CN102818822A - Device and method for measuring prothrombin time and hematocrit (HCT%) by analyzing change in reactance in a sample - Google Patents
Device and method for measuring prothrombin time and hematocrit (HCT%) by analyzing change in reactance in a sample Download PDFInfo
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- CN102818822A CN102818822A CN2011102855640A CN201110285564A CN102818822A CN 102818822 A CN102818822 A CN 102818822A CN 2011102855640 A CN2011102855640 A CN 2011102855640A CN 201110285564 A CN201110285564 A CN 201110285564A CN 102818822 A CN102818822 A CN 102818822A
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Abstract
Devices and methods for measuring prothrombin time and hematocrit (HCT%) by analyzing the change in reactance in a sample are presented. A diagnostic device for measuring HCT and prothrombin time of a fluid includes a relative electrode-type sensor device and a blood test card assembly including one or more pairs of electrodes, wherein alternating current (AC) provided by the sensor device is used to measure and calculate prothrombin time and HCT of blood test using the reactance analysis.
Description
Related application is quoted alternately
The application's case is by being proposed on June 9th, 2010; Title be " utilize analyzing reactance change " to measure the diagnostic device and the method for prothrombin time and blood cell volumetric ratio (HCT%) the 61/353rd; The non-temporary patent application case of No. 137 U.S. Provisional Patent Application cases, the complete content of above-mentioned application case is incorporated this paper into way of reference.
Technical field
The present invention relates to a kind of biochemical detection device, be particularly to a kind of utilization and analyze reactance change to measure the diagnostic device and the method for prothrombin time and blood cell volumetric ratio (HCT%).
Background technology
Human body blood coagulation reaction can be divided into external path (extrinsic pathway) and inherent path (intrinsic pathway).When human body is injured, at first can start external path with the blood coagulation in control volume reaction, this blood coagulation reaction needs tissue factor (tissue factor) in addition except needs blood, be factor X (factor X) catalysis of tool activity not factor Xa (factor Xa).Moreover; Factor Xa becomes fibrin ferment (thrombin, factor IIa) to factor (prothrombin, factor II) through the effect of factor Va (factor Va), acidic phospholipid and calcium ion; And fibrin ferment becomes fibrin to fibrinogen (fibrinogen) again; Strengthen accumulating in the blood platelet of endothelial cell injury, and fibrin ferment also can be promoted the effect of factor XIII, each other fibrin molecule Colaesce and stable fibers albumen.Accordingly, prothrombin time (prothrombin? Time) in addition to the inspections can be extrinsic coagulation factor activation system is functioning correctly detect pointer, but also can be used to observe the oral anticoagulant therapy, liver function, deficiency of vitamin K, coagulation factor deficiency , disseminated intravascular coagulation syndrome (DIC) assessment and monitoring.
The method in known detection clotting time is when solidifying with analyzing blood; Soluble protein changes the coacervation that insolubility protein is produced in this serum; And utilize and detect like optical meanss such as change color, reflection, refraction, cold light and fluorescence, yet this analytical approach needs a large amount of blood sample and highly purified reagent and expends than the long time, like United States Patent (USP) the 5th; Shown in 418, No. 141.But these detection modes needed detection times is long, consumptive material is many, and real be inconvenient.
Other has known electrochemical detection method, United States Patent (USP) the 3rd, 699; No. 437; Its for observe impedance from initially to the rate of descent of the comparison of minimum point, with its result of calculation as the foundation of judging blood coagulation, for impedance (impedance) or resistance (resistance) signal as the blood coagulation measurement mechanism.And after it, United States Patent (USP) the 6th, 060 is also arranged, No. 323, the 6th; 338, No. 821, the 6th, 066, No. 504, the 6th; 673, No. 622, and the 6th, 046; No. 051 etc., the open measurement Demand Design of complying with becomes unitary electrode or plurality of electrodes, utilizes the difference of blood clotting front and back viscosity, and the method for the impedance variations that is caused is to measure the technology of blood sample blood coagulation.Yet this technology can be because of blood cell volume different test errors that cause of the electrolyte concentration in the blood between individuality when.Moreover, United States Patent (USP) the 7th, 005, No. 857 patent discloses a kind of blood coagulation pick-up unit that comprises automatic blood sampling in addition, and this testing mechanism decides the clotting time for the variation of measuring two interelectrode capacitances (capacitance) or impedance (impedance).Therefore, these technology improve the simplicity of detection greatly, but can't reach the precision that optical means detects.
In view of this, but be necessary in fact to provide a fast detecting, the convenient use and the measurement prothrombin time (PT) of accuracy height and the biology sensor of blood cell volumetric ratio (HCT%).
Summary of the invention
In view of this, one of the present invention purpose is to provide a kind of and utilizes reactance (reactance X) carries out measuring method to blood.Wherein this reactance is analyzed blood properties analysis more accurately can be provided, and effectively reduces test error and improve the accuracy of measuring.
Another object of the present invention is to provide a kind of detection system of measuring prothrombin time and HCT% with the reactance analytic approach; This system comprises sensor and use test sheet thereof; Mean this test piece comprise a pair of or plural to noble metal electrode, be arranged on the same plane respectively or on the non-same plane, be to utilize sensor that one alternating current (Alternating current is provided; AC), measure and computing prothrombin time and HCT% with the reactance analytic approach.
Another purpose in the present invention is to provide a kind of test card assembly that increases the contact area of blood and reaction reagent.According to some embodiments of the invention, said test card assembly adopts the material of multiple hole, and for example glass plate (FR-4) is as at least a portion of this test card substrate.Because at least a portion of this test card substrate; Be preferably on whole surfaces and have poriness; For example can have a plurality of holes, hole, reach the hole on its surface; So material can be disperseed blood better and equably, increases the contact area of blood and reagent thus, and effectively improves the shortcoming of traditional non-hole material.According to the present invention, can reduce effectively or eliminate because of using non-hole material substrate to cause blood cohesion to improve, cause the not good problem of surface of contact of blood and reagent.
According to the present invention on the one hand, the diagnostic device of a kind of measurement blood cell volumetric ratio (HCT%) and/or prothrombin time is provided, it comprises comparative electrode type sensor device; And the test card assembly, comprise one or many to working electrode; Wherein interchange (AC) signal is provided by this sensor device, by the reactance analysis to measure and to calculate prothrombin time and the blood cell volumetric ratio in the blood testing.
In an embodiment, this sensor device comprises that the test card accommodating unit is to hold this test card assembly; The temperature maintenance unit is with control and keep this test card accommodating unit to steady temperature; AC signal generation unit provides the alternating current of frequency and voltage to this test card assembly; The signal receiving element, intercepting is from the response signal of this test card component responds; One processor calculates this response signal and obtains this blood cell volumetric ratio and the result of this prothrombin time; And display unit, show from this blood cell volumetric ratio that this microprocessor calculated and the testing result of this prothrombin time.
According to a further aspect of the invention, the method for a kind of measurement blood cell volumetric ratio (HCT%) and prothrombin time is provided, it comprises provides test card assembly to test card accommodating unit; The temperature of controlling and keep this test card accommodating unit is to steady temperature; Provide sample to be detected to this test card assembly; The alternating current that CF and voltage are provided by AC signal generation unit is to this test card assembly; Receive response signal by this test card assembly, and calculate this response signal by microprocessor and obtain this blood cell volumetric ratio and this prothrombin time; And provide testing result to display unit to show.
Description of drawings
The 1st figure shows the block schematic diagram of the diagnostic device of according to some embodiments of the invention measurement blood cell volumetric ratio (HCT) and/or prothrombin time.
The 2nd figure one of shows according to the present invention the exploded perspective view of the blood testing card assembly of embodiment, and wherein dotted line is represented the relative position between each member.
3A and 3B figure demonstration side by side utilize electron microscope observation test card assembly not have the microstructure photo of hole and tool hole substrate.
The 4th figure system shows the process flow diagram according to the diagnostic method of the measurement blood cell volumetric ratio (HCT%) of the embodiment of the invention and prothrombin time.
The 5th figure demonstration impedance variations is to the experimental data figure of clotting time (second), and its expression is measured the slope variation when whole blood sample is solidified with general impedance measurement.
The 6th figure demonstration reactance change is to the experimental data figure of clotting time (second), and its expression is measured the slope variation when whole blood sample is solidified with the reactance measurement method.
The 7th and 8 figure show experimental data figures, and it representes that respectively PT is to the calibration curve (the 7th figure) of impedance rate of change and the expression PT calibration curve (the 8th figure) to the reactance change rate.
The 9th and 10 figure show an example, in 60 seconds, measure resistance value and reactance value in per 0.5 second by the LCR ammeter.
The 11st and 12 figure show the experiment examples, and it representes that respectively PT is to the calibration curve of impedance rate of change (impedance change rate) and the expression PT calibration curve to reactance change rate (reactance change rate).
The 13rd and 14 figure show experimental data figures, the PT that its PT that representes respectively to proofread and correct is proofreaied and correct by impedance measurement and expression real number PT to real number PT by reactance measurement.
15A and 15B figure shows experimental data figure, and it is illustrated respectively on poriness substrate and the imporosity substrate of test card and carries out coagulation analysis.
The 16A～16C figure shows experimental data figure, and it representes respectively under different frequency, to carry out coagulation analysis according to the embodiment of the invention through the reactance measurement method.
The primary clustering symbol description
100 diagnostic devices
110 test card assemblies
120 sensor devices
122 test card accommodating unit
124 AC signal generation units
The unit is calculated at 126 phasing degree
128 signal receiving elements
130 microprocessors
132 temperature sensors
134 temperature maintenance unit
136 display units
210 insulated substrates
220 electrode systems
222 sample areas
224 conversion zones
225 test electrodes
226 working electrodes
228 reference electrodes
230 separate layers
232 gaps
236 passages
240 top covers
242 introducing ports
244 vent ports
S410-S480 measures the step of blood cell volumetric ratio and prothrombin time
For making the present invention can be more obviously understandable, hereinafter is special lifts embodiment, and cooperates appended graphicly, elaborates as follows:
Embodiment
Below specify and be accompanied by the example of graphic explanation with a plurality of embodiment, as the present invention's reference frame.In graphic or instructions were described, similar or identical part was all used identical figure number.And in graphic, the shape of embodiment or thickness can enlarge, and indicate with clear or convenient.Moreover, graphic in each assembly part will it should be noted that the assembly that does not illustrate among the figure or describe, for having the form that common knowledge the knowledgeable is known in the affiliated technical field to describe explanation respectively.Moreover, when describe one deck be positioned at another layer or a substrate it " on ", can represent to be located immediately at another layer or above the substrate, perhaps can represent has the middle layer to be present in therebetween.
More of the present invention to implement examples be not to be accompanied by that the application is graphic to be explained in more detail.It should be noted that the characteristic that in graphic, is shown does not illustrate with specific ratio.Known member, material and process technique can be selected to omit to avoid optionally fuzzy embodiments of the invention.Member, material and process technique described in those embodiment is merely the describing mode that discloses the present invention's use, and it is not in order to limit the present invention.
In view of above-mentioned known technology problem, following examples provide a kind of and utilize the reactance analysis (hematocrit, system HCT%) also are commonly referred to as the reactance measurement module to measure prothrombin time and blood cell volumetric ratio.More particularly, can use detection system to put characteristic and measurement precision to improve a corpse or other object for laboratory examination and chemical testing.Utilize reactance to be directed against the analysis of blood clotting measurement characteristics or the detection of blood cell volumetric ratio, more preferably be applied to the quantitative test in clotting time.In hereinafter, the number percent of blood cell volumetric ratio general reference Packed Red Blood Cells in the volume of whole blood.
One of the present invention embodiment provides a kind of comparative electrode type sensor device, and it has test card and comprises one or more pairs of working electrodes.The substrate of said test card can be made up of porous material or imporosity material.Said working electrode can be made up of precious metal, and it comprises but is not limited to: gold (Au), silver (Ag), palladium (Pd), platinum (Pt), the alloy of above-mentioned metal and the combination in any of above-mentioned metal.In the present invention's one side; With the alternating current module or to exchange and the direct current interactive module; Provide test signal to this blood testing card to make it have hunting of frequency; This frequency range for about 0.1KHz to about 50KHz, and voltage supplied to be carrying out reactance measurement, this voltage range can be between about 0.05V about 5V extremely.As relevant with measured value in this embodiment system; Said " pact " means in this area that tool knows that usually the knowledgeable implements to measure and the careful operation measuring equipment, uses this measuring equipment to reach measurement purpose and measuring accuracy and measurement magnitude variations that expectability reaches.
In a preferred aspect, when the reaction between enzyme and the blood causes the blood clotting phenomenon,, mainly cause the difference of slope to carry out the reactance analysis according to time length in the coagulation process by the reaction signal that sensor device received and handled.In an embodiment, said electrode can be gold electrode.In this specific embodiment; Adopt an alternating current module to carry out reactance measurement according to vibration concussion test signal from the response of blood testing card; Wherein when the reaction of enzyme and blood causes the blood clotting phenomenon; By the reaction signal that sensor device received and handled, mainly cause the difference of slope to carry out the reactance analysis according to time length in the coagulation process.
The principle of carrying out reactance measurement according to some embodiments of the invention is as follows.In alternating circuit (ACcurcuit), impedance is that resistance (R) adds that reactance (X) takes advantage of the summation of in the phasing degree (θ), shown in the following formula:
Wherein reactance (X) is the imaginary part of complex impedance (Z), be used to represent inductance (L) and electric capacity (C) inhibition to electric current, and resistance (R) is the real part of complex impedance.Such as those skilled in the art knowledge, reactance is along with the change of frequency of alternating circuit, along with capacitance variations and/or along with inductance changes and changes.Reactance change in alternating circuit, the electric current wave mode of alternating circuit and the phase place of voltage waveforms also change thereupon.Being defined as of said impedance:
Z=R+jX, and | Z|=(R
2+ Z
2)
1/2(1)
Wherein Z is impedance (impedance), and R is resistance (resistance), and j is the phasing degree, and X is reactance (reactance); And
X=X
C+ X
L, X
L=2 π fL, and X
C=1/2 π fC (2)
X wherein
CFor capacitive reactance (capacitor reactance), be X
LInduction reactance (inductor reactance) is circular constant, and f is a frequency, and L is an inductance, and C is an electric capacity.
In an embodiment aspect, when operation, the AC signal generation unit of said detection system provides interchange (AC) test signal.When blood sample between electrode, induced charge can stressed and mobile formation electric capacity in electric field.When blood sample solidifies, between working electrode, constituted medium, thereby hindered electric charge and moved and make electric charge be accumulated on the conductor.This charges accumulated can cause capacitive reactance to produce.In a preferred aspect, the frequency that the AC signal generation unit provided (f) of detection system is a definite value, so inductance (L) and induction reactance (XL) also is definite value, so the variable quantity of capacitive reactance (XC) equals the variable quantity of reactance, shown in following formula.
X
C2-X
C1＝X
2-X
1 (3)
X wherein
C2-X
C1Be capacitive reactance (X
C) variable quantity, and X
2-X
1Variable quantity for reactance.
By the variable quantity of measuring unit's reactance under the time, in the time of can learning blood clotting its relatively the variable quantity of capacitive reactance under the unit interval and under the unit interval changes in capacitance amount.With the present invention, the electric resistance measuring module assistance, can be calculated by the slope of the prothrombin time (blood coagulation time) in length.
The 1st figure shows the block schematic diagram of the diagnostic device of according to some embodiments of the invention measurement blood cell volumetric ratio (HCT) and/or prothrombin time.Shown in the 1st figure; The diagnostic device 100 of a kind of measurement blood cell volumetric ratio (HCT) and/or prothrombin time comprises comparative electrode type sensor device 120 and has one or many test card assemblies 110 to working electrode; Wherein interchange (AC) signal is provided by this sensor device, by the reactance analysis to measure and to calculate prothrombin time and the blood cell volumetric ratio in the blood testing.This sensor device 120 comprises that test card accommodating unit 122 is to hold this test card assembly 110; Temperature maintenance unit 134 is with control and keep this test card accommodating unit to steady temperature; AC signal generation unit 124 provides the alternating current of frequency and voltage to this test card assembly 110; 128 interceptings of signal receiving element are from the response signal of this test card component responds; Microprocessor 130 calculates the result that these response signals are also obtained this blood cell volumetric ratio and this prothrombin time, and display unit 136 shows this blood cell volumetric ratio that calculated from this microprocessor 130 and/or the testing result of this prothrombin time.
The 2nd figure system shows that wherein dotted line is represented the relative position between each member according to the exploded perspective view of the blood testing card assembly of the embodiment of the invention.Said blood testing card assembly comprises insulated substrate 210, electrode system 220, separation and responding layer 230 and top cover 240.Insulated substrate 210 is for being electrically insulated, and its material can comprise but be not limited to the substrate that is made up of porous material.In an embodiment, the substrate of test card assembly comprises a plurality of holes, its diameter range on the whole between about 0.1 μ m to about 10 μ m; About 0.01 μ m is to about 100 μ m, and about 0.1 μ m is to about 50 μ m, and about 0.1 μ m is to about 20 μ m; About 0.1 μ m is to about 5 μ m, or about 5 μ m are to about 10 μ m.Electrode system 220 can be made up of any conductive material, and it comprises but is not limited to the combination in any of carbon, Jin-Yin, copper, carbon silver, palladium, platinum, nickel, other materials similar or above-mentioned material.Said electrode system 220 can comprise one or more pairs of noble metal electrodes, establishes respectively as on identical or the different plane.For example, one group of test electrode 225 comprises pair of electrodes 226,228.According to principle of the present invention, above-mentioned structure does not limit test electrode 225 is arranged with specific configuration, or limits the number of electrode.Also can extra electrode be provided according to different application requirements.This electrode system further is electrically connected to the electrode system (not illustrating) of measurement mechanism.
Illustrated separate layer 230 comprises gap 232, establishes as on the electrode system 220.Said separate layer 230 can also comprise conversion zone 224, reaction reagent of exposed portions serve (not illustrating) and sample areas 222.Channel 236 can be communicated with sample areas 222 and conversion zone 224.Said conversion zone 224 is preferably dimensioned to be the electrode 226 and 228 that can be enough to exposed portions serve.In this embodiment, conversion zone 224 is the zones in order to the measurement prothrombin time, and sample areas 222 is in order to measure the zone of blood cell volumetric ratio.
Cap layer 240 is established the top as for separate layer 230.In an embodiment, this cap layer 240 can comprise introducing port 242 and vent port 244, and it is connected to sample areas 222 and conversion zone 224 respectively.The size system of sample space is determined by the thickness of separate layer 230.
3A and 3B figure demonstration respectively utilize electron microscope observation test card assembly not have the microstructure photo of hole and tool hole substrate.In 3B figure, display aperture hole dia magnitude range can be between about 0.1 μ m to about 10 μ m, the about 3.39m of mean diameter; And the situation of being evenly distributed of hole is about 5.04 * 106/cm2 hole.
The 4th figure system shows the process flow diagram according to the diagnostic method of the measurement blood cell volumetric ratio (HCT) of the embodiment of the invention and prothrombin time.The method of said measurement blood cell volumetric ratio (HCT) and prothrombin time comprises test card assembly to test card accommodating unit (step S410) is provided; Control and keep temperature to the steady temperature (step S420) of this test card accommodating unit; Provide sample to be detected to this test card assembly (step S430); The alternating current that CF and voltage are provided by AC signal generation unit is to this test card assembly (step S440); Draw response signal from this this AC signal of test card component responds, relatively this response signal and this AC signal calculate the phase angle variations (phasing degree skew) of this AC signal, and calculate electric capacity and this blood cell volumetric ratio (step S450) by microprocessor; Be modified to this prothrombin time (step S460) with algorithm this electric capacity of conversion and with reference to this blood cell volumetric ratio; (international normalized ratio INR) revises this prothrombin time by an AC signal generation unit (step S470) with the regular ratio in the world; And provide testing result to display unit to show (step S480).
According to some embodiments of the invention, said response signal be digitized and with discrete Fourier conversion (discrete fourier transformation, DFT).Therefore, the computing method of real part and imaginary part are represented as follows respectively.
Wherein X (k) is the Fourier value of digital signal, and x (n) is the original value of digital signal, and n is the current point of digital signal, and N is the sum of digital signal.Moreover the phasing degree can draw according to following formula calculating real part and imaginary part:
Phasing degree=tan-1 (Im/Re) (3)
Wherein Im is that imaginary value (for example reactance) and Re are real number value (for example resistance).Shown in above formula (3), will squint along with the change of reactance in the phasing degree in sample.
In some embodiment, in above step S450 narration, the step that relatively gets response signal and original AC signal from pattern detection comprises: by measuring response signal and the amount that applies voltage calculating reactance; Calculate the impressed voltage wave mode and measure the phase angle variations between the wave mode; Calculate reactance by said phase angle variations.Will be appreciated that,, be attributable to the change of electric capacity in the sample as the variation at previous said phasing degree because alternating current has fixing frequency.Because the change of electric capacity causes reactance change in sample, can calculate HCT and prothrombin time (PT) by reactance change, further discuss as follows.
From the measured reactance that obtains, can calculate HCT by interpolation method (interpolation).The concrete example that calculates the blood cell volumetric ratio is below described.Tradition uses the method for impedance computation blood cell volumetric ratio also to be described as comparative example.
The 5th and 6 figure show experimental data figure, and it representes that respectively impedance and reactance are along with higher blood cell volumetric ratio changes.Shown in the data plot of the 6th figure, in this particular example, the reactance of locating different HCT (29.3 and 47%) at the 11st second is respectively 620.29,625.17 and 676.59 nurses difficult to understand (ohm).Then, calculate the relation (the 7th figure) of HCT and impedance or the relation (the 8th figure) of HCT and reactance.Shown in the 5th figure, in this particular example, the optimum impedance sample time of HCT is about more than 20 seconds, and impedance is to the calibration curve coincidence formula y=90.253x+2347.7 of HCT.Moreover shown in the 6th figure, the optimum impedance sample time of HCT is about more than 11 seconds, and reactance is to the calibration curve coincidence formula y=3.1304x+529.68 of HCT.It should be understood that x to represent HCT and y representes impedance or reactance.
The 9th and 10 figure show an example, in 60 seconds, measure resistance value and reactance value in per 0.5 second by the LCR ammeter.In an example, blood and the various samples whole from the experimental subjects collection are by adding the different anticoagulants of measuring (heparin (heparin)) in whole blood of gathering.For example, being used for the heparin concentration in modulation clotting time (PT) is about between every milliliter of 1U to 30U.Then, analyze said blood sample to record impedance or reactance by LCR ammeter (Hioki Model No.3532-50) with different PT.
The 11st and 12 figure show the experiment examples, and it representes that respectively PT is to the calibration curve of impedance rate of change (impedance change rate) and the expression PT calibration curve to reactance change rate (reactance change rate).In this particular example, impedance or reactance change rate can calculate in U.S. 10 seconds by the LCR ammeter.For example; Change rate between 30 to 40 seconds can be tried to achieve by following formula: Impedance change rate 30 to 40=(Z40-Z30)/(Time40-Time30); Wherein Z is impedance; And Reactance change rate 30 to 40=(X40-X30)/(Time40-Time30), wherein X is reactance.Calculation procedure has impedance and the reactance change rate of different PT blood samples for repeatedly calculating, and confirms that thus PT is to the calibration curve (the 7th figure) of impedance rate of change and the expression PT calibration curve (the 8th schemes) to the reactance change rate.Said PT is to the calibration curve coincidence formula y=-0.1849x+4.562 of impedance rate of change, and PT is to the calibration curve coincidence formula y=-0.0256x+0.3604 of reactance change rate.It should be understood that x to represent real number PT and y representes impedance or reactance change rate.
Shown in the 11st and 12 figure, the diagnostic result of reactance measurement method (the 12nd figure) manifests more excellent standard deviation (SD value) compared to the diagnostic result (the 11st figure) of traditional impedance measurement.More particularly, adopt the advantage of reactance measurement method to be significantly to reduce the standard deviation of reactance measurement method according to the present invention, and be about 0.9986 in this example.In view of this, adopt the general traditional impedance measurement of reactance measurement method more accurate, even and the process of prolongation blood clotting, the skew of slope also is acceptable, so logarithm value is proofreaied and correct more easily.
On the other hand, in this particular example, PT is about 0.939 to the linear regression value (R2) of the calibration curve of impedance rate of change, shown in the 11st figure.In view of this, impedance measurement more possibly cause coarse measurement result.
In above-mentioned example, can measure the impedance and the reactance of a blood sample by the LCR ammeter, and difference computing impedance rate of change and reactance change rate.More particularly, HCT system is by using the HCT calibration curve to calculate according to following formula: HCT=(impedance-2347.7)/90.253 or HCT=(reactance-529.68)/3.1304.Then, calculate real number PT by the PT calibration curve.Different HCT can corresponding different PT calibration curves.In this particular example, PT system is by using the PT calibration curve to calculate according to following formula: PT=(impedance change rate-4.562)/-0.1849 or PT=(reactance change reate-0.3604)/-0.0256.
The 13rd and 14 figure show experimental data figures, the PT that its PT that representes respectively to proofread and correct is proofreaied and correct by impedance measurement and expression real number PT to real number PT by reactance measurement.The PT value that will calculate through calibration curve with solidify the real number PT value that analyser (Sysmex CA-500series) measures through automatic blood and compare.
The increase of said HCT or minimizing can influence the value of prothrombin time (PT) and impedance or reactance change rate.More particularly, higher H CT can cause the increase of impedance or reactance change rate value.Therefore, the process of measurement in PT described in some embodiment can comprise that HCT revises step.Therefore, device according to some embodiments of the invention comprises internal storage, in order to store the interpolate value between said HCT and the impedance variations.
In the present invention knows on the one hand, by PT value that above example calculated can by the regular ratio in the world (international normalized ratio, INR) correction, shown in following formula:
Wherein INR is international regular ratio, and PT is a prothrombin time, and ISI is international susceptibility index (international sensitivity index).
15A and 15B figure shows experimental data figure, and it is illustrated respectively on poriness substrate and the imporosity substrate of test card and carries out coagulation analysis.Shown in figure, adopt the poriness substrate to analyze and to obtain more excellent result.
The 16A～16C figure shows experimental data figure, and it representes respectively under different frequency, to carry out coagulation analysis according to the embodiment of the invention through the reactance measurement method.Measuring respectively between 15 seconds to 50 seconds clotting time is blood sample, and the survey frequency of 0.1kHz, 10kHz and 50kHz is provided, and detection value of reading of gained is respectively 0.9636,0.9923 and 0.9828 with the R2 value of the calculating of regretional analysis.In this example, show compared to frequency 0.1kHz by regretional analysis, use the survey frequency of 10kHz and 50kHz can obtain higher accuracy rate.
Though the present invention with various embodiment openly as above, so it is not in order to limit scope of the present invention, to have common knowledge the knowledgeable in any affiliated technical field, in spirit that does not break away from the present invention and scope, when doing a little change and retouching.The claim person of defining that the present invention's protection domain attaches after looking is as the criterion.
Claims (17)
1. diagnostic device of measuring blood cell volumetric ratio and/or prothrombin time comprises:
Comparative electrode type sensor device; With
The test card assembly comprises one or many to working electrode;
Wherein interchange (AC) signal is provided by this sensor device, by the reactance analysis to measure and to calculate prothrombin time and/or the blood cell volumetric ratio (hematocrit) in the blood testing.
2. diagnostic device as claimed in claim 1, wherein this reactance is analyzed and is comprised:
Draw response signal from this this AC signal of test card component responds, relatively this response signal and this AC signal calculate the phase angle variations of this AC signal, and calculate electric capacity and this blood cell volumetric ratio.
3. diagnostic device as claimed in claim 2, wherein this reactance is analyzed and is also comprised:
Calculate electric capacity; And
Be modified to this prothrombin time with algorithm this electric capacity of conversion and with reference to this blood cell volumetric ratio.
4. diagnostic device as claimed in claim 3, wherein this reactance is analyzed and is comprised that also (international normalized ratio INR) revises this prothrombin time with the regular ratio in the world.
5. diagnostic device as claimed in claim 1, wherein this test card assembly comprises one or many to noble metal electrode, is located at respectively on same level or the Different Plane.
6. diagnostic device as claimed in claim 1, wherein this test card assembly comprises the substrate that is made up of porosint.
7. diagnostic device as claimed in claim 6, wherein this substrate of this test card assembly have hole diameter range approximately between 0.1 micron to 10 microns.
8. diagnostic device as claimed in claim 1, wherein this sensor device comprises:
The test card accommodating unit is to hold this test card assembly;
The temperature maintenance unit is with control and keep this test card accommodating unit to steady temperature;
AC signal generation unit provides the alternating current of frequency and voltage to this test card assembly;
The signal receiving element, intercepting is from the response signal of this test card component responds;
Microprocessor calculates this response signal and obtains this blood cell volumetric ratio and the result of this prothrombin time; And
Display unit shows from this blood cell volumetric ratio that this microprocessor calculated and the testing result of this prothrombin time.
9. diagnostic device as claimed in claim 8, wherein this microprocessor compares this response signal and original AC signal, calculates the phase angle variations of this AC signal, and calculates electric capacity and this blood cell volumetric ratio.
10. diagnostic device as claimed in claim 9, wherein this microprocessor further with this electric capacity of algorithm conversion, is modified to this prothrombin time with reference to this blood cell volumetric ratio, and with regular this prothrombin time of ratio correction in the world.
11. a method of measuring blood cell volumetric ratio and/or prothrombin time comprises:
Test card assembly to test card accommodating unit is provided;
The temperature of controlling and keep this test card accommodating unit is to steady temperature;
Provide sample to be detected to this test card assembly;
The alternating current that CF and voltage are provided by AC signal generation unit is to this test card assembly;
Receive response signal by this test card assembly, and calculate this response signal by microprocessor and obtain this blood cell volumetric ratio and/or this prothrombin time; And
Provide testing result to display unit to show.
12. like the said measurement blood cell volumetric ratio (HCT%) of claim 11 and the method for prothrombin time; Wherein said by this test card assembly reception response signal; And calculate the step that this response signal is obtained this blood cell volumetric ratio and/or this prothrombin time by microprocessor, comprising:
Draw response signal from this this AC signal of test card component responds, relatively this response signal and this AC signal calculate the phase angle variations of this AC signal, and calculate electric capacity and this blood cell volumetric ratio.
13. like the said measurement blood cell volumetric ratio of claim 12 and the method for prothrombin time; Wherein said by this test card assembly reception response signal; And calculate the step that this response signal is obtained this blood cell volumetric ratio and/or this prothrombin time by microprocessor, also comprise:
Calculate electric capacity; And
Be modified to this prothrombin time with algorithm this electric capacity of conversion and with reference to this blood cell volumetric ratio.
14. like the said measurement blood cell volumetric ratio of claim 13 and the method for prothrombin time, wherein saidly receive response signal, and calculate the step that this response signal is obtained this prothrombin time, also comprise by microprocessor by this test card assembly:
(international normalized ratio INR) revises this prothrombin time with the regular ratio in the world.
15. like the said measurement blood cell volumetric ratio of claim 11 and the method for prothrombin time, wherein this test card assembly comprises one or many to noble metal electrode, is located at respectively on same level or the Different Plane.
16. like the said measurement blood cell volumetric ratio of claim 11 and the method for prothrombin time, wherein this test card assembly comprises the substrate that is made up of porosint.
17. like the said measurement blood cell volumetric ratio of claim 11 and the method for prothrombin time, wherein this substrate of this test card assembly have hole diameter range approximately between 0.1 micron to 10 microns.
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| US13/156,693 | 2011-06-09 | ||
| US13/156,693 US8828322B2 (en) | 2010-06-09 | 2011-06-09 | Device and method for measuring prothrombin time and hematocrit by analyzing change in reactance in a sample |
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