensor estimation capillary blood here.
Table 5 illustrates three and measures circulation [G]
CISF, FCB[G]
FCBComparison.Data show, when attempting to use the CISF that is demarcated by FCB to measure the concentration of glucose of estimating among the FCB, its absolute error is relatively large.
Table 5. is measured the accuracy evaluation of concentration of glucose among the estimation FCB by the CISF that uses single-point FCB
| Measure circulation | ??[G] CISF，FCB??(mg/dL) | ??[G] FCB??(mg/dL) | Absolute error |
| Rise | ????227 | ????311 | ????84 |
| Stable | ????505 | ????348 | ????157 |
| Descend | ????380 | ????195 | ????185 |
Table 6 illustrates three and measures circulation [G]
CISF, TISF[G]
FCBComparison.[G]
CIS, TISFBe illustrated in the concentration of glucose in the CISF sample, it uses TISF and FCB sample to demarcate.Equation .4 derives to calculate [G]
CISF, TISF
Equation .4
Table 6. is measured the accuracy evaluation of concentration of glucose among the estimation FCB by the CISF that uses TISF sample and FCB sample
| Measure circulation | [G] CISF，TISF(mg/dL) | ??[G] FCB??(mg/dL) | Absolute error |
| Rise | ????156 | ????311 | ????155 |
| Stable | ????347 | ????348 | ????1 |
| Descend | ????261 | ????195 | ????66 |
The relatively demonstration of table 5 and table 6, when the ISF pick off by TISF and FCB timing signal, the measurement of glucose provides preferably estimation to capillary blood glucose concentration among the CISF.When with table 6 in when only using the situation of FCB sample to compare, for the situation of using TISF sample and FCB sample, " stablize " in the table 5 and the measurement circulation absolute error of " decline " less." rising " measurement circulation absolute error is bigger in the table 6.Yet, for the situation of the table 6 that uses some delays to alleviate, total mean error less (74mg/dL compares with 142mg/dL in the table 5 in the table 6).Therefore, even collect and measure CISF,, still there is the progress of estimation capillary glucose concentration ability here if the ISF pick off is demarcated by TISF and FCB without postponing to alleviate.
Table 7 illustrates three and measures circulation [G]
TISF[G]
FCBComparison.This data show, less with the absolute error of the concentration of glucose among TISF sample (referring to table 7,0 to 35/dL) replaced C ISF sample (referring to table 5,84 to 185mg/dL) the estimation FCB, TISF sample and CISF sample all use FCB to demarcate.Therefore, when using ISF glucose sensor estimation capillary blood glucose concentration, it is obviously superior to use delay to alleviate on degree of accuracy.
The TISF that table 7. is demarcated by single-point FCB measures the accuracy evaluation of concentration of glucose among the estimation FCB
| Measure circulation | ????[G] TISF，FCR????(mg/dL) | ?????[G] FCR?????(mg/dL) | Absolute error |
| Rise | ????311 | ????311 | ????0 |
| Stable | ????380 | ????348 | ????32 |
| Descend | ????230 | ????195 | ????35 |
Although the disposable test bar of Miao Shuing is used to measure the ISF glucose in this embodiment, demarcation notion discussed here also can be applicable to the pick off of any measurement ISF glucose, particularly those semicontinuous and continuous glucose sensors.Previously described scaling method shows, uses to postpone to alleviate to have improved CISF, TISF or capillary glucose concentration estimation for accuracy before demarcation.Therefore, in case known present disclosure, one one of ordinary skill in the art will appreciate that, the calibration algorithm of describing in the present embodiment can be used for the system according to embodiment of the present invention.For example, the calibration algorithm formula can be used for sampling or analysis module, to calculate capillary blood glucose concentration according to the ISF measurement data.
Embodiment 4: the ISF glucose that is undertaken by the pressure rings circulation postpones to alleviate method
22 person under inspection (12 male, 10 women that suffer from diabetes; 91 types, 13 2 types; Median age 53.5 years old; Body Mass Index median (BMI) 25.4; Time median since the morbidity: 18.0) participated in the normally test of committee's approval, wherein three duplicate samples of gathering every 15 minutes (measuring circulation) have been carried out glucose measurement in five to six hour interval.
In test process, impel the glucose skew by oral 75g glucose solution (12 persons under inspection are regarded as " 75g load person under inspection ") or normal diet custom (10 persons under inspection are regarded as " NEH person under inspection ").The person under inspection controls the picked-up of its prescription injection of insulin agent or oral medicine.
Three kinds of samples that are used for glucose measurement are, by standard finger capillary blood thrust the finger capillary blood samples of collection and two kinds of ISF samples (as described below, contrast with test I SF sample), every kind is obtained from arm of each person under inspection.The acquisition time of all samples is measured the interval at each and is produced the data of every kind of sample to (time, glucose) by computer time stamp record.The finger capillary blood glucose is by two One Touch
The Ultra blood-glucose meter (can be from LifeScan, Milpitas, CA obtains) measure twice.Here Ji Lu dextrose equivalent is average to twice blood-glucose meter reading of each sample.
It is different on mode to collect the ISF sample from every arm.(select at random) on an arm, be chosen to be contrast ISF arm, each discrete ISF sample is collected from the different sampling of forearm dorsal part site.The ISF of an about microlitre gathers by little standard-sized being needled in skin layer～2mm skin depth.Pressure rings by the 5.5mm diameter applies on skin-power of 15N so that the collection of ISF sample (acquisition time median 3.Osec, N=553), this ISF sample deposits to the One Touch of change subsequently
The detection zone of Iltra detector bar is to detect glucose.Change this and contact, thereby this ISF can Direct Sampling and in this detection zone deposition with adapter with the ISF sample system.
On the another arm, be chosen to be test I SF arm, the continuous ISF collecting device of prototype is installed to the forearm dorsal part.This equipment is attached on the arm by the medical rubber patch, and it comprises little standard-sized pin to thrust the degree of depth of the about 2mm of skin, also comprises the pressure rings around this pin, and this pressure rings is shifted onto on the skin to collect the ISF sample.In this test, equal the 320nL ISF sample of the displacement volume of pin, be collected in the capillary glass tube of 0.5 μ L (commercial can be from Drummond Scientific, Broomall, PA obtains).
In case collected the ISF of necessary amount, capillary tube is removed, and ISF is extruded into the OneTouch of change
On the Ultra glucose measurement bar to measure glucose.The change of this second makes capillary tube directly sample is extruded into measurement zone, and the amount that must detect is lacked than the amount that is generally used for this.For these two kinds of ISF glucose detection, the detector bar of change will be demarcated in advance by the ISF succedaneum, thereby the ISF glucose can directly directly be determined by contrast ISF and test I SF sample.
For the collection of test I SF sample, pressure only in 320nL sample collection process, apply (acquisition time median 85sec, N=530).After collecting needed amount, the pressure that is applied on the ring of pin stops, although pin continues to reside in the skin.No longer exerted pressure in the intercycle at these equilibrated per 15 minutes.
In order to be relatively ISF and blood glucose value of basis with time, just each sample need be mated from time and its blood glucose value that health obtains.For test I SF sample, this means that carry out a circulation time axle offset resides in (dead volume 320nL) the pin at the 320nLISF sample that particular cycle is collected from last collection circulation beginning actually with explanation always.Like this, can carry out accurate physiological to the finger blood sample that same relative time is collected postpones to detect.
The exemplary time course chart of person under inspection's acquisition is shown in Figure 15.This illustrate three kinds in the sample glucose measurements and the curve of time.For the test I SF with the skew of circulation time, time shaft is actual represent in three kinds of samples respectively time since the health extraction.Time migration has illustrated practical work, and under the situation of test I SF, sample extracts from health, but still resides in the collar aperture of 320nL, waits for being squeezed into capillary tube at next time point measurement.Therefore, this chart has reacted the physiological glucose delay between ISF and blood sample accurately.
The comparison of all data that 22 persons under inspection are collected is shown in Figure 16 A and the 16B, and it illustrates the method comparison diagram that is superimposed upon on the clarke error grid (Clarke Error Grid).Clarke error grid statistical table, return statistical table (slope, intercept and correlation coefficient, R), the standard error (Sy.X) between blood and the ISF value, with reference to the average percentage between finger blood glucose value and the ISF dextrose equivalent depart from average percentage absolute error (MPAD) shown in the table 8.Detect by all, test I SF comparison is better according to the blood glucose estimation that ISF provides.
| Statistic | Contrast ISF | Test I SF |
| % among the A | ????53.9％ | ????72.3％ |
| % among the B | ????39.6％ | ????26.3％ |
| % among the C | ????0.2％ | ????0.9％ |
| % among the D | ????6.3％ | ????0.0％ |
| % among the E | ????0.0％ | ????0.0％ |
| Slope | ????0.69 | ????0.99 |
| Intercept | ????64.7 | ????22.2 |
| ????Sy.x | ????52.5 | ????34.1 |
| ????R | ????0.81 | ????0.95 |
| Average deviation (%) | ????4.9 | ????10.0 |
| ????MPAE | ????22.3 | ????14.6 |
Table 8
Should be noted that in test I SF measures and have significant system deviation.Figure 17 illustrates the ISF measured deviation chart of these two ISF measurements with respect to reference finger blood value, is marked and drawed by the acquisition time of sample in test process, and wherein the time at zero point is the beginning of each test.The figure shows out the person under inspection's of 12 75g loads data, scope and the trend too high owing to these person under inspection's blood glucose are bigger than NEH person under inspection, therefore are used to explain that this viewpoint is best.The summary sinusoidal offset pattern reflection time course chart that contrast ISF detects just, in blood glucose rising normally minus skew of interval, changes positive skew into to EOT usually when glucose descends.Yet this test I SF has the skew of substantially flat for the testing time, and its mean deviation is 10.7% (total is 10%, comprises all persons under inspection, referring to table 8).This smooth offset response is potential to demonstrate simple calibration offset, and this calibration offset can simply be corrected by deduct 10% from all test I SF values.
Figure 18 illustrates when carrying out this skew rectification, test I SF glucose is for the recurrence chart with reference to finger blood glucose, and, when the average central skew just is being applied to test (correcting from 10% skew of table 8) and is contrasting ISF (correcting from 4.9% skew of table 8) when detecting, table 9 illustrates the clarke error grid, return and the error statistics table.It is less should to be offset the effect of rectification on overall accuracy for contrast ISF.Yet when using the skew rectification, the overall accuracy of test I SF has appreciable raising.Most of component that this expression test I SF detects error may be simple calibrated error, and it can solve by stricter scaling method.
| Statistic | The skew of contrast ISF is corrected | The skew of test I SF is corrected |
| % among the A | ????54.3％ | ????85.8％ |
| % among the B | ????38.7％ | ????14.2％ |
| % among the C | ????0.2％ | ????0.0％ |
| % among the D | ????6.7％ | ????0.0％ |
| % among the E | ????0.0％ | ????0.0％ |
| Slope | ????0.65 | ????0.89 |
| Intercept | ????64.0 | ????20.0 |
| ????Sy.x | ????53.4 | ????30.7 |
| ????R | ????0.79 | ????0.95 |
| Average deviation (%) | ????1.2 | ????-1.0 |
| ????MPAE | ????22.2 | ????10.9 |
Table 9
The practical situation (contrast ISF result's contrast can obviously be found out from table 8 and table 9) that contrast ISF measurement is subjected to little effect shows that detecting any calibrated error for these all is the error accessory constituent.These results have shown for example when the synthetic processing of slow pressure rings is applied to the ISF sample area, with respect to the potentiality of finger blood sugar test raising ISF glucose detection.
Each person under inspection is calculated each ISF sample and with reference to the average glucose time delay between the finger blood sample, determine when with discrete contrast ISF sample retardation ratio than the time, by the delay amount of alleviating of continuous ISF extraction equipment acquisition.When being used for time shaft that ISF measures and sliding, measure delay between ISF and the blood glucose by seeking minimum error between these measurements with respect to the blood measuring time shaft.For particular subject, the distance (time on) of sliding time axle to obtain minimum error is exactly average detection delay.This method was used to calculate in 25 minutes the average control ISF time delay for 57 hyperglycemia persons under inspection in the past.To this method improvement, so that it is used for individual person under inspection's calculating rather than is used for the complex data collection calculating.For example, Figure 19 A and 19B illustrate error and time chart, and it is used for when Pretesting a person under inspection being determined average control and test I SF time delay.
Table 10 illustrates the summary sheet of the average delay time that two kinds of ISF samples of individual person under inspection calculate with respect to finger blood glucose separately.Here 15 persons under inspection in only having represented 22.For other seven persons under inspection (in the 75g load group in 12 one, among 10 NEH persons under inspection six), or enough be not used to the data calculated, perhaps they do not demonstrate in the too high scope of blood glucose and carry out significant delay and determine needed enough changes.It is as shown in the table, and for each person under inspection, test I SF sample obviously reduces with respect to contrast ISF sample time delay.On meansigma methods, the delay that realized 35.8 minutes is shortened, and average retardation was cut to 2.5 minutes from 38.3 minutes, and perhaps physiological postpones to have shortened 95%.
| The person under inspection | Test-types | Contrast ISF delay (minute) | Test I SF delay (minute) | Delay variance (minute) | Percentage ratio postpones to alleviate |
| ????1 | The 75g load | ????38 | ????-3 | ????41 | ?108％ |
| ????2 | The 75g load | ????42 | ????-1 | ????43 | ?102％ |
| ????3 | The 75g load | ????40 | ????15 | ????25 | ?63％ |
| ????4 | The 75g load | ????28 | ????-3 | ????31 | ?111％ |
| ????5 | The 75g load | ????28 | ????6 | ????22 | ?79％ |
| ????6 | The 75g load | ????39 | ????3 | ????36 | ?92％ |
| ????7 | The 75g load | ????60 | ????1 | ????59 | ?98％ |
| ????8 | The 75g load | ????50 | ????9 | ????41 | ?82％ |
| ????9 | The 75g load | ????42 | ????8 | ????34 | ?81％ |
| ???10 | The 75g load | ????40 | ????-8 | ????48 | ?120％ |
| 11 | The 75g load | ????60 | ????10 | ????50 | ?83％ |
| 12 | ???NEH | ????28 | ????1 | ????27 | ?96％ |
| 13 | ???NEH | ????27 | ????2 | ????25 | ?93％ |
| 14 | ???NEH | ????27 | ????-8 | ????35 | ?130％ |
| 15 | ???NEH | ????25 | ????5 | ????20 | ?80％ |
| All person under inspection's combinations | 38.3 | ????2.5 | ??35.8 | ????95％ |
| 11.5 | ????6.6 | ??11.3 | ????18％ |
| 75g load person under inspection | ????42.5 | ????3.4 | ????39.1 | ????93％ |
| ????1.3 | ????5.6 | ????6.2 | ????21％ |
| The NEH person under inspection | ????26.8 | ????0.0 | ??26.8 | ????100％ |
| ????1.3 | ????5.6 | ??6.2 | ????21％ |
Table 10
Enjoyably, by the method that comprises that hemoperfusion increases, the skew naturally between ISF and the blood glucose has significant minimizing, for example the pressure rings applying method of the adjusting of using in the test of here describing.Therefore, its modulated pressure that is supposition applies in this test produces and increases the dabbling effect of ISF sample sites peripheral blood, and has significantly alleviated physiological delay (just, the ISF glucose postpones).
Although preferred implementation of the present invention is shown here and description, be apparent that to those skilled in the art this embodiment only is to provide by way of example.Those of ordinary skills will expect not deviating from multiple variation of the present invention, change and replacement.
A kind of system that is used for monitoring user tissue fluid (ISF) analyte, this system comprises: cartridge case, this cartridge case are included as the analysis module that user is measured analyte among the ISF; And local controller module, this local controller module and this cartridge case electronic communication, this local controller is arranged to from analysis module and receives measurement data and store this data, wherein this analysis module comprises that configuration is used for being injected into analyte sensor in the user target site to small part, and wherein this analysis module comprises that at least one is applicable to pressure is applied near the pressure rings on the health target site, and wherein this analysis module is configured to make pressure rings to exert pressure in the mode of vibration, and the ISF glucose postpones therefore to alleviate.The analysis module of aforementioned system uses here and postpones to alleviate chemical substance further to alleviate the delay of ISF glucose.The analysis module of aforementioned system uses ultrasonic further to alleviate the delay of ISF glucose here.The analysis module of aforementioned system uses heat to postpone further to alleviate the ISF glucose here.The analysis module of aforementioned system uses vacuum to postpone further to alleviate the ISF glucose here.The analysis module of aforementioned system uses electrode potential to postpone further to alleviate the ISF glucose here.The analysis module of aforementioned system uses the non-vibration mechanically actuated of health to postpone further to alleviate the ISF glucose here.
A kind of system that is used to extract body fluid and monitoring glucose wherein, this system comprises: disposable cartridge case, it comprises: the sampling module that is used for extracting from health humoral sample; And the analysis module that is used for measuring the glucose of humoral sample; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein at least one in analysis module and the local controller module used a kind of calibration algorithm, and this algorithm depends on the concentration of glucose measured and from the measurement data of analysis module from capillary blood.In the foregoing system of this section, humoral sample is the ISF sample and has the ISF glucose from the measurement data that analysis module obtains and postpone to alleviate.Sampling module in the foregoing system of this section comprises at least one pressure rings.Sampling module in the foregoing system of this section is configured to pressure rings and can exerts pressure in the mode of vibration, postpones thereby alleviate the ISF glucose.Sampling module in the foregoing system of this section comprises and thrusts part that at least one pressure rings and this pressure rings can be exerted pressure with mode of vibration, postpone thereby alleviate ISF.
Be used for monitoring the system of user body fluid analyte, this system comprises: disposable cartridge case, and it comprises: the analysis module that is used for measuring the humoral sample analyte; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein at least one in analysis module and the local controller module used a kind of calibration algorithm, and it depends on the concentration of glucose measured and from the measurement data of analysis module from capillary blood.In the foregoing system, humoral sample is the ISF sample and has the ISF glucose from the measurement data that analysis module obtains and postpone to alleviate.Sampling module in the foregoing system of this section comprises at least one pressure rings.Sampling module in the foregoing system of this section is configured to pressure rings and can exerts pressure in the mode of vibration, postpones thereby alleviate the ISF glucose.Sampling module in the foregoing system of this section comprises and thrusts part that at least one pressure rings and this pressure rings can be exerted pressure with mode of vibration, postpone thereby alleviate ISF.
Be used to extract the system of humoral sample and monitoring analyte wherein, this system comprises: disposable cartridge case, and it comprises: the sampling module that is used for extracting humoral sample in health; Analysis module with the analyte that is used for measuring humoral sample; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein this sampling module uses the sample extraction technology based on micro-dialysis.The glucose that sampling module configuration in the foregoing system of this section is used for extracting tissue fluid (ISF) sample and is used to measure this ISF sample, and wherein this sampling module comprises that further the ISF glucose postpones alleviator.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance.In the foregoing system of this section this is used to alleviate the ultrasonic ISF of the alleviating glucose delay of device use that the ISF glucose postpones.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used heat to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used vacuum to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used electrode potential to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used the mechanically actuated of health to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance, ultrasonic, heat, and vacuum, at least two combination alleviates the ISF glucose and postpones in the mechanically actuated of electrode potential and health.
Be used to extract humoral sample and monitor the wherein system of analyte, this system comprises: disposable cartridge case, and it comprises: the sampling module that is used for extracting humoral sample in health; With the analysis module that is used for measuring the humoral sample analyte; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein the sample extraction technology of this sampling module based on Ultrafiltration.The glucose that sampling module configuration in the foregoing system of this section is used for extracting tissue fluid (ISF) sample and is used to measure this ISF sample, and wherein this sampling module comprises that further the ISF glucose postpones alleviator.In the foregoing system of this section this is used to alleviate the device that the ISF glucose postpones and uses the ISF glucose to postpone to alleviate chemical substance.In the foregoing system of this section this is used to alleviate the ultrasonic ISF of the alleviating glucose delay of device use that the ISF glucose postpones.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used heat to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used vacuum to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used electrode potential to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used the mechanically actuated of health to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance, ultrasonic, heat, and vacuum, at least two combination alleviates the ISF glucose and postpones in the mechanically actuated of electrode potential and health.
Be used to extract the system of humoral sample and monitoring analyte wherein, this system comprises: disposable cartridge case, and it comprises: the sampling module that is used for extracting humoral sample in health; Analysis module with the analyte that is used for measuring humoral sample; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein this sampling module uses the sample extraction technology based on laser.The glucose that sampling module configuration in the foregoing system of this section is used for extracting tissue fluid (ISF) sample and is used to measure this ISF sample, and wherein this sampling module comprises that further the ISF glucose postpones alleviator.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance.In the foregoing system of this section this is used to alleviate the ultrasonic ISF of the alleviating glucose delay of device use that the ISF glucose postpones.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used heat to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used vacuum to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used electrode potential to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used the mechanically actuated of health to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance, ultrasonic, heat, and vacuum, at least two combination alleviates the ISF glucose and postpones in the mechanically actuated of electrode potential and health.
Be used to extract the system of humoral sample and monitoring analyte wherein, this system comprises: disposable cartridge case, and it comprises: the sampling module that is used for extracting humoral sample in health; Analysis module with the analyte that is used for measuring humoral sample; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein this sampling module uses the sample extraction technology based on the counter ion electro-osmosis method.The glucose that sampling module configuration in the foregoing system of this section is used for extracting tissue fluid (ISF) sample and is used to measure this ISF sample, and wherein this sampling module comprises that further the ISF glucose postpones alleviator.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance.In the foregoing system of this section this is used to alleviate the ultrasonic ISF of the alleviating glucose delay of device use that the ISF glucose postpones.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used heat to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used vacuum to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used electrode potential to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate the device that the ISF glucose postpones and uses the mechanically actuated of health to alleviate the ISF glucose.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance, ultrasonic, heat, and vacuum, at least two combination alleviates the ISF glucose and postpones in the mechanically actuated of electrode potential and health.
Be used to extract the system of humoral sample and monitoring analyte wherein, this system comprises: disposable cartridge case, and it comprises: the sampling module that is used for extracting humoral sample in health; Analysis module with the analyte that is used for measuring humoral sample; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein this sampling module uses the sample extraction technology based on electroporation.The glucose that sampling module configuration in the foregoing system of this section is used for extracting tissue fluid (ISF) sample and is used to measure this ISF sample, and wherein this sampling module comprises that further the ISF glucose postpones alleviator.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance.In the foregoing system of this section this is used to alleviate the ultrasonic ISF of the alleviating glucose delay of device use that the ISF glucose postpones.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used heat to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate the device that the ISF glucose postpones and uses vacuum to alleviate delay.In the foregoing system of this section this is used to alleviate the device that the ISF glucose postpones and uses electrode potential to alleviate delay.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used the mechanically actuated of health to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance, ultrasonic, heat, and vacuum, at least two combination alleviates the ISF glucose and postpones in the mechanically actuated of electrode potential and health.
Be used to extract humoral sample and monitor the wherein system of analyte, this system comprises: disposable cartridge case, and it comprises: the sampling module that is used for extracting humoral sample in health; With the analysis module that is used for measuring the humoral sample analyte; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein this sampling module uses based on ultransonic sample extraction technology.The glucose that sampling module configuration in the foregoing system of this section is used for extracting tissue fluid (ISF) sample and is used to measure this ISF sample, and wherein this sampling module comprises that further the ISF glucose postpones alleviator.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance.In the foregoing system of this section this is used to alleviate the ultrasonic ISF of the alleviating glucose delay of device use that the ISF glucose postpones.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used heat to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used vacuum to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used electrode potential to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used the mechanically actuated of health to alleviate the ISF glucose to postpone.In the foregoing system of this section this is used to alleviate device that the ISF glucose postpones to be used and postpones to alleviate chemical substance, ultrasonic, heat, and vacuum, at least two combination alleviates the ISF glucose and postpones in the mechanically actuated of electrode potential and health.
Be used to extract the system of the humoral sample and the monitoring analyte wherein of user, this system comprises: disposable cartridge case, and it comprises: the analysis module that is used for measuring the analyte of humoral sample; And with the local controller module of this disposable cartridge case electronic communication, the local controller configuration is used for receiving measurement data and storing this data from analysis module, wherein analysis module comprises that configuration is used for inserting to small part the analyte sensor of user.Analyte sensor in this section system noted earlier be ISF glucose analyte pick off and wherein this analysis module further comprise and be used to alleviate the device that glucose postpones.Being used to alleviate the device that the ISF glucose postpones in this section system noted earlier is that at least one pressure rings is applied to user when analyte sensor is applicable to pressure when small part is inserted user.
Should be appreciated that the various embodiments of selecting of the present invention described herein can be used to realize the present invention.Intention is determined scope of the present invention with claims, and the method and structure in these claim scopes with and equivalent therefore be capped.
Claims (13)
1, a kind of system that is used to extract tissue fluid (ISF) sample and monitoring analyte wherein, this system comprises:
Cartridge case comprises:
Be used for extracting the sampling module of ISF sample from the physical target site; And
Be used for measuring the analysis module of the analyte of ISF sample; And
With the local controller module of this cartridge case electronic communication, this local controller configuration is used for receiving measurement data and storing this data from this analysis module.
Wherein this sampling module comprises that at least one is applicable near the pressure rings that health is exerted pressure target site, and
Wherein this sampling module configuration makes this pressure rings to exert pressure with mode of vibration, thereby is postponed to be alleviated by the ISF glucose in the ISF sample of sampling module extraction.
2, the system as claimed in claim 1, wherein this pressure rings configuration is used for exerting pressure about 85 seconds in about 15 minutes sampling circulation.
3, the system as claimed in claim 1, wherein this sampling module also comprises and thrusts degree of depth control element.
4, system as claimed in claim 3, wherein this thrusts degree of depth control element and combines with at least one pressure rings of sampling module.
5, the system as claimed in claim 1, wherein this sampling module comprises and thrusts part, and this thrusts part and can be independent of this at least one pressure rings and move.
6, the system as claimed in claim 1, wherein this sampling module comprises and thrusts part, and this thrusts part and fixes with respect at least one pressure rings of this sampling module.
7, the system as claimed in claim 1, wherein this employing module is used and is postponed to alleviate chemical substance further to alleviate the delay of ISF glucose.
8, the system as claimed in claim 1, wherein to alleviate chemical substance be the histamine chemical substance in this delay.
9, the system as claimed in claim 1, wherein this sampling module uses ultrasonic further to alleviate this ISF glucose delay.
10, the system as claimed in claim 1, wherein this sampling module uses heat to postpone further to alleviate this ISF glucose.
11, the system as claimed in claim 1, wherein this sampling module uses vacuum to postpone further to alleviate this ISF glucose.
12, the system as claimed in claim 1, wherein this sampling module uses electrode potential to postpone further to alleviate this ISF glucose.
13, the system as claimed in claim 1, wherein this sampling module uses the non-vibration mechanically actuated to health to postpone further to alleviate this ISF glucose.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47673303P | 2003-06-06 | 2003-06-06 | |
| US60/476,733 | 2003-06-06 | ||
| US10/653,023 | 2003-08-28 | ||
| US10/861,749 | 2004-06-04 |
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| CN1700884A true CN1700884A (en) | 2005-11-23 |
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| CN 200480001020 Pending CN1700884A (en) | 2003-06-06 | 2004-06-07 | Systems for extracting bodily fluid and monitoring an analyte therein |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107076725A (en) * | 2014-08-05 | 2017-08-18 | 三和生物科技有限公司 | Field diagnosing system and its method |
| CN110873656A (en) * | 2018-08-31 | 2020-03-10 | 恩德莱斯和豪瑟尔分析仪表两合公司 | Sampling container, sampling system and sampling method for processing liquid samples |
| CN111107679A (en) * | 2019-12-02 | 2020-05-05 | 天津大学 | Flexible temperature control system |
-
2004
- 2004-06-07 CN CN 200480001020 patent/CN1700884A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107076725A (en) * | 2014-08-05 | 2017-08-18 | 三和生物科技有限公司 | Field diagnosing system and its method |
| CN110873656A (en) * | 2018-08-31 | 2020-03-10 | 恩德莱斯和豪瑟尔分析仪表两合公司 | Sampling container, sampling system and sampling method for processing liquid samples |
| US11926457B2 (en) | 2018-08-31 | 2024-03-12 | Endress+Hauser Conducta Gmbh+Co. Kg | Sampling container, sampling system and sampling method for processing a liquid sample |
| CN111107679A (en) * | 2019-12-02 | 2020-05-05 | 天津大学 | Flexible temperature control system |
| CN111107679B (en) * | 2019-12-02 | 2021-06-04 | 天津大学 | Flexible temperature control system for extraction of reverse iontophoresis |
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