CN101128735A - Low volume assay apparatus and method - Google Patents

Abstract

A method and apparatus for determining a coagulation property of a sample of fluid, the method comprising causing oscillation of at least one magnet (10), wherein said oscillation comprises: a first oscillation within a first frequency range for a first period of time; and a second oscillation within a second frequency range different to said first frequency range for a second period of time.

Description

Low volume assay apparatus and method

Technical field

(1) thus the present invention relates to instrument and the method that viscosity that the analyzing biologic fluids sample determines that the hemostasis disturbance causes changes.

Background technology

(2) more particularly, but not utterly, the invention discloses the instrument and the method for the coagulating property that is used to measure fluid sample.In a plurality of embodiment, this method and instrument can be used for judging solidifying or prothrombin time (PT) of blood or plasma sample.This can be expressed as international normalized ratio (internationalised normalised ratio) (INR).Other interpretable coagulating properties comprise the measured value of measuring the platelet aggregation degree, thrombosis and/or thromboclastic speed or amount, clot strength, form fibrin grumeleuse or needed time of thrombus, the APFI (APTT) that part activates, activated coagulation time (ACT), PROTEIN C activationary time (PCAT), adder time (RVVT) and thrombin time (TT).

(3) blood clotting in the live body (thrombosis) is a worldwide major causes of death.The people and the operating patient of experience that suffer from heart or vascular diseases have thrombosed danger, and thrombus may cause life-threatening clinical condition.This class people is treated with dilute blood or anticoagulation medicine (as warfarin or aspirin) usually.Yet the amount of anticoagulant must remain on proper level in the blood flow: may cause undesirable solidifying very little, and may cause hemorrhage too much, this all causes life-threatening consequence.As a result of, develop routine and condense filler test (routine coagulation screening test) so that the coagulated state of assessment blood or blood plasma.

(4) having developed multiple instrument uses for the laboratory and uses as real-time test (POCT).In addition, also developed such equipment, it allows patient to monitor their blood clotting at home, as InRatio ^TMMonitor (Hemosense) and CoaguChek ^TMMonitor (Roche), they can judge prothrombin time (PT).CoaguChek ^TMEquipment is applicable to capillary blood, and wherein design receives the testing apparatus insertion testing tool of capillary blood samples.The sample of capillary blood can puncture finger tip by lancet easily and obtain.

(5) manyly be used to judge that the legacy equipment volume of fluid sample congealing property is big, Heavy Weight makes them be unsuitable for the user and carries.The user may be required often to test they self or setting time of other people blood so that guarantee good health.The instrument that therefore, need have the portability that has improved.

(6) rate of setting of fluid sample is reacted the temperature effect when taking place.The portable equipment of judging the fluid sample congealing property can be exposed in the broad temperature range, therefore increases for example detection error of prothrombin time (PT).Therefore, coagulation devices provides heating arrangement, and it is used for heating fluid sample to specified temp.

(7) thus the user may be required to use lancet to obtain capillary blood often tests their own or patients.Such capillary blood samples normally from traditional body extremity, is obtained as finger tip.Yet these places are sensitizing ranges, contain many nerve endings, and obtain a large amount of blood samples, and promptly 25 μ L or more substantial sample are painful.And, if the zone that punctures is not applied significantly big pressure, be difficult to obtain so big amount usually.This can cause being used for the problem of quantity not sufficient of the fluid sample of equipment, and these equipment require user's repeated test under many circumstances.Prior art equipment usually requires sizable amount.

The measurement of (8) condensing is normally time-based, for time-based measurement, can accurately judge the time that congealing reaction begins and think that time of having taken place of condensing is important.

(9) prior art generally includes the disposable apparatus that uses with instrument, and the user inserts instrument with this equipment, applies the sample that will test then.Equipment is important by filling rightly, because all may cause measuring error such as underfill and factor that bubble occurs.

Summary of the invention

(10) the purpose of this invention is to provide instrument and the method that accurately to judge the time of coagulation event generation in the fluid sample.

(11) further aim of the present invention provides with instrument and uses so that judge the equipment of the setting time of fluid, and wherein testing apparatus has low volume requirement.

(12) further aim of the present invention provides instrument, and it provides heating arrangement and temperature monitoring device, and they can heat the temperature of fluid sample and surveillance equipment apace.The entity that temperature device and heating arrangement preferably separate.The temperature of equipment in the temperature range of cavity, and supposition to be included in the temperature of the fluid in the cavity identical with the temperature of equipment.In this respect, thus enough thin to allow the heat transmission between fluid and the equipment be favourable to the equipment plastic casing.

(13) the further aspect of the present invention provides the instrument of measuring setting time, and it is easy to carry about with one and has low power requirements.

(14) this equipment and instrument constitute this instrument together.Instrument provides the device of this equipment of reception, and this equipment is used in combination so that test with instrument.This equipment is normally disposable, and instrument is designed to and can re-uses.Replacedly, instrument and equipment can be provided as single integral unit, thereby have eliminated the needs of insertion and positioning equipment.

(15) the present invention limits with claim.

(16) according to first aspect, a plurality of embodiment provide the instrument of the congealing property that is used to judge fluid sample, and this instrument comprises the receiving trap of solenoid and receiving equipment.

(17) according to further aspect, a plurality of embodiment provide the instrument of the congealing property that is used to judge fluid sample, and this instrument comprises single solenoid, and this solenoid has the one or more windings that limit the inner space.The equipment receiving trap can be provided with like this, so that equipment can be positioned at the inside of described inner space at least in part.

(18) according to further aspect of the present invention, a plurality of embodiment provide such equipment, and it uses the coagulated state of judging fluid sample with instrument, and this equipment has at least one fluid chamber, and it contains magnetic or magnetizable body.

(19) according to further aspect, a plurality of embodiment provide such equipment, and it uses with instrument so that judge the coagulated state of fluid sample, and this equipment has at least two fluid chamber, and each cavity all contains magnetic or magnetizable body.

(20) according to further aspect, a plurality of embodiment provide such instrument, it is used to judge the coagulated state of liquid, this instrument comprises the fluid chamber that is used for preserving a certain amount of described fluid, be arranged on magnetic and solenoid in this cavity, this solenoid and described magnetic cooperation also in use are provided to provide magnetic field, and this magnetic field moves forward and backward magnetic in cavity.

(21) according to further aspect, a plurality of embodiment provide the solenoid that is used in the instrument, so that judge the coagulated state of fluid sample, described solenoid has the winding of one or more qualification interior space dimension, so that equipment can be positioned at its inside to small part.

(22) according to further aspect, a plurality of embodiment provide the method for judging the fluid sample coagulated state, it may further comprise the steps: provide fluid sample in containing the cavity of magnet, thereby and apply magnetic field to this cavity and make magnet move forward and backward in cavity to pass through fluid sample.

(23) according to further aspect, a plurality of embodiment provide instrument, and it has temperature heating and monitoring arrangement, to specified temp or temperature range, and accurately monitor the temperature of described sample by its Fast Heating fluid sample.

(24) many aspects of the present invention will be described in greater detail below.

(25) device of receiving equipment is provided by instrument, and it can be any device that equipment accurately and repeatedly is kept in the instrument or is preserved by instrument.This equipment receiving trap can be a cavity for example, and equipment is placed or is inserted in wherein.Can adopt interchangeable equipment to receive and save set such as lock ﹠ key mechanism, wherein can be provided with like this by the auxiliary assembly that equipment provides, so that cooperate with common unit on proving installation and mesh, vice versa.

(26) in the situation that the instrument with single solenoid is provided, cavity can be provided with like this so that at least partially in the inner space, as being limited by one or more coil winding.

(27) in the situation that the solenoid with air-core is provided, solenoid can twine around the axis of centres, so that form air space or air-core.Coil can have the form of open tube.Yet other forms also can consider, as the triangle of elongation, and ellipse, square or the like, every kind of shape all limits the inner space.

(28) equipment that uses with instrument is provided with at least one fluid chamber so that receive fluid sample.This equipment can provide the fluid that is communicated with cavity extraly and use or apply port and apply in a plurality of flow channels that port and cavity be communicated with one with fluid.One or more outlets can offer equipment so that allow entering of fluid sample.The size of fluid passage is preferred to be selected like this, so that fluid can also flow to cavity under the influence of capillary force.The size of cavity can be selected like this, so that fluid is not subjected to the gravity appreciable impact, so that test can be carried out on the surface that may not be complete level.Yet other transport fluid also can consider by the device of equipment, as electroosmotic flow, and magnetic drive pump.

(29) being provided in the cavity is the reagent that can influence the fluid sample coagulated state, and its character depends on the test that will carry out.For example, when the test that will carry out is when judging prothrombin time, reagent will comprise factor I.Further, fluid chamber can comprise identical or different reagent, carries out thereby it can be used to control guarantee to test correctly.Further be provided in described cavity or each cavity is magnetic.Single magnetic is preferred, though described cavity or each cavity can provide one or more magnetics.

(30) equipment can have any suitable form, comprises one or more magnets.According to embodiment, equipment is to provide with the calibration tape form of extending.Except sample applies port and any air out, the fluid passage will be substantially to the environmental sealing in the equipment.Equipment can be by rolling a large amount of substrates, injection moulding, and other manufacture method manufacturings of knowing by the Microfluidics field.

(31) position of the relative solenoid of cavity is chosen such that so that in use, and when it moved around in fluid chamber, magnet was by high field density (that is a large amount of magnetic lines of force).This produces powerful to magnet and therefore produces high power efficiency.

(32) in the situation of solenoid, cavity is set so that be positioned at the central cavity that limits by coil to small part, so that corresponding to position with high field density with central air core.

(33) be that equipment can be placed in the zone of high magnetic field intensity by using the advantage that hollow electromagnetic coil provided.This equipment can be placed or at least in part in the inner space that is limited by electromagnet, the magnet of equipment is effective as the center magnetic core of electromagnet near coil.Electromagnet can have hollow, the core of part hollow or non-hollow.At core is in the situation of part hollow or non-hollow, and core can partially or completely be filled with non magnetic or not magnetizable object.Core by partially filled situation non magnetic or not magnetizable object in, this non magnetic or not magnetizable object should allow equipment to small part to be placed in the inner space by electromagnet definition.Equipment is placed in the hollow core of electromagnet and makes it be placed in the zone of high magnetic field intensity, this makes that the magnet by equipment provides the maximum field disturbance when producing the motion of large-signal.And, use single electromagnet, particularly have the electromagnet of hollow core, reduce weight, the power requirement of size and equipment.Have in the high-intensity situation at electromagnet, high field intensity can be extended out outside the coil itself.In such circumstances, need not equipment is placed in the hollow coil, but near the coil place.Yet it is preferred that equipment to small part is placed in the coil.

(34) magnet or the magnetizable body in order to obtain high field intensity, it is favourable selecting to have large-sized relatively magnetic.This makes it possible to use the large scale cavity, and need not the whole volumetric blood requirement of actual increase.This provides multiple advantage for manufacturing.

(35) according to specific aspect, the invention provides the equipment that uses with instrument, it is used for judging the congealing property of fluid sample, described equipment has at least one cavity and is used for the splendid attire fluid sample, this cavity or each cavity contain magnet or magnetizable body so that cooperate with equipment, wherein the magnet volume to the ratio of the volume of cavity greater than 0.2.According to further embodiment, it is greater than 0.3.According to another embodiment, it is greater than 0.4.According to another embodiment, it is greater than 0.5.

(36) in order to produce signal at magnetic field sensor, magnet need move in cavity.Displacement is big more, and the disturbance in magnetic field is then big more, so signal is big more.Yet displacement is big more, and the volume of desired equipment is also big more.In order to produce large-signal, be necessary the kicker magnet of highfield.Yet magnet is big more, and available displacement is more little in cavity.Supposing to provide the equipment with little volume requirement, when magnet moves around in cavity, has the magnet displacement or the movement clearance of an optimized scope.Movement clearance between magnet and the cavity wall can be between 300 to 600 microns.According to further embodiment, movement clearance is between 450 and 550 microns.According to further embodiment, scope is between 490 to 510 microns.

(37) be similar to the volume requirement of optimizing cavity and magnet, have certain clean gap in the transversely hope across direction of motion between the wall body of magnet one side and respective cavities, clean gap described here is between 50 to 150 microns.According to further embodiment, this clean gap is between 75 to 125 microns.According to further embodiment, this clean gap is between 95 to 105 microns.According to specific example, this clean gap is 100 microns.

(38) can provide detect that magnet moves and/or the device of position in cavity.Such device preferably includes magnetic field sensor, as hall effect sensor, and magnetoresistive transducer, search coil or any other detect the device of changes of magnetic field.In one embodiment, provide a sensor at least, each sensor is related with respective chamber.In operation, except others, will be subjected to the influence of the relative sensing station of magnet by the magnetic field of sensor measurement.Therefore, sensor output can be used to judge position and/or the motion of magnet in cavity.Sensor also can respond the rate of change in the magnetic field of detecting motion.

(39) magnet of equipment preferably has high field density, promptly has high magnetic field intensity in the per unit volume.Therefore high field density is transmitted high residual amount of energy to magnet, reduces to make the magnet required power that moves back and forth in cavity.This allows to use the solenoid of low magnetic field intensity, thereby reduces the power requirement of equipment.Use the solenoid of the low magnetic field intensity of relative magnet also to produce high signal to noise ratio (S/N ratio).The further advantage that is provided by this layout is that reduce can be repeatedly and the needs of relative magnetic field sensor positioning equipment exactly.And then allow the tolerance of bigger equipment locating device and therefore reduce manufacturing cost.

(40) shape of magnet, energy density and weight are the important parameters of being considered.The weight of magnet influences its inertia, and weight is big more, makes its desired energy that moves also high more.On the contrary, the energy density of magnet is high more, and then it contains more high-energy, therefore requires the power low more (that is, from electromagnet) that moves it.Length also will be influential to energy density distribution.Around the usually close the center minimum of the magnetic density of magnets magnetic fields, increase towards its pole shoe.The speed and its length that increase along magnet length magnetic field are inversely proportional to.Therefore, for two magnets of the different length with same overall field density, short magnet is along bigger with long magnet of the magnetic density rate of change of its length direction.This is a bit important consideration, and for example, the total magnetic field is relative with measuring, and uses magnetic field sensor, as magnetic field intensity or the size of hall effect sensor measurement in the time of any specific.Therefore, short magnet produces bigger signal with long magnet on hall effect sensor, even magnet may have identical overall field density.The thickness of magnet also will influence the signal of sensor measurement.The light filling bar of thin magnet or magnet will produce high field density, yet the section that thick magnet or magnet are thicker will produce lower magnetic density in specific part.Yet thin magnet also may have less gross mass, and this will cause lower magnetic density.The global shape of magnet and aspect ratio also may be influential to magnetic density.For example, rectangle will produce along certain energy density distribution of its length with in certain energy distribution at its pole-face place.The rugby shape magnet will produce the energy density distribution different with rectangular magnet.And the energy density that the end of rugby shape magnet (magnetic pole) located will be very high, and this is because the polar area of each magnetic pole is little.Therefore, the magnetic field intensity on the magnet face all is meant whole or average magnetic field intensity.The aspect ratio of magnet also is important consideration.The inventor points out that when being subjected to the influence of magnetic field of electromagnet, aspect ratio was less than 2: 1 (length: width) may cause the magnet in the cavity to twist.Aspect ratio is 3: 1 or the bigger magnet that is applicable to coagulation devices that provides.

(41) according to further aspect, the invention provides and judge and to solidify the equipment of incident, described equipment has the cavity that contains magnet or magnetizable objects, wherein the aspect ratio of magnet central authorities (just width is to thickness) than its each pole shoe (end) greatly.

(42) according to another aspect, the invention provides and judge the equipment of incident that solidifies, described equipment has the cavity that contains magnet or magnetizable objects, and this magnetizable objects can be magnetized along its length, and wherein said aspect ratio (just length is to width) was greater than 2: 1.Be preferably greater than 3: 1.

(43) usually, the energy density of magnet, shape, the energy of material and magnet coil should be selected like this, so that the signal to noise ratio (S/N ratio) of its generation is 90% or bigger.

(44) pick-up unit that also can provide other or extra being used to judge magnet positions, as optics, laser, or radio-frequency unit.

(45) according to an embodiment, the instrument that is used to judge the fluid sample congealing property is provided, described instrument is formed with the equipment that contains magnet by having solenoidal instrument, this magnet is provided in the cavity, and wherein said solenoidal magnetic field intensity was at least 1: 2 the ratio of the magnetic field intensity of magnet tip.According to embodiment, this ratio was at least 1: 3.According to further embodiment, this ratio was at least 1: 4 or is higher.

(46) another embodiment provides the equipment that uses with instrument, and it is used for judging the congealing property of fluid sample, and this equipment contains one at least in the tip or the facial magnet more than or equal to 30mT magnetic field.According to further embodiment, magnetic field is more than or equal to 40mT.According to further embodiment again, magnetic field is more than or equal to 50mT.

(47) yet, further embodiment provides the equipment that uses with instrument, it is used for judging the congealing property of fluid sample, wherein this equipment is with the fluid sample work less than 3 μ L.Traditionally, the reduction of such sample flow can obtain from capillary by using lancet.

(48) Gong You viewpoint is that the capillary blood samples that is used for test setting time is existed lower capacity limitation, this is owing to be present in high-caliber interstitial fluid (interstitial fluid) in these samples, interstitial fluid and then produce the measuring error of setting time.Yet, unaffected substantially from the RBC number of pointing the low-down GR grain capacity gross tubule blood sample that obtains, and therefore can carry out the measurement of condensing accurately to the small amounts of blood of easy acquisition.

(49) fill so that use with the equipment of judging the fluid sample congealing property in order to ensure the equipment of finishing, each cavity of equipment has at least one filling channel and a plurality of exit passageway.Passage can be provided in the corner of each cavity.Passage is arranged on the every nook and cranny of test chamber so that guarantee the complete filling of test chamber, reduces the possibility that air gap forms simultaneously; This guarantees consistent coagulation detection result.

(50) equipment also can provide such device, and as one or more unidirectional kapillary blocks, it is used for guaranteeing that in a single day fluid sample enters cavity, just can not forced the outflow cavity by moving back and forth of magnet.

(51) further embodiment provides the method for judging the congealing property of fluid sample, make thus magnet in the mode that moves around by the fluid in the cavity.For example, the size of the signal that obtains from hall effect sensor depends on the movement rate of magnet.Along with the rate travel of magnet by fluid begins to reduce, the size of signal begins to reduce.Can be used as that magnet movement stops fully setting time or be reduced to the time of certain threshold value when following when signal magnitude.

(52) in addition, thus can improve the fluid homogeneity before the measurement mutually at the second frequency place mutually in the initial mixing at first frequency place.

(53) and, in case fluid begins access arrangement, move to the precalculated position by making magnet, cavity consistent filled and can be realized around the limited capillary flow of magnet by guaranteeing.

(54) energy that is fed to solenoid can be the form of pulse, causes that magnet moves with the form of small-pulse effect motion in cavity effectively.Verified this can cause the linear movement of magnet and help to prevent the magnet distortion, and the magnet distortion can make magnet adhere to or rest in the cavity, and this can take place when relatively large energy offers magnet.The quantity of pulse can be constant in each magnet translation (that is, finishing moving back and forth), also can change.For example, in case sensor has detected the end that magnet has arrived cavity, it can be notified instrument to stop the conveying capacity pulse and give coil, therefore, has reduced the energy requirement of instrument.The polarity reversal of magnetic coil then, electric pulse is applied on the coil once more, thereby allows the magnet travelling backwards to pass through cavity.Between moving back and forth each or some certain time interval can be arranged, just, for magnet stops effectively, this time interval can change or keep constant.For example, the time interval can offer an opportunity so that sample forms thrombus.Instrument can have the default time interval.Replacedly, the duration section in the time interval and quantity can be judged by measuring process self, for example judge by the feature of measuring-signal.Along with fluid begins to solidify, the pulse that can require larger amt moves on to the other end with magnet from an end of cavity.Instrument can measure that moving magnet requires energy on fixing distance, or measures the distance that the pulse of using fixed energies is moved.When carrying out measurement, magnet can move the whole distance or the partial distance of cavity.

(55) equipment that uses with the instrument of judging the fluid sample congealing property contains test chamber, and it is used to receive fluid sample, and test chamber also contains the magnet that can be used to stir fluid sample.Stirring is not the necessary precondition condition of measuring, but can be favourable.If test chamber is filled with the material beyond the fluid sample, if or the fluid sample in the test chamber contain air, then this may all have adverse effect to the accuracy of any measurement.And measuring accuracy can be subjected to the harmful effect of the unevenness of the coagulation reagent in the fluid; Mix mutually the fluid sample in advantageously mix reagent and the cavity.

(56) embodiment provides the equipment that uses with the instrument of the congealing property of judging fluid sample, described equipment has at least one cavity and is used for the splendid attire fluid sample, this cavity or each cavity contain magnet or magnetizable objects, so that be used with equipment, wherein the volume of magnet to the ratio of the volume of cavity greater than 0.4.

(57) volume of magnet can be greater than 0.5 to the ratio of cavity volume.Can test piece be set and comprise the sample that is less than 3 microlitres so that receive.Replacedly, can test piece be set and comprise the sample that is less than 1 microlitre so that receive.In further alternative embodiment, can test piece be set so that receive and comprise the sample that is less than 0.7 microlitre.

(58) thus described cavity or each cavity can be set receives the sample that comprises less than 3 microlitres.Replacedly, described cavity or each cavity can be set and comprise the sample that is less than 1 microlitre so that receive.In further alternative embodiment, described cavity or each cavity can be set so that receive and comprise the sample that is less than 0.7 microlitre.

(59) in a further embodiment, cavity is set in case on direction of motion moving magnet, wherein clear distance between the wall body of magnet one side and respective cavities or capillary gap are to form on the direction transverse to direction of motion.In alternative embodiment, clear distance or capillary gap are between 75 to 125 microns.In alternative embodiment, clear distance or capillary gap are between 95 to 105 microns.In another alternative embodiment, clear distance or capillary gap are at 100 microns.

(60) in one embodiment, cavity is set in case on direction of motion moving magnet, wherein the mobile space between the wall body of magnet one side and respective cavities forms on direction of motion.

(61) in another embodiment, mobile space is preferably between 450 to 550 microns.In alternative embodiment, mobile space is more preferably between 490 microns and 510 microns.In further alternative embodiment, mobile space most preferably is 500 microns.

(62) further embodiment provides fluid sample strip, its equipment with the congealing property of judging fluid sample uses, described test piece has the cavity of at least one splendid attire fluid sample, this cavity or each cavity contain magnet so that be used with equipment, described test piece are set so that receive the sample that comprises less than 3 microlitres.In alternative embodiment, test piece is set so that receive the sample that comprises less than 1 microlitre.In further alternative embodiment, test piece is set so that receive the sample that comprises 0.7 microlitre.

(63) further embodiment provides fluid sample strip, its equipment with the congealing property of judging fluid sample uses, described test piece has the cavity of at least one splendid attire fluid sample, this cavity or each cavity contain magnet so that cooperate with equipment, cavity or each cavity are set so that receive the sample that comprises less than 3 microlitres.In alternative embodiment, cavity or each cavity are set so that receive the sample that comprises less than 1 microlitre.In further alternative embodiment, cavity or each cavity are set so that receive the sample that comprises 0.7 microlitre.

(64) further embodiment provides fluid sample strip, its equipment with the congealing property of judging fluid sample uses, described test piece has the cavity of at least one splendid attire fluid sample, this cavity or each cavity contain magnet so that be used with equipment, described cavity wherein is set, so that moving magnet on moving direction, wherein clear distance between the wall body of magnet one side and respective cavities or capillary gap are to form on the direction transverse to direction of motion.

(65) in an alternative embodiment, clear distance or capillary gap are preferably between 75 to 125 microns.

(66) in an alternative embodiment, clear distance or capillary gap are preferably between 95 to 105 microns.

(67) in alternative embodiment, clear distance or capillary gap most preferably are 100 microns.

(68) further embodiment provides fluid sample strip, its equipment with the congealing property of judging fluid sample uses, described test piece has the cavity of at least one splendid attire fluid sample, this cavity or each cavity contain magnet so that be used with equipment, described cavity wherein is set, so that moving magnet on the magnet direction, and wherein the movement clearance between the wall body of magnet one side and respective cavities is to form being parallel on the direction of direction of motion.

(69) in alternative embodiment, two opposite sides of magnet are on the plane perpendicular to moving direction.

(70) in alternative embodiment, movement clearance is preferably between 450 to 550 microns.

(71) in alternative embodiment, movement clearance is preferably between 490 to 510 microns.

(72) in alternative embodiment, movement clearance most preferably is 500 microns.

(73) further embodiment provides the equipment of judging the fluid sample congealing property, and this equipment comprises that solenoid and test piece receive cavity so that receive fluid sample strip, wherein:

Receiving cavity to the small part test piece is arranged in the solenoid.

(74) the further embodiment instrument that provides the equipment that is used for the congealing property of judging fluid sample to use, this instrument comprises solenoid, it has the equipment receiving trap of hollow inner core and receiving equipment.

(75) in alternative embodiment, test piece receives cavity device receiving trap (stripreceiving cavity device receiving means) and is positioned at such position, so that equipment can be arranged in the inner space that is limited by solenoid to small part.

(76) in alternative embodiment, described solenoid has axle, and test piece reception cavity provides along described axle.

(77) in alternative embodiment, described solenoid has the core volume, and test piece reception cavity provides in this core volume.

(78) further embodiment provides the instrument of the congealing property that is used for judging fluid sample, and described equipment comprises:

Test piece receives cavity, and it is used for receiving fluid sample strip,

Heating element, it is used for that test piece is received cavity and remains on predetermined temperature, and

Temperature sensor, it is used for monitoring the temperature of fluid sample device.

(79) in alternative embodiment, described heating element is a resistive coil.

(80) in alternative embodiment, described heating element comprises printed pattern of resistive carbon ink.

(81) in alternative embodiment, described heating element is that amber ear card (Peltier) equipment that heats described cavity is set.

(82) in alternative embodiment, the polarity that is applied to the voltage on the amber ear card equipment can be reversed, and is cooled to predetermined temperature so that equipment is received cavity.

(83) in alternative embodiment, predetermined temperature is 37 ℃.

(84) further embodiment provides the method for the congealing property of judging fluid sample, described method to comprise cavity inner fluid sample is remained on predetermined temperature.

(85) further embodiment provides the equipment that uses with the instrument of judging the fluid sample congealing property, described equipment has at least one cavity and is used for the splendid attire fluid sample, this cavity or each cavity contain the magnet that is used with equipment, and this cavity or each cavity have the minimum-B configuration intensity of 50mT in the tip.

(86) in alternative embodiment, the minimum-B configuration intensity that this magnet or each magnet have in the tip at 55mT between the 65mT.

(87) in alternative embodiment, the minimum-B configuration intensity that this magnet or each magnet have in the tip is 60mT.

(87) in alternative embodiment, described magnet comprises NdFe ₃The B magnet.

(88) further embodiment provides the test piece of using with the equipment of judging the fluid sample congealing property, described test piece has at least one cavity and is used for the splendid attire fluid sample, this cavity or each cavity contain the magnet that is used with equipment, this cavity or each cavity have a plurality of gas point or gas bleeding points (gas trap point) of catching, and wherein each cavity has the passage that is connected on it catching the gas point.

(89) in alternative embodiment, at least one described passage is a filling channel.

(90) in alternative embodiment, at least one described passage is an exit passageway.

(91) in alternative embodiment, each catches the gas point is the angle of this cavity or each cavity.

(92) in alternative embodiment, this cavity is cube shaped substantially.

(93) further embodiment provides the equipment of judging the fluid sample congealing property, and this equipment comprises an optical sensor, and it is used for detecting first incident and second incident.

(94) further embodiment provides the method for the congealing property of judging fluid sample, and it comprises makes at least one magnet vibration, and wherein said vibration comprises:

First vibration of the lasting very first time section in the first frequency scope.

(95) in alternative embodiment, described first incident is that fluid enters incident.

(96) in alternative embodiment, wherein said second incident is that cavity fills up incident.

(97) in alternative embodiment, optical sensor is provided to ask filling channel and the exit passageway of looking into cavity.

(98) in alternative embodiment, optical sensor is provided to detect the variation of the transport property of filling channel and exit passageway.

(99) in alternative embodiment, optical sensor is provided to detect the reducing of transport property that is entered filling channel that each described passage causes and exit passageway by fluid.

(100) further embodiment provides the fluid sample strip of using with the equipment of judging the fluid sample congealing property, and described test piece has at least one location feature structure, and it is provided to interact with the corresponding setting element of equipment.

(101) in alternative embodiment, the location feature structure is the recess in the fluid sample strip surface.

(102) in alternative embodiment, the location feature structure is the hole in the fluid sample strip surface.

Description of drawings

(103) for the present invention can more be expressly understood, embodiment will be described with reference to the drawings, wherein:

Fig. 1 illustrates the synoptic diagram of the equipment that uses with instrument;

Fig. 2 illustrates along the equipment xsect of X-X line among Fig. 1;

Fig. 3 illustrates the instrument of using with equipment;

Fig. 4 illustrates the xsect that is inserted into the equipment in the instrument;

Fig. 5 illustrates two magnets in the equipment of being arranged on;

Fig. 6 illustrates the method that power is applied to the instrument coil;

Fig. 7 is illustrated in and solidifies the signal of exporting from two hall effect sensors in the test;

Fig. 8 illustrates the control circuit of instrument;

Fig. 9 illustrates the process flow diagram of the method for operating equipment; With

Figure 10 illustrates the process flow diagram of the method for moving magnet.

Embodiment

(104) Fig. 1 illustrates the synoptic diagram of equipment.This evaluation method selecting optimal equipment comprises the lower floor 12 and the lid 13 of shaping.Shown in lower floor 12 are 40 millimeters long, 8 mm wides, 0.8 millimeters thick.Lower floor 12 is shaped so that have a plurality ofly in its surperficial feature structure, and these feature structures form the top surface of the equipment of assembling.

(105) by example, the feature structure of the lower floor of the equipment of the signal shown in Fig. 1 will be described below.Triangular sample applies feature structure 2 to be had 0.3 millimeter the degree of depth and is attached at least one access road 3, is two access roades in this example, and access road 3 has 0.15 millimeter the degree of depth and 0.3 millimeter width.Each access road 3 and then be connected to a jiao of inlet end of one of two adjacent test chambers or cavity 4.Test chamber 4 has 3.5 millimeters length, 1.2 millimeters width and 0.34 millimeter the degree of depth.A plurality of exit passageways 5,6 are attached on the test chamber, and exit passageway has 0.15 millimeter the degree of depth and 0.15 millimeter width.Exit passageway 5 is that the inlet end at test chamber 4 illustrates, and two exit passageways 6 are to illustrate at each angle of the endpiece of test chamber 4, thereby allows to catch the discharge of gas, and the described inlet end of wherein said test chamber 4 is in the opposite end of endpiece.

(106) Fig. 1 illustrates the equipment that comprises two test chambers.Measure separately 4.8 millimeters of these test chambers from each cavity center.Cavity separately should make the influence minimum of the magnetic signal related with magnet in the cavity to hall effect sensor, this hall effect sensor and another cavity-associated, and vice versa.The optimal distance that cavity separates will be by determining such as the size of magnet and the factor of field intensity.

(107) should notice that passage is provided at the every nook and cranny of test chamber 4, test chamber 4 has substantially and is the xsect of rectangle, and has the little and limited degree of depth on the plane perpendicular to described xsect.Should notice further that filling and exit passageway have the degree of depth that equals test chamber 4.Yet, fill with exit passageway and can have the degree of depth different with test chamber 4.For example, fill and the degree of depth that exit passageway has between 0.15 millimeter to 0.1 millimeter.Fill preferably consistent along the length direction of passage with the degree of depth of exit passageway.

(108) a plurality of outlets 7,8 are formed in the lower floor, and each exit passageway 5,6 all is attached to respectively in the outlet 7,8.Shown in schematic device in, two exit passageways 6 are left away and are stopped in public outlet 8 from test chamber 4.Outlet 7,8 circular recess that are included in lower floor's top surface, it has 1 millimeter the diameter and 0.4 millimeter the degree of depth.Equipment further comprises pilot hole 9, and it passes equipment; This discusses in more detail below.In addition, capillary breaks (capillarybreak) is provided at the junction of exit passageway and outlet (not shown).Fluid sample can pass through up to capillary breaks along exit passageway like this.

(109) thus provide one way stop features to guarantee reagent when being put in the cavity with liquid form, it is retained in the cavity up to drying.Yet when requiring blood to flow in the cavity, block does not hinder it and flows.

(110) lower floor of injection moulding will handle in plasma chamber so that produce hydrophilic layer on little feature structure of top surface and lower floor.Then, commercial available thromboplastin solution is contained in each test chamber 4 of lower floor.Preferably, each test chamber 4 contains at least 0.4 mul of thromboplastin solution.The thromboplastin solution subsequent drying.

(111) the design test chamber holds fluid sample for test.The volume of testing desired blood depends on the inside dimension of equipment and the external dimensions of each magnet 10.This volume can be less than 3 microlitres.Particularly, at 3 microlitres between 0.1 microlitre.More preferably, at 3 microlitres between 0.5 microlitre.Most preferably, at 2.75 microlitres between 0.75 microlitre.Preferably, this volume comprises the volume of test chamber and the volume of outlet and filling channel.

(112) each test chamber 4 of equipment contains neodymium magnet 10.Magnet 10 can comprise NdFe ₃B.Each neodymium magnet 10 shown in Fig. 1 has 3 millimeters * 1 millimeter * 0.25 millimeter size.Test chamber 4 shown in Fig. 1 has and is of a size of 3.5 millimeters * 1.2 millimeters * 0.34 millimeter.Therefore, the fluid volumes of test chamber institute splendid attire is 0.7mm ³Or 0.7 μ L.Magnet size is 0.53 to the ratio of test chamber size.

(113) magnet preferably has high magnetic field intensity.Yet, have been found that in the device fabrication process, be difficult to high-intensity magnet like this is placed and is retained in the cavity.When equipment has the more than one cavity that comes in close proximity to each other, when each cavity all contained magnet, this is difficulty particularly, and this is because the characteristic that magnet has mutual repulsion or attracts each other.This problem can overcome by following method: in cavity, place metallic object, thereby top laminate seal chamber be provided or block cavity to small part, and therefore original position with the metallic object magnetization to required magnetic field intensity.The top laminate prevents that magnet from leaving cavity and making the cavity setting that comes in close proximity to each other.Also provide and made the facilitated method of this kind equipment in batches, and allowed other metal constructions that can attract magnet to place near equipment.Therefore, an aspect of of the present present invention provides the method for manufacturing equipment, and it may further comprise the steps: the metallic object that can be magnetized in cavity is provided, and any moving of restriction metallic object in cavity magnetized this metallic object subsequently when metallic object occurs in described cavity.

(114) each magnet size is all through selecting, so that it fills each test chamber substantially.This guarantees high magnetic field intensity and further advantage is provided, promptly only requires small amount of fluid sample to come filled chamber.And all fluids are substantially all stirred in test in the test chamber.

(115) and, each magnet 10 relative test chamber 4 sizing so that have clear distance or capillary gap around it when magnet is arranged in detection chambers, thereby promotes test chamber to fill and guarantee to finish the filling of test chamber.Above-mentioned size provides the capillary gap of 100 μ m around magnet, and this is suitable for this purpose.Similarly, provide 500 μ m crest clearances, this is allowing enough magnets to move so that reasonable signal from magnetic field sensor 24 is provided, thereby and allows enough capillarities to guarantee that test chamber fills and do not have and provide optimal value between the bubble.Further advantage is can adopt bigger cavity and the low volume that not be used in equipment requires the aspect to give way.And, provide big cavity and big magnet to make manufacturing process easier.

(116) field intensity that preferably has of each magnet 10 is greater than 50mT, more preferably in the tip greater than 60mT the end of the magnet South Pole and the arctic (that is).

(117) Fig. 2 illustrates the xsect of complete device along X-X line among Fig. 1.Each test chamber 4 of complete device contains reagent 11, for example solidifies reagent (as thromboplastin), also contains magnet 10.Apparatus shown 1 comprises the lower floor 12 of injection moulding, thromboplastin 11, at least one neodymium magnet 10 and the laminate lid 13 that adheres in the lower floor 12.

(118) form the electromagnet 20 of the meter unit that the equipment 1 of the incident of solidifying uses shown in Fig. 3 and Fig. 4 in the test fluid sample.This equipment can be inserted in the electromagnet hollow core 50.When equipment was in the use location, each magnet 10 in each test chamber 4 can be positioned in the hollow core of magnet 20.

(119) the female feature structure that is provided by this equipment can be set so that cooperate with corresponding public feature structure on the instrument and mesh.Replacedly, public feature structure can be provided and is provided with so that cooperate with corresponding female feature structure on the instrument and mesh by equipment.

(120) magnet 10 has the arctic-south axis, and it is parallel to the arctic-south axis of electromagnet.Magnet 10 is orientation in test chamber 4 preferably, so that the end of the arctic is arranged on the end near the test chamber of filling channel.Therefore, known magnetic field can be applied on the equipment, so that moving magnet 10 is to the particular end of test chamber 4.By the material in the magnetization test piece, can guarantee further when magnet is energized that it moves on same direction.

(121) Fig. 4 illustrates the cross sectional view of instrument 20, and wherein equipment 1 has inserted, and is that xsect is shown.Instrument 20 comprises conductive coil 21, and the position that a hall effect sensor 24 detects the magnet 10 in each test chamber 4 is set at least.Instrument 20 also comprises at least one optical sensor 22,23, and these optical sensors preferably include led light source and conventional optical transistors.Operating in more detail below of the use of optical sensor and optical sensor discussed.

(122) according to an embodiment, coil 21 has the direct current resistance of 70 ohm (ohm) and by the 5V power drives.

(122 ') coil 21 can have the form of open pipe.Coil can have the xsect of Any shape, as: triangle, ellipse, rectangle, square, circle, or the like.

(123) shown in multi-cavity body configuration in, hall effect sensor 24 provides for each test chamber 4.When hall effect sensor 24 preferably being set being centered at test chamber 4 with convenient magnet, the mid point of the surveyed area of hall effect sensor aligns with an end of magnet 10.In addition, well heater 42 and temperature sensor 45 contiguous cavitys provide.

(124) instrument comprises first optical sensor of setting, and it is used for detecting the sample fluid by each access road 3 of each test chamber 4; Instrument comprises second optical sensor that also comprises setting, and it is used for detecting the sample fluid that passes through along each exit passageway 5 when equipment is inserted in the instrument.Replacedly, second optical sensor can be set so that detect the sample fluid that passes through along each exit passageway 6.

(125) common, the magnetic field intensity of the equipment 1 that is produced by coil 21 is about 15mT.This magnetic field intensity than prior art instrument is little, and preferably reduces the power consumption of equipment, makes that equipment is light and move more cheap.

(126) Fig. 8 illustrates the functional-block diagram of the control circuit of instrument 20.Microprocessor 40 receives the input of each hall effect sensor 24, each optical sensor 22 and temperature sensor 45.Microprocessor 40 is connected to amplifier 43 and 44, and these two amplifiers provide power to coil 21 and heating element 42 respectively.Microprocessor further is connected to display 41, and it can be used for showing measurement result to the user.This result can be shown as, for example setting time or international normalized ratio (INR) value.

(127) heating element 42 can comprise resistance coil, and it produces heat when electric current flows through wherein.Heating element can comprise the ceramic wafer that is printed with resistive carbon ink on it.Such heating element can have the resistance of 18ohm.Heating element 42 replacedly comprises Peltier equipment.Peltier equipment as heat pump and preferably be connected to heat sink on.

(128) equipment and instrument be used to carry out measure before, heating element 42 preferably is used for heating arrangement and receives cavity and equipment to predetermined temperature, temperature is by temperature sensor 45 monitoring.Temperature sensor 45 can comprise traditional thermoelectric pile, and it is provided to measure the infrared radiation that is sent by equipment.Therefore, thermoelectric pile and equipment are separated by the clearance; The clearance is about 3 millimeters.Thermoelectric pile output with its towards the proportional voltage signal of temperature of infrared light supply.Preferred temperature sensor 45 is towards equipment 1, but not heating element 42; The temperature of the temperature of temperature sensor so measuring equipment rather than heating element 42, heating element 42 may be warmmer or colder than equipment 1.This has just reduced the error that device temperature of being caused by some variablees is measured, and these variablees as flatness of thermo-lag, contact pressure, equipment or the like, thereby and allow to realize that feedback control loop remains on predetermined desirable value with temperature accurately.This so judge accurately for the result provides more because setting time depends on temperature.

(129) when equipment and instrument reached predetermined temperature, instrument 20 showed indication on display 41.This indication can be " setup test ".In case receive this indication, the user can introduce fluid sample to equipment.If the environment temperature of equipment and instrument is greater than predetermined temperature, then heating element 42 is a Peltier equipment, and opposite polarity electric current can be applied on the Peltier equipment so that cooling device and equipment receive cavity.

(130) predetermined temperature will depend on the character of the test that will carry out.In the measurement of prothrombin time, temperature can be chosen as 37 ℃.

(131) below with reference to the description setting time equipment of measuring fluid sample and the operation of instrument.The equipment that equipment is inserted into instrument receives in the cavity.The sample that fluid sample is placed on the front end of equipment applies feature structure 2 places.Fluid moves into device interior by capillarity.Fluid applies the feature structure 2 from sample and extracts, and enters each test chamber 4 along each access road 3.Sample fluid continues to flow through each access road 3, fills each detection chambers 4 and continues outflow by exit passageway 5 and 6.When the fluid sample in exit passageway 5 and 6 arrived capillary breaks 7 and 8 respectively, sample fluid stopped to flow.Thereby the complete filling test chamber is guaranteed in each corner that passage is arranged on test chamber, reduces to form the possibility of clearance simultaneously; This helps to guarantee consistent coagulation detection result.

(132) in a preferred embodiment, fluid moves through equipment by capillarity.Yet, also can consider to carry other standard set-up of liquid access arrangement, as electroosmotic flow.

(133) as mentioned above, provide optical sensor so that detection of sample fluid enters incident and/or test chamber fills up incident.The sample fluid incident of entering can be defined as sample fluid in the checkout equipment filling channel.The test chamber incident of filling up may be defined as detection of sample fluid at least one exit passageway of equipment.

(134) in case detect sample fluid in the access road 3 of equipment 1, just fluid enters incident, and instrument 20 picks up counting.

(135) and, enter incident in case detect fluid, thereby filling signal just is applied to the magnetic field that coil 21 produces fixed polarities, applies feature structure 2 away from coil 21, as shown in Figure 5 so that the magnet 10 in the test chamber 4 is ejected towards the sample of equipment 1.The location of magnet guarantees that cavity can repeat to be filled by fluid sample in the filling stage.Therefore, be favourable at known stationkeeping magnet so that for the difference test provides consistent filling characteristic.Filling signal was kept 3 seconds, and this rear chamber just is assumed to be and fills up.

(136) after filling signal, mixed signal just is applied on the coil 21, and mixed signal produces has the oscillating magnetic field of opposite polarity.Mixed signal preferably produces oscillating magnetic field around coil 21, oscillation frequency is about 8Hz.Mixed signal kept for 5 seconds so that guarantee fluid sample and the mixing of reagent 11, as shown in Figure 2.

(137) after mixed signal, measuring-signal just is applied on the coil 21.Measuring-signal produces has the oscillating magnetic field of opposite polarity, and initial oscillation is about mixing frequency signal half.Mixed signal preferably produces oscillating magnetic field around coil 21, initial oscillation is about 4Hz.In applying the measuring-signal process, the oscillation period in the magnetic field around the coil 21, preferably the phase increased by 15 milliseconds weekly.The example that applies the method for power to coil schematically illustrates in Fig. 6.

(138) measuring-signal is applied on the coil 21, and is up to detecting coagulation event, as described in more detail below.

(139) when coil 21 is connected to the 5V power supply, it draws the DC current of 71mA.In order to reduce power consumption, the dutycycle of coil working is 50%, and frequency is 50Hz.This reduces average current consumption to about 35mA.Further, in any one semiperiod, magnet can only be energized in the semiperiod in part.The electric current of being supplied has first polarity in part in first semiperiod, and the electric current of being supplied has second polarity in part in second semiperiod then, and second polarity is opposite with first polarity.For example, if magnet vibrates with 2Hz, then the semiperiod is the 250ms duration.In first semiperiod, the signal of first polarity is applied on the coil, and the time is 100ms, and then, in second semiperiod, the signal of second polarity is applied on the coil, and the time is 100ms.Preferred first or the signal of second polarity comprise pulse voltage; Duty of ratio can reduce so that save power.

(140) current impulse on the reverse direction preferably includes the application of alternating-current voltage source; Alternating-current voltage source can comprise square-wave signal, sinusoidal signal, or triangular signal.

(141) in order to detect the motion of magnet, processed from the signal that each hall effect sensor 24 of instrument 20 is exported, as shown in Figure 7.From the tip of the peak amplitude 31 indication magnets 10 of the signal of each hall effect sensor output along with the motion of its vibration.To-and-fro movement is carried out in the magnetic field that signal output indication magnet response coil 21 is applied.Along with magnet begins slack-offly, show that fluid sample or blood are experiencing coagulation event, the amplitude of magnet movement and speed and reduce 32 from the peak amplitude and/or the speed of hall effect sensor output signal accordingly.The amplitude of the voltage after coagulation event takes place can be indicated setting strength, and therefore this value can be used to judge the set strength of particular fluid sample.And after coagulation event, by continuing that magnet is moved back and forth by sample, equipment also can be used for judging thromboclastic speed.If desired, magnetic field intensity can begin to increase, thereby makes magnet movement pass through sample.

(142) each magnet 10 is all along the major axis magnetization that is parallel to certain direction, in this direction, and to-and-fro movement when magnet 10 applies alternating magnetic field at coil 21.Therefore, minimum and maximum endways along the magnetic field of magnet length orientation measurement in centre.Along with the change in displacement of magnet in test chamber 4, the output signal of hall effect sensor also changes.Therefore, can calibrate the output signal of hall effect sensor 24, thus the displacement of definition magnet in test chamber 4.Along with the magnet tip moves through hall effect sensor 24, the relation between hall effect sensor output signal and the magnet displacement is not linear.This is non-linear to be resolved in calibration process.

(143) distance of displacement conversion for moving, promptly the end position of magnet is deducted.Therefore, magnet mobile distance in period demand is directly measured.This value reduces along with thrombosis.

Time when (144) coagulation event can be defined as the time that magnet stops to move or slow to particular range.This is easy to judge by the measuring-signal amplitude, or judges by the change of signal amplitude or the speed of change.Fluid sample or thrombus (stoping magnet to move), and can be further defined as the predetermined reduction of hall effect sensor output amplitude from average amplitude.

The scope that (144 ') amplitude changes can depend on all multiple-factors, as the INR of blood, and the size and dimension of magnet, and the magnet field intensity is with respect to the ratio or the difference of electromagnet field intensity.For example, when signal amplitude be the signal averaging amplitude 70% the time, average signal amplitude is the mean value of the amplitude of all measurements in the special time scope, this special time scope was as preceding 5 seconds of measuring, then coagulation event can be considered as taking place.

(145) replacedly, can carry out the moving average smoothing processing, measure amplitude reduction value then the magnet movable signal.

(146) Fig. 9 illustrates the method flow of operating instrument.This method comprises that detecting 71 fluids with optical sensor 22,23 enters incident, and the fluid incident of entering makes the timer that condenses start working 72 and apply the initializing signal of 73 coils 21.The timer that condenses is implemented by microprocessor 40.Form to chamber full signal in case detect 74 from another or same optical sensor 22,23, or 75 surpassed 3 seconds the expiry schedule time, then instrument applies 76 mixed signals to coil 21 and kept 5 seconds.Applying mixed signal after 5 seconds 77, measuring-signal is applied in 78 to coil, and detects the amplitude that 79 magnets move.By multiply by measured value as 70% with a mark, magnitude determinations 80 threshold values that move from the magnet of measuring.Apply the amplitude that 78 measuring-signals move to magnet up to instrument detecting and reduce 81 to the value less than threshold value, this has defined the generation of coagulation event.In case detect coagulation event, the timer that condenses quits work 82; Measuring-signal stops; And the setting time of measuring is by instrument output 83.

(147) Figure 10 illustrates the process flow diagram of the method for moving magnet, and described method comprises mobile 91 magnets; Detect the position of 92 magnets; The position of judging 93 magnets that whether detected is in preset range; And,, then move 94 described magnets once more if the magnet positions that is detected is not in preferable range.

(147 ') describes below the method for this equipment of manufacturing shown in Figure 1.Lower floor 1 is preferably formed by injection molding technology well known in the art by polystyrene.Shown lower floor's 40 millimeters long, 8 mm wides, 0.8 millimeters thick.Lower floor is shaped in injection moulding process, so that have a plurality of little feature structures at top surface.

(148) lower floor of injection mo(u)lding handles in plasma chamber.Plasma chamber makes on little feature structure of top surface and lower floor and forms hydrophilic layer.

(149) commercial available thromboplastin solution is deposited in each test chamber 4 of lower floor.Thromboplastin solution can deposit with deposition station, the deposition station of deposition station as being provided by Britain HorizonInstruments Ltd.UK company.Preferably, at least 0.4 mul of thromboplastin solution is deposited in each test chamber 4.Obvious to those skilled in the art, a plurality of other known thromboplastin solution also are applicable to this instrument.

(150) Chen Ji thromboplastin solution allows lower floor pass through heated cavity and drying, and the time by heating cavity is 10 minutes, and when temperature is about 65 ℃ 4 minutes, when temperature is about 45 ℃ then 6 minutes.

(151) be deposited in each test chamber 4 of lower floor and after the drying, neodymium magnet 10 is placed in each test chamber 4 of equipment 1 in thromboplastin solution.

(152) lid is set in the lower floor also fixed thereon.Lid preferably includes the polystyrene laminate 125 of 125 micron thickness and preferably is fixed in the lower floor by cementing agent.The interchangeable method that lid is fixed to lower floor also is possible.

(153), thereby make excessive lid stock remove from the edge of lower floor in case lid is fixed in the lower floor, and the 25W carbon dioxide laser is used to cut the lid stock laminate.The 25W laser instrument also is used for stinging the lid that is through on the outlet 7,8, so that produce oral pore.In use, when the sample that is introduced in equipment 1 when sample fluid applied in the feature structure 2, outlet opening allowed air to escape from test chamber 4.

(154) structure given here has certain advantage.Use the kicker magnet material, as NdFe ₃B as each magnet 10 of test chamber 4 because multiple former thereby favourable.

(155) at first, require to produce less magnetic field, thereby so that produce specific expulsive force magnet 10 by the fluid sample in the test chamber 4 by solenoid 21.Coil 21 can be therefore less and will be consumed less power, so instrument 20 can have less power supply.Advantageous particularly when this is portable and battery-powered in instrument 20.

(156) second, stronger magnet 10 produces higher signal intensity at hall effect sensor 24.Therefore, the signal to noise ratio (S/N ratio) of hall effect sensor output is reduced, thereby allows to improve the accuracy in detection of coagulation event.

(157) location hall effect sensor 24, align with an end of magnet 10 when being positioned at test chamber 4 central with convenient magnet, therefore the change of maximize magnetic field, and along with magnet moves to the opposite end, hall effect sensor 24 output signals from an end of test chamber 4.This also advantageously improves the signal to noise ratio (S/N ratio) of each hall effect sensor 24 output signal.Hall effect sensor is general locatees with cavity as close as possible so that produce the signal of maximum.

(158) when the central authorities of each cavity measure, two test chambers shown in Fig. 1 are separated 4.8 millimeters.

(159) two cavity location located adjacent one another and fully close each other, as shown in Figure 5, so that can stability magnets and stops them to twist in cavity when being subjected to the magnetic field of electromagnet in the magnetic field of interactive each magnet each other.Further advantage is, the equipment that makes when cavity is arranged close to each other is can size less and reduce the size of heating element.Yet, being provided with if cavity is too close each other, the magnet in cavity can disturb moving of magnet in another cavity, as shown in figure 13.A magnet mobile is subjected to the interference of another magnet can show as a magnet to be attracted by another magnet, cause the friction of magnet and cavity wall, hinder moving of magnet.Any such interference may cause instrument to indicate coagulation event improperly potentially.Therefore, two cavitys will have the minimum interval, and wherein the minimum interval may be defined as minor increment, and this minor increment is that magnet does not significantly disturb and moves necessaryly each other, and this remarkable interference can make instrument indicate coagulation event improperly in early days.Ideally, cavity can be located so that moving of each magnet do not interfere with each other.Yet some interference allows, as long as it does not influence each result of setting time.Interval between the cavity will also can be judged by the magnetic density of each magnet.Magnetic density is big more, and then required interval is big more.Therefore, there is the optimal spacing scope between two cavitys, wherein, if cavity is too close, then magnet may disturb moving each other on sizable degree, if and their are apart from too far away, then may cause magnet in use to twist, and may cause need be bigger the test test piece and bigger well heater.For the equipment with two cavitys, each all has and is of a size of 3 millimeters * 1 millimeter * 0.25 millimeter, and the NdFe that has the 50mT field intensity in the tip ₃B magnet, 0.48 millimeter interval show that the magnet that can provide suitable is stable, and each magnet can significantly not disturb each other.Each cavity central authorities is proved to be inappropriate at a distance of 4 millimeters interval, because magnet has the interference of certain degree each other.

(160) output signal of magnetic field sensor is directly proportional with magnetic field intensity.Therefore, absolute position and/or the rate travel of magnet in cavity can obtain from the output signal of hall effect sensor 24.In interchangeable instrument, may only need to cross test chamber 4 for magnet 10, and need not to drive coil to a certain amount of power of coil 21 inputs.Coil 21 is provided to the magnetic field that the short time persistent signal produces the short time.If the output signal of hall effect sensor does not indicate magnet to be in the end of measurement, as the end of test chamber 4, another short duration signal is applied to coil 21 so.If fluid sample does not condense, then magnet 10 will finally arrive the end of test chamber 4, and this process can repeat, and its short-and-medium duration signal is applied on the coil 21 with opposite polarity.By this mode, thereby the power of minimum is imported into moving magnet 10 on the coil 21.This advantageously reduces the power consumption of instrument 20.And such measuring method can be used for when high INR, or judges setting time when more weak solidifying.Under such situation, it is sensitiveer that the pulse that applies the short duration makes that equipment solidifies incident to detection.In case fluid sample condenses, 10 of magnets are prevented from across test chamber 4, and this detects by hall effect sensor 24, as mentioned above.Replacedly or extraly, the power that is fed to coil can change in measuring process.

(161) apply too high power to solenoid and can cause the excessive energy of instrument use.This may cause any power-limited, and as consuming excessively of battery, this can reduce mission life and increase running cost.And, by detecting the position of magnet in oscillatory process, only need minimum energy to carry out work, saved the energy content of battery.

(162) in above-mentioned example, the polarity of magnet 10 is known, i.e. its orientation in test chamber 4, and therefore must be applied to test chamber so that moving magnet to the polarity in precalculated position also is known in filling process.In alternative embodiment, polarity orientation the unknown of magnet 10, therefore preliminary filling signal is applied on the coil 21, and the position of magnet 10 is detected by hall effect sensor or optical sensor.If magnet is in required precalculated position, then filling signal is held, as mentioned above.If magnet is not in required precalculated position, then the polarity of filling signal is inverted and the position of magnet 10 is detected once more.If instrument does not detect this magnet or each magnet 10 is in desired location, then can produce error signal.

(163) in above-mentioned example, provide the device that is used for detecting magnet 10 position in test chamber 4.In alternative embodiment, provide and detected the device that magnet 10 moves.In operation, will be reduced owing to the change of fluid sample viscosity by moving of sensor measurement, the change of fluid viscosity is caused by the hemostasis disturbance.

(164) replacedly, at least one optical sensor can be used to detect the position of this magnet or each magnet 10.In operation, the change that reduces to indicate fluid sample viscosity of the change frequency of the optical transmission property of test chamber 4, the change of fluid sample viscosity is caused by the hemostasis disturbance.Magnet 10 appears at the precalculated position of test chamber 4 or removes the optical signalling that decision is measured by optical sensor from the precalculated position of cavity 4.

(165) the replaceable structure of at least one optical sensor is described now.Optical sensor can be each test chamber and provides, and optical sensor is positioned and detects the light transmission of access road 3 and exit passageway 5.Take place in case first transmission reduces incident, then detect fluid in the access road 3, and, then in exit passageway 5, detect fluid in case second transmission reduces the incident generation.Therefore, optical sensor of each cavity can be used to that test fluid enters incident and cavity fills up incident.

(166) though be noted that the specific examples of the signal that is applied to coil 21 and describe with regard to dutycycle and frequency that these signals only provide with example in the above.Being applied on the coil duty of ratio must and be determined by employed coil and power supply greater than 0%.The frequency of oscillator signal, as be applied to mixed signal on the coil 21 and measuring-signal preferably between 1Hz and 50Hz.

(167) in the above example, each test chamber 4 comprises reagent 11.In an alternative embodiment, two test chambers 4 are provided, wherein only a cavity 4 contains reagent 11, and another test chamber 4 is used as control in measuring process.

(168) in the above example, can enter event detection setting time from the fluid that is detected, and may be defined as the time zero this moment.The interchangeable measurement of time zero can be by measuring the filling characteristic of the soluble equipment 1 of delay that this is default with default delay routine instrument 20.

(169) replacedly, but instrument 20 detection of sample fluid enter incident and test chamber fills up incident, and zero computing time according to predetermined algorithm, filling characteristic definition that it is measured by equipment 1.The detection that cavity fills up incident can be used for triggering and apply filling signal to coil 21 and be converted to and apply mixed signal to coil 21, and replaces the above-described 3 second fixing time.

(170) further, judge that the given example of minimizing that magnet moves back and forth the output signal of the hall effect sensor 24 that stops to provide as an example.Also can adopt interchangeable judgement magnet to move back and forth the method that stops.

(171) provide and judged that fluid sample condenses or the method for congealing property, thereby be to be arranged in fluid sample magnet mobile range and to detect predetermined the reducing of this amplitude then and judge that the generation of coagulation event obtains by before condensing, measuring by the initial viscosity of the method fluid sample.

Claims (26)

1. a method of judging the fluid sample congealing property comprises making at least one magnet vibration, and wherein said vibration comprises:

First vibration that has continued very first time section in the first frequency scope; With

Second vibration that continued for second time period in being different from the second frequency scope of described first frequency scope.

2. the method for claim 1, wherein said first frequency is greater than described second frequency.

3. method as claimed in claim 1 or 2, wherein said method further comprise increases by second period of oscillation, promptly begins every pulse regular time increment from initial second frequency.

4. method as claimed in claim 3, wherein said every pulse regular time increment is 0.15 millisecond.

5. as the described method of each claim in the claim 1 to 4, wherein said first frequency is between 5 to 12Hz.

6. as the described method of each claim in the claim 1 to 5, wherein said first frequency is between 7 to 10Hz.

7. as the described method of each claim in the claim 1 to 6, wherein said first frequency is 8Hz substantially.

8. as the described method of each claim in the claim 1 to 7, wherein said very first time section is between 2 to 8 seconds.

9. as the described method of each claim in the claim 1 to 8, wherein said very first time section is between 4 to 6 seconds.

10. as the described method of each claim in the claim 1 to 9, wherein said very first time segment base originally is 5 seconds.

11. as the described method of each claim in the claim 1 to 10, wherein said second frequency is between 2 to 6Hz.

12. as the described method of each claim in the claim 1 to 11, wherein said second frequency is between 3 to 5Hz.

13. as the described method of each claim in the claim 1 to 12, wherein said second frequency is 4Hz substantially.

14. the method for the congealing property of fluid sample in the judgment device, this equipment comprise sample chamber and magnet movably therein, described method comprises:

Test fluid enters incident;

After detecting fluid and entering incident, make described magnet move to the precalculated position and continue very first time section.

15. method as claimed in claim 14 wherein makes described magnet comprise that in the step that very first time section moves to the precalculated position signal that applies first polarity is to solenoid.

16. as claim 14 or 15 described methods, wherein said very first time section is between 2 to 6 seconds.

17. as claim 14 or 15 described methods, wherein said very first time section is between 2 to 4 seconds.

18. as claim 14 or 15 described methods, wherein said very first time section is 3 seconds.

19. as the described method of each claim in the claim 14 to 18, wherein said very first time section stops when cavity fills up incident detecting.

20. the method for fluid sample congealing property in the judgment device, this equipment comprise fluid sample cavity and magnet movably therein, described method comprises:

Move this magnet or each magnet;

Detect the position of this magnet or each magnet; And

According to the result who detects step, move described magnet once more.

21. the method for fluid sample congealing property in the judgment device, this equipment comprise fluid sample cavity and magnet movably therein, described method comprises:

Move this magnet or each magnet;

Detect the position of this magnet or each magnet;

The position that judges whether this magnet of being detected or each magnet is in preferred range; And

Result according to determining step moves described magnet once more.

22. the method for fluid sample congealing property in the judgment device, this equipment comprise fluid sample cavity and magnet movably therein, described method comprises by following steps vibrates described magnet in two preferable range:

Move this magnet;

Detect the position of this magnet;

The position that judges whether the described magnet that detected is in described two preferable range in the required scope;

If this magnet in the required scope, does not move this magnet so once more in described two preferable range;

If described magnet in the required scope, waited for before moving described magnet once more that then predetermined amount of time finishes in described two preferable range.

23. a method of judging the fluid sample congealing property, wherein fluid sample strip contains fluid sample, and at least one magnet is set at wherein vibration, and described method comprises:

Make described at least one magnet vibration;

Detect the vibration of described at least one magnet;

Be reduced to threshold value according to the amplitude of the vibration that detects described at least one magnet and judge coagulation event to get off, wherein said threshold value be by: during the initial time section of described vibration, measure the amplitude of described at least one magnet vibration, and the predetermined score that the amplitude of measuring on average moves is defined as described threshold value judges.

24. method as claimed in claim 23, wherein said threshold value be by: adopt the mean value of a plurality of measured values of the amplitude of the vibration of at least one magnet described in the initial time section of described vibration, and the predetermined score that the amplitude of measuring on average moves is defined as described threshold value judges.

25. as claim 23 or 24 described methods, wherein said predetermined score is between 50% and 90%.

26. as claim 23 or 24 described methods, wherein said predetermined score is between 65% and 75%.

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