JP2008525784A - Low volume analyzer and method - Google Patents

Abstract

A method and apparatus for determining a coagulation characteristic of a bodily fluid sample, comprising causing vibration of at least one magnet, wherein the vibration includes a first vibration in a first frequency range over a first time period, a second vibration, Second vibration in a second frequency range different from the first frequency range over a period of time.
[Selection] Figure 1

Description

  The present invention relates to an apparatus and method for analyzing biological fluid samples and detecting coagulation disorders leading to viscosity changes.

  More particularly, an apparatus and method for measuring the coagulation characteristics of a fluid sample is disclosed, but not limited thereto. In embodiments, the method and apparatus can be used to determine the clotting time or prothrombin time (PT) of a blood sample or plasma sample. This may be expressed as an Internationalized Normalized Ratio (INR). Other clotting properties that can be determined include platelet aggregation ability, measurement of the rate and amount of clot formation and / or clot dissolution, clot strength, to form a fibrin clot. Time required for activation, activated partial thromboplastin time (APTT), activated clotting time (ACT), protein C activation time (PCAT), RVTT (Russell's viper venom time) And measurement of thrombin time (TT).

  Coagulation of blood in vivo, or thrombosis, is one of the major causes of death worldwide. People with heart or vascular disease and patients undergoing surgical procedures are at risk of developing blood clots that can lead to fatal clinical symptoms. This type of people is often treated with blood anticoagulants, such as warfarin and aspirin, or anticoagulants. However, the amount of anticoagulant in the bloodstream must be maintained at an appropriate level. If the amount is too low, undesirable coagulation can occur, while if the amount is too high, it can lead to haemorrhaging. As a result, routine clotting screening tests have been developed to assess blood or plasma clotting status.

  Various devices have been developed for use in laboratories and point of care testing (POCT). In addition, devices have been developed that allow patients to monitor their blood clotting at home. Such devices include the InRatio ™ monitor (Hemosense) and Coag Chek ™ monitor (Roche) devices that determine prothrombin time (PT). The CoagChek ™ device is suitable for using capillary blood, and a test device designed to receive a sample of capillary blood is inserted into the test meter. Conveniently, a capillary blood sample can be taken by incising the tip of a finger with a lancet.

  Many of the conventional devices that determine the coagulation characteristics of a bodily fluid sample are large and heavy and are not suitable for the user to carry around. Users may be required to regularly check their or others' blood clotting times to maintain health. Therefore, there is a need for a device with improved portability.

  The solidification rate of the body fluid sample is affected by the temperature at which the reaction occurs. Portable devices for determining the clotting characteristics of a bodily fluid sample may be exposed to a wide range of temperatures, resulting in increased detection error, for example, of prothrombin time. For this purpose, the coagulation device comprises heating means that operate to heat the body fluid sample to a certain temperature.

  The user may be required to periodically examine himself or the patient with a lancet to take capillary blood. This type of capillary blood sample is usually taken from an easily picked body tip such as a fingertip. However, this is a sensitive area containing many nerve endings, and taking large blood samples, ie blood samples on the order of 25 μL or more, can be painful. Furthermore, it is often difficult to obtain such a significant amount of blood without applying sufficient pressure to the incised area. In this case, the amount of the bodily fluid sample applied to the device becomes insufficient, which often leads to a problem that the user is required to repeat the test. Such devices are often required in prior art devices.

  Coagulation measurements are often time-based. Important for such time-based measurements is that the time at which the coagulation reaction begins and the time at which coagulation is considered to occur can be accurately determined. Prior art devices are typically disposable devices that are used with a meter, and the user inserts the device into the meter and then provides a sample of the body fluid to be examined. Factors such as lack of volume or the presence of bubbles can lead to measurement errors, so it is important to properly fill the device.

  It is an object of the present invention to provide an apparatus and method that can accurately determine the time at which a clotting event occurs in a body fluid sample.

  Another object of the present invention is to provide a test device that is used with an instrument for determining the clotting time of a body fluid and meets low volume requirements.

  Another object of the present invention is to provide a measuring instrument comprising a heating means capable of rapidly heating a body fluid sample and capable of monitoring the temperature of the device, and a temperature monitoring means. It is preferable that the temperature monitoring means and the heating means are separate. The temperature of the device in the detection chamber region assumes that the temperature of the body fluid contained in the detection chamber is the same as the temperature of the device. In this regard, it is advantageous to make the device's plastic housing sufficiently thin to allow heat transfer between the body fluid and the device.

  A further object of the present invention is to provide a measuring instrument for measuring clotting time that is easy to carry and has low power requirements.

  Moreover, you may form an apparatus with a device and a measuring instrument. The instrument is provided with means for receiving the device, and the device is used with the instrument to perform the test. The device is usually disposable and the instrument is designed to be reused. Alternatively, the instrument and device may be provided as a single integrated unit, which eliminates the need to insert and position the device.

  The invention is set out in the claims.

  According to a first aspect, an embodiment provides an instrument for determining a coagulation characteristic of a body fluid sample, the instrument comprising an electromagnetic coil and device receiving means for receiving a device.

  According to another aspect, an embodiment provides an instrument for determining a coagulation characteristic of a sample body fluid, the instrument having a single or multiple windings and defining an interior space. An electromagnetic coil is provided. The device receiving means may be configured so that the device can be arranged in at least a part of the internal space.

  According to another aspect, an embodiment provides a device for use with an instrument for determining a coagulation state of a bodily fluid sample, the device comprising at least one bodily fluid chamber containing a magnetic or magnetizable body. Have.

  According to another aspect, embodiments provide a device for use with an instrument for determining the coagulation state of a body fluid sample, the device comprising at least two magnet bodies or magnetizable bodies each containing Has a body fluid chamber.

  According to another aspect, embodiments provide an apparatus for determining a solidification state of a liquid. This apparatus includes a body fluid chamber for holding a certain amount of body fluid, a magnetic body disposed in the body fluid chamber, and an electromagnetic coil. The electromagnetic coil cooperates with the magnetic body and is configured to provide a magnetic field for reciprocating the magnetic body in the body fluid chamber when in use.

  According to another aspect, embodiments provide an electromagnetic coil for use in an instrument for determining the coagulation state of a body fluid sample. The electromagnetic coil has one or a plurality of windings, and defines an internal space dimensioned so that the device can be arranged at least in part of the coil.

  According to another aspect, embodiments provide a method for determining a coagulation state of a body fluid sample. The method includes providing a body fluid sample in a chamber containing a magnetic body and applying a magnetic field to the body fluid chamber to reciprocate the magnetic body in the body fluid sample in the body fluid chamber.

  According to another aspect, an embodiment provides a meter comprising heating means and temperature monitoring means for rapidly heating bodily fluids to a specific temperature or temperature range and accurately monitoring the temperature of the sample.

  Various aspects of the invention are described in more detail below.

  The device receiving means provided by the instrument may be any means capable of holding the device accurately and reproducibly within or by the instrument. The device receiving means may be, for example, a hole in which the device is placed or inserted. Other device receiving and holding means such as lock and key mechanisms may be employed. In this case, the female structure provided by the instrument may be configured to cooperate and engage with a corresponding male structure on the inspection device. The reverse is also possible.

  When a measuring instrument having a single electromagnetic coil is provided, the hole may be disposed within at least a portion of the internal space defined by one or more windings of the coil.

  If an air-core electromagnetic coil is provided, the electromagnetic coil may be wound around a central axis to form an internal space or air core. The coil may be in an open tube form. However, other forms such as a long triangle, an ellipse, a rectangle, and a square that define the internal space may be considered.

  A device used with a meter is provided with at least one body fluid chamber for receiving a body fluid sample. In addition, the device is provided with a body fluid application port that is fluidly connected to the body fluid chamber, and one or more flow paths that are fluidly connected to the body fluid application port and the body fluid chamber. One or more vents may be provided in the device to allow entry of bodily fluid samples. The dimensions of the body fluid passage are preferably selected so that the body fluid can flow into the body fluid chamber under the influence of capillary force. The dimensions of the body fluid chamber are preferably selected so that the flow is not significantly affected by gravity and the test can be performed even if the surface is not completely horizontal. However, other means of transporting bodily fluids within the device may be envisaged, such as electroosmotic flow and magnetic pumps.

  A reagent capable of affecting the coagulation state of the body fluid sample is provided in the body fluid chamber. The nature of the reagent depends on the test being performed. For example, if the test performed is a determination of prothrombin time, the reagent is thromboplastin. There may be a separate body fluid chamber containing the same or different reagent that functions as a controller to ensure that the test is performed correctly. A magnetic body is provided in the body fluid chamber. Although one or more magnetic bodies can be provided in the body fluid chamber, a single magnetic body is preferred.

  The device may be in any suitable form including one or more magnets. According to an embodiment, the device is provided in the form of an elongated specimen. The body fluid path is closed from the environment within the device, away from the sample application port and any vents. The device can be manufactured by multiple substrate lamination, injection molding, and other manufacturing methods known in the field of microfluidics.

  The position of the bodily fluid chamber relative to the electromagnetic coil is selected such that, in use, it passes through a high magnetic field density (ie, there are many lines of magnetic force) as the magnet reciprocates within the bodily fluid chamber. This creates a large force on the magnet and thus increases power efficiency.

  In the case of an electromagnetic coil having an air core in the center, a body fluid chamber is disposed in at least a part of the central cavity defined by the coil so as to correspond to a position having a high magnetic field density.

  One of the effects obtained by using a hollow electromagnetic coil is that the device can be arranged in a region of high magnetic field strength. The device can be placed in close proximity to the coil, or at least in a portion of the interior space defined by the electromagnet. The magnetic body of the device effectively acts as the central magnetic core of the electromagnet. The electromagnet may be a hollow core, a partially hollow core, or a non-hollow core. If the core is partially hollow or non-hollow, the core may be partially or completely filled with a non-magnetic or non-magnetisable body. If the core is partially filled with a non-magnetic or non-magnetizable body, it should be possible to place the device in at least a portion of the interior space defined by the electromagnet. By disposing the device inside the hollow core of the electromagnet, it is possible to dispose the device in a high magnetic field strength region. This maximizes the magnetic field perturbation by the device's magnetic material during operation, generating a large signal. Furthermore, the use of a single electromagnet, particularly a hollow core electromagnet, reduces the weight, size and power requirements of the device. If the electromagnet has high strength, the high magnetic field strength may spread beyond the coil itself. In such a case, the device need not be placed inside the hollow coil, but it must be placed close to the coil. However, it is preferred to place the device in at least a portion of the coil.

  To obtain a magnet or magnetizable body with a high magnetic field strength, it is advantageous to select a magnetic body with a relatively large size. This makes it possible to increase the size of the body fluid chamber used without substantially increasing the requirements for total blood volume. This gives various advantages in manufacturing.

  According to certain aspects, the present invention provides a device for use with an instrument for determining the coagulation characteristics of a body fluid sample. The device includes at least one cavity that contains a bodily fluid sample, the cavity including a magnet or magnetic body that cooperates with the device. The ratio of the volume of the magnet to the volume of the cavity is greater than 0.2. According to another embodiment, the ratio is greater than 0.3. According to yet another embodiment, the ratio is greater than 0.4. According to yet another embodiment, the ratio is greater than 0.5.

  In order to generate a signal by the magnetic field sensor, it is necessary to move the magnetic body in the body fluid chamber. The greater the distance traveled, the greater the disturbance of the magnetic field and therefore the signal. However, the larger the moving distance, the larger the capacity condition of the device. In order to produce a large signal, it is desirable to provide a large magnetic body having a high magnetic field. However, the larger the magnetic body, the smaller the distance that can be moved in the cavity. If it is desirable to provide a device with low capacity requirements, when the magnetic material reciprocates within the body fluid chamber, there is an optimum range of distance that the magnetic material travels or movement gap. The gap for movement between the magnetic body and the wall of the body fluid chamber may be between 300 μm and 600 μm. According to another embodiment, the gap for movement is between 450 μm and 550 μm. According to yet another embodiment, the range is between 490 μm and 510 μm.

  Similarly, in order to optimize the volume requirements of the body fluid chamber and the magnetic body, it is desirable that there be a clearance gap perpendicular to the direction of motion between the side of the magnet and the corresponding cavity wall. This gap is between 50 and 150 μm. According to another embodiment, the gap is between 75 μm and 125 μm. According to another embodiment, the gap is between 95 μm and 105 μm. According to a particular embodiment, the gap is 100 μm.

  Means may be provided for detecting the movement and / or position of the magnetic material within the fluid chamber. This type of means is preferably a magnetic field sensor such as a Hall effect sensor, a magnetic field sensor, a magnetostrictive sensor, a search coil or any other means for detecting changes in the magnetic field. In one embodiment, at least one sensor is provided and each sensor is associated with a respective body fluid chamber. During operation, the magnetic field measured by the sensor is affected by the position of the magnetic body relative to the sensor. Therefore, the output of the sensor can be used to determine the position and / or movement of the magnetic body within the body fluid chamber. The sensor may be responsive to the rate of change of the magnetic field that detects movement.

  The magnetic body of the device is preferably selected so as to have a high magnetic field density, ie a high magnetic field strength per unit volume. A high magnetic field density provides the magnet with high residual energy, thus reducing the power requirements necessary to reciprocate the magnet in the body fluid chamber. This allows the use of low field strength electromagnetic coils that reduce the power requirements of the device. When an electromagnetic coil having a lower magnetic field strength than that of a magnetic material is used, the signal-to-noise ratio is increased. A further advantage obtained with this arrangement is to reduce the requirement for reproducible and accurate positioning of the device relative to the magnetic field sensor. This increases the tolerance required for the device positioning means, thus reducing manufacturing costs.

  The shape, energy density and weight of the magnetic material are important parameters to consider. The weight of the magnet affects its inertia, the higher the weight, the greater the energy required to move the magnet. Conversely, the higher the magnet's energy density, the more energy the magnet contains and thus less force required to move the magnet (from the electromagnet). The length affects the energy density aspect. The magnetic field density around the magnet is typically minimal near its center and increases towards the pole piece. The rate of increase of the magnetic field along the length of the magnet is inversely proportional to its length. Therefore, when there are two magnets with different lengths having the same magnetic field density as a whole, the smaller magnet has a higher rate of change in magnetic field density along the length than the longer magnet. For example, it is important to measure the spread or magnitude of a magnetic field at any particular time using a magnetic field density sensor, such as a Hall effect sensor, as opposed to measuring the overall magnetic field. Therefore, even if the magnets as a whole have the same magnetic field density, a shorter magnet causes a larger signal to be generated in the Hall effect sensor than when the magnet is longer. The thickness of the magnet also affects the signal measured by the sensor. A thin magnet, or thin part of the magnet, has a high magnetic field density, while a thick magnet or thick part of the magnet has a low magnetic field density in that particular part. However, thin magnets also reduce the overall mass, which leads to low magnetic field density. The overall shape and aspect ratio of the magnet can also affect the magnetic field density. For example, a rectangular shape produces a certain energy density cross section along its length and a certain energy cross section at its pole face. In a magnet shaped like a rugby ball, an energy density cross section different from that of a rectangular body is generated. Furthermore, the energy density at both ends (magnetic poles) of the rugby ball-shaped magnet is very high because the surface area of each magnetic pole is small. Thus, any reference to the magnetic field strength at the surface of the magnet is related to the overall or average magnetic field strength. The aspect ratio of the magnet is also an important consideration. The present inventor has shown that if the aspect ratio is less than 2: 1 (length: width), the magnet can be twisted in the body fluid chamber when exposed to the magnetic field of the electromagnet. When the aspect ratio is 3: 1 or more, a magnet suitable for use in a solidification device is obtained.

  According to another aspect, the present invention provides a device for determining a clotting event. The device includes a chamber that houses a magnetic or magnetizable body and has an aspect ratio (ie width to thickness) at the center of the magnet that is greater than the aspect ratio at each pole piece (both ends).

  According to yet another aspect, the present invention provides a device for determining a clotting event. The device comprises a chamber containing a magnetized or magnetizable body magnetized along the length direction and has an aspect ratio (ie length to width) greater than 2: 1. Preferably, the aspect ratio is greater than 3: 1.

  In general, the magnet energy density, shape, material and magnetic coil energy should be selected such that the signal to noise ratio is greater than 90%.

  Other detection means for determining the position of the magnetic body or additional detection means (for example, means by optical, laser, radio frequency) may be provided.

  According to one embodiment, an apparatus for determining a coagulation characteristic of a body fluid sample is provided. This apparatus includes a measuring instrument having a solenoid and a device that houses a magnetic material in the room. The ratio of “magnetic field strength of the solenoid” to “magnetic field at the tip of the magnetic material” is at least 1: 2. According to one embodiment, the ratio is at least 1: 3. According to another embodiment, the ratio is 1: 4 or more.

  Another embodiment provides a device for use with an instrument for determining the coagulation characteristics of a body fluid sample. The device houses at least one magnet having a magnetic field of 30 mT or more at the tip or surface. According to another embodiment, it is 40 mT or more. According to yet another embodiment, it is 50 mT or more.

  Another embodiment provides a device for use with an instrument for determining the coagulation characteristics of a body fluid sample. The device works with less than 3 μl body fluid sample. Such a small amount of body fluid can be easily obtained from capillaries using a lancet.

  Capillary blood samples that can be used for clotting time testing because the interstitial fluid present in such samples is high and the stromal fluid introduces errors in the clotting time measurement It is generally believed that there is a lower limit on the amount of. Surprisingly, however, the total number of red blood cells in a very small capillary blood sample obtained from the finger is not substantially affected, so accurate clotting measurements can be performed with a small amount of blood that can be easily obtained. it can.

  Each cavity of the device is provided with at least one filling channel and a plurality of vent channels to allow the device used in the device for determining the coagulation characteristics of the body fluid sample to be completely filled with body fluid. It is done. The flow path may be provided at each corner of the cavity. By disposing the flow path at each corner of the detection chamber, the detection chamber can be surely completely filled while reducing the possibility of bubble formation. Thereby, a uniform coagulation detection result is obtained.

  The device may be provided with means such as one or more one-way capillary stops. This means serves to prevent the bodily fluid sample once entering the detection chamber from being pushed out of the detection chamber by the reciprocating motion of the magnetic material.

  Another embodiment provides a method for determining a coagulation characteristic of a bodily fluid sample by reciprocating a magnet in the bodily fluid sample in a detection chamber. For example, the amplitude of the signal obtained from the Hall effect sensor is determined by the moving speed of the magnet. When the moving speed of the magnetic substance in the body fluid starts to decrease, the amplitude starts to decrease. The solidification time can be regarded as the time when the motion of the magnetic material is completely stopped or the time when the amplitude of the signal falls below a certain threshold.

  In addition, body fluid homogeneity can be improved by preceding the first mixing stage at the first frequency with the measuring stage at the second frequency.

  Furthermore, when the body fluid starts to enter the device, the detection chamber can be uniformly filled by moving the magnet to a predetermined position so as to surely cause a prescribed capillary flow around the magnet.

  The energy supplied to the electromagnetic coil may be pulsed. This effectively moves the magnet in the detection chamber in the form of small pulse movements. This has been found to be a linear movement of the magnet and helps to prevent the magnet from twisting. Magnet twisting can occur when a large amount of energy is supplied to the magnet, causing the magnet to stick to the detection chamber or to move the magnet inside the detection chamber. The number of pulses per magnet translation (ie, full reciprocation) may be constant or variable. For example, when the sensor detects that the magnet has reached the end of the detection chamber, it may send a signal to the instrument to stop sending energy pulses to the coil, thereby reducing the energy requirement of the instrument. . Thereafter, the polarity of the magnetic coil is reversed, and another electric pulse is applied to the coil, so that the magnet moves back in the detection chamber. There may be a time interval between each reciprocation or several reciprocations. That is, the magnet may be able to be stopped virtually. This time interval may vary or be constant. The time interval may be useful, for example, to give the sample an opportunity to make a clot. The measuring instrument may have a preset time interval. Alternatively, the duration and number of time intervals may be determined by the measurement process itself. For example, it may be determined by the characteristics of the measurement signal. As the body fluid begins to solidify, the number of pulses required to move the magnet from end to end in the detection chamber increases. The meter may measure the energy required to move the magnet a fixed distance, or may measure the distance traveled when given a pulse of constant energy. When performing the measurement, the magnet may move the entire distance of the detection chamber or a part of the distance.

  A device for use with an instrument for determining a coagulation characteristic of a bodily fluid sample includes a detection chamber for receiving the bodily fluid sample. The detection chamber includes a magnet that can be used to agitate the body fluid sample. Agitation is not necessarily a requirement for measurement, but may be an advantage. If the detection chamber is filled with a substance other than the body fluid sample, or if the body fluid sample in the detection chamber contains air, it can have a very detrimental effect on the accuracy of any measurements performed. Furthermore, the accuracy of the measurement can be affected by the heterogeneity of the coagulation reagent within the body fluid. Advantageously, the reagent and the body fluid sample are mixed in the detection chamber in the mixing stage.

  Embodiments provide a device for use with an instrument for determining the coagulation characteristics of a body fluid sample. The device comprises at least one cavity that contains a bodily fluid sample, the cavity containing a magnetic or magnetizable body that cooperates with the device. The ratio of magnet volume to cavity volume is greater than 0.4.

  The ratio of the magnet volume to the cavity volume may be greater than 0.5. The specimen may be configured to accept an amount of sample less than 3 μl. Alternatively, the test strip may be configured to accept an amount of sample less than 1 μl. In another variation, the test strip is configured to accept a sample volume of 0.7 μl.

  The cavity may be configured to receive an amount of sample less than 3 μl. In a variation, the cavity may be configured to accept an amount of sample less than 1 μl. In another variation, the cavity is configured to receive a volume of 0.7 μl of sample.

  In other embodiments, the cavities are arranged such that the magnet moves in the direction of movement. A clearance or capillary gap is formed between the magnet side and the corresponding cavity wall in a direction perpendicular to the direction of motion. In one variation, the clearance or capillary gap is between 75 μm and 125 μm. In one variation, the clearance or capillary gap is between 95 μm and 105 μm. In another variation, the clearance or capillary gap is 100 μm.

  In one embodiment, the cavity is arranged so that the magnet moves in the direction of movement. A movement gap is formed in the direction of movement between the side surface of the magnet and the corresponding wall of the cavity.

  In another embodiment, the gap for movement is preferably between 450 μm and 550 μm. In one variation, the gap for movement is more preferably between 490 μm and 510 μm. In another variation, the gap for movement is most preferably 500 μm.

  Another embodiment provides a bodily fluid sample piece for use with a device for determining the coagulation characteristics of a bodily fluid sample. The sample piece comprises at least one cavity for containing a body fluid sample, the cavity containing a magnet that cooperates with the device. The sample strip is configured to accept less than 3 μl of sample. In a variation, the sample piece is configured to accept samples less than 1 μm. In another variation, the sample piece is configured to receive 0.7 μl of sample.

  Another embodiment provides a bodily fluid sample piece for use with a device for determining the coagulation characteristics of a bodily fluid sample. The sample piece comprises at least one cavity for containing a body fluid sample, the cavity containing a magnet that cooperates with the device. The cavity is configured to accept less than 3 μl of sample. In a variation, the cavity is configured to accept less than 1 μl of sample. In another variation, the cavity is configured to receive 0.7 μl of sample.

  Another embodiment provides a bodily fluid sample piece for use with a device that determines the coagulation characteristics of the bodily fluid sample. The sample piece comprises at least one cavity for containing a body fluid sample, the cavity containing a magnet that cooperates with the device. The cavity is arranged such that the magnet moves in the direction of movement. A clearance, that is, a capillary gap, is formed between the side surface of the magnet and the corresponding wall surface of the cavity in a direction perpendicular to the direction of motion.

  In one variation, the clearance or capillary gap is preferably between 75 μm and 125 μm.

  In one variant, it is more preferred that the clearance or capillary gap is between 95 μm and 105 μm.

  In one variation, the clearance or capillary gap is most preferably 100 μm.

  Another embodiment provides a bodily fluid sample piece for use with a device that determines the coagulation characteristics of the bodily fluid sample. The sample piece comprises at least one cavity for containing a body fluid sample, which contains a magnet that cooperates with the device. The cavity is arranged to move the magnet in the magnet direction, and a gap for movement is formed between the side surface of the magnet and the corresponding wall surface of the cavity in a direction parallel to the movement direction.

  In one variation, the two opposing sides of the magnet are in a plane perpendicular to the direction of motion.

  In one variant, the gap for movement is preferably between 450 μm and 550 μm.

  In one variation, the gap for movement is more preferably between 490 μm and 510 μm.

  In one variation, the gap for movement is most preferably 500 μm.

  In another embodiment, a device for determining the coagulation characteristics of a body fluid sample is provided. The device comprises an electromagnetic coil and a sample piece receiving hole for receiving a body fluid sample piece. At least a portion of the sample piece receiving hole is disposed within the electromagnetic coil.

  Another embodiment provides an instrument for use with a device that determines a coagulation characteristic of a body fluid sample. The instrument comprises an electromagnetic coil having a hollow inner core and device receiving means for receiving the device.

  In one variation, the sample piece receiving hole and the device receiving means are installed at a position where the device can be arranged in at least a part of the range of the internal space defined by the electromagnetic coil.

  In one variant, the electromagnetic coil has an axis and the sample piece receiving hole is provided along this axis.

  In one variation, the electromagnetic coil has a core volume and the sample piece receiving hole is provided within the core volume.

  Another embodiment provides an instrument for determining a coagulation characteristic of a body fluid sample. The apparatus includes a sample piece receiving hole for receiving a body fluid sample piece, a heating element for maintaining the sample piece receiving hole at a predetermined temperature, and a temperature sensor for monitoring the temperature of the body fluid sample device. Prepare.

  In one variant, the heating element is a resistance coil.

  In one variation, the heating element comprises a printed pattern of electrically resistive carbon ink.

  In one variant, the heating element is a Peltier element arranged to heat the cavity.

  In one variation, the polarity of the voltage applied to the Peltier element may be reversed in order to cool the device receiving hole to a predetermined temperature.

  In one variation, the predetermined temperature is 37 ° C.

  Another embodiment provides a method for determining a coagulation characteristic of a body fluid sample. The method includes maintaining a body fluid sample in the cavity at a predetermined temperature.

  Another embodiment provides a device for use with an instrument that determines the coagulation characteristics of a body fluid sample. The device comprises at least one cavity for containing a body fluid sample. The cavity houses a magnet that cooperates with the device. The magnet has a minimum magnetic field strength of 50 mT at its tip.

  In one variation, the magnet has a minimum magnetic field strength of 55 mT to 65 mT at the tip.

  In one variation, the magnet has a minimum magnetic field strength of 60 mT at the tip.

  In one variation, the magnet is an NdFe3B magnet.

  Another embodiment provides a strip for use with a device that determines the coagulation characteristics of a body fluid sample. The strip includes at least one cavity for containing a body fluid sample, the cavity containing a magnet that cooperates with the device. This cavity has a plurality of gas collection points. Each of the at least one cavity has a flow path connected at each gas collection point.

  In a variant, at least one channel is a filling channel.

  In one variation, at least one flow path is a vent flow path.

  In one variation, each gas collection point is located at the corner of each cavity.

  In one variation, the cavity is substantially cubic.

  Another embodiment provides a device for determining a coagulation characteristic of a body fluid sample. The device includes a single optical sensor for detecting both the first event and the second event.

  In another embodiment, a method for determining a coagulation characteristic of a body fluid sample is provided. The method includes vibrating at least one magnet, the vibration including a first vibration within a first frequency range over a first period, and the like.

  In one variation, the first event is a body fluid entry event.

  In one variation, the second event is a detection chamber full event.

  In one variation, the optical sensor is configured to examine both the filling and vent channels of the detection chamber.

  In one variation, the optical sensor is configured to detect a change in transfer characteristics of the filling channel and the ventilation channel.

  In one variation, the optical sensor is configured to detect a decrease in transfer characteristics of the filling channel and the ventilation channel caused by body fluid flowing through each channel.

  Another embodiment provides a bodily fluid sample piece for use with a device that determines the coagulation characteristics of the bodily fluid sample. The sample piece comprises at least one positioning structure configured to interact with a corresponding positioning element of the device.

  In one variation, the positioning structure is a recess in the surface of the body fluid sample piece.

  In one variation, the positioning structure is a hole in the body fluid sample piece.

  In order that the present invention may be more clearly understood, embodiments thereof will be described with reference to the accompanying drawings.

  A schematic of the device is shown in FIG. The device preferably comprises a molded lower layer 12 and a lid 13. The illustrated lower layer 12 has a length of 40 mm, a width of 8 mm, and a thickness of 0.8 mm. Lower layer 12 is shaped such that multiple structures on the lower surface form the upper surface of the assembled device.

  For example, the structure of the lower layer of the schematic device shown in FIG. 1 will be described. The triangular sample application structure 2 has a depth of 0.3 mm and is connected to at least one (two in this embodiment) inlet channel 3 having a depth of 0.15 mm and a width of 0.3 mm. Each inlet channel 3 is connected to the corner of one inlet end of two adjacent detection chambers or cavities 4. The detection chamber 4 has a length of 3.5 mm, a width of 1.2 mm, and a depth of 0.34 mm. A plurality of ventilation channels 5 and 6 are connected to the detection chamber. The ventilation channel has a depth of 0.15 mm and a width of 0.15 mm. One ventilation channel 5 is shown at the inlet end of the detection chamber 4, and two ventilation channels 6 are shown at each corner of the outlet end of the detection chamber 4. The gas confined by the ventilation channel can be released. The entrance end of the detection chamber 4 is opposite to the exit end.

  FIG. 1 shows a device with two detection chambers. These detection chambers are separated by 4.8 mm when measured from their respective centers. Separate the detection chamber so that the magnet signal associated with the magnet in one detection chamber does not affect or minimize the Hall effect sensor associated with the magnet in the other detection chamber Should. The reverse is also true. The optimum separation distance of the detection chamber is determined by factors such as the size of the magnetic material and the strength of the magnetic field.

  It should be noted that a flow path having a substantially rectangular cross section and having a small but finite depth in the direction perpendicular to the plane of the cross section is at each corner of the detection chamber 4. It should also be noted that the depth of the filling channel and the discharge channel is the same as the depth of the detection chamber 4. However, the depth of the filling flow path and the discharge flow path may be different from the depth of the detection chamber 4. For example, the depth of the filling channel and the discharging channel may be between 0.15 mm and 0.1 mm. It is preferable that the depths of the filling channel and the discharging channel are uniform along the length of the channel.

  A plurality of vents 7 and 8 are incorporated in the lower layer. The ventilation channels 5 and 6 are connected to the ventilation ports 7 and 8, respectively. In the schematic device shown, the two vent channels 6 exit the detection chamber 4 and end with a common vent 8. The vents 7 and 8 are circular recesses having a diameter of 1 mm and a depth of 0.4 mm on the upper surface of the lower layer. The device further comprises a positioning hole 9 passing through the device. This will be described in detail later. In addition, the capillary is interrupted at the junction of the ventilation channel and the ventilation hole (not shown). Thus, the bodily fluid sample can move through the vent channel to a capillary break.

  When the reagent is put in the detection chamber in a liquid state, a one-way stop structure is provided so that the reagent stays in the detection chamber until the reagent is dried. However, if it is necessary to pour blood into the detection chamber, the stop structure does not interfere with the process.

  The injection molded lower layer is handled in a plasma chamber to create the upper hydrophilic layer and the lower microstructure. Subsequently, a commercially available thromboplastin solution is deposited in each lower detection chamber 4. Preferably, each detection chamber 4 contains at least 0.4 μl of thromboplastin solution. The thromboplastin solution is then dried.

  The detection chamber is designed to contain a body fluid sample for examination. The amount of blood required for the test is determined by the internal dimensions of the device and the external dimensions of each magnet 10. This blood volume may be less than 3 μl. In particular, the blood volume is between 3 μl and 0.1 μl. More preferably, the blood volume is between 3 μl and 0.5 μl. Most preferably, the blood volume is between 2.75 μl and 0.75 μl. Preferably, the blood volume includes the capacity of the detection chamber, the ventilation channel, and the filling channel.

Each detection chamber 4 of the device houses a neodymium magnet 10. The magnet 10 may be NdFe3B. Each neodymium magnet 10 shown in FIG. 1 has dimensions of 3 mm × 1 mm × 0.25 mm. The detection chamber 4 shown in FIG. 1 has dimensions of 3.5 mm × 1.2 mm × 0.34 mm. Therefore, the amount of body fluid stored in the detection chamber is 0.7 mm ³ or 0.7 μl. The ratio of the magnet size to the detection chamber size is 0.53.

  The magnetic body preferably has a high magnetic field strength. However, it has been found difficult to place and hold such high strength magnets in the detection chamber during device manufacture. This is because magnets tend to pop out and stick together, and this is especially true when the device comprises a plurality of detection chambers in close proximity to each other and each detection chamber contains a magnet. The problem is that a metal body is placed in the detection chamber and an upper laminate is provided that seals or at least partially blocks the detection chamber, followed by magnetizing the metal body at that location to achieve the desired magnetic field strength. This can be solved. The presence of the upper laminate prevents the magnetic body from leaving the detection chamber and allows the detection chambers to be arranged close to each other. It also provides a convenient way to mass produce such devices and allows other metal structures that attract magnetic materials to be placed close to the device. Accordingly, one aspect of the present invention includes the steps of providing a magnetizable metal body in the detection chamber, limiting any movement of the metal body in the detection chamber, and subsequently magnetizing the metal body while in the detection chamber. A device manufacturing method is provided.

  The size of each magnet may be selected to substantially fill each detection chamber. This guarantees a high magnetic field strength and offers the further advantage that the amount of body fluid sample required to fill the detection chamber is small. Furthermore, substantially all of the body fluid in the detection chamber is agitated during the examination.

  In addition, when the magnets are in the detection chamber, the size of each magnet 10 relative to the detection chamber 4 is increased so that a clearance or capillary gap is created around the magnet to facilitate filling the detection chamber and completely fill the detection chamber. Decide. The dimensions described above provide a 100 μm capillary gap around the magnet, which is suitable for this purpose. Similarly, an end gap of 500 μm is obtained. This gap is an optimum value that allows the magnet to move by a sufficient amount to provide a reasonable signal from the magnetic field sensor 24, and has a sufficient capillary effect that can fill the detection chamber without creating bubbles. generate. A further advantage is that a larger detection chamber can be employed without compromising the low capacity requirements of the device. Furthermore, the manufacturing process can be more easily performed by providing a large detection chamber and a large magnetic body.

  Each magnet 10 preferably has a magnetic field strength greater than 50 mT, and more preferably has a magnetic field strength of 60 mT at the tip (ie, at both ends of the N and S poles of the magnet).

  FIG. 2 shows the completed device in the XX section of FIG. Each detection chamber 4 of the completed device contains a reagent 11 that is a coagulant such as thromboplastin and a magnet 10. Device 1 is shown including an injection molded lower layer 12, thromboplastin 11, at least one neodymium magnet 10, and a thin layered lid 13 bonded to lower layer 12.

  An electromagnet 21 that forms part of the instrument used with the device to detect sample body fluid coagulation events is shown in FIGS. The device may be inserted into the hollow core 50 of the electromagnet. When the device is in the use position, each magnet 10 in each detection chamber 4 is located in the hollow core of the electromagnet 21.

  The female structure provided by the device may be arranged to cooperate and engage with the corresponding male structure of the instrument. Alternatively, the male structure may be provided and arranged by the device to cooperate and engage with the corresponding female structure of the instrument.

  Magnet 10 has a north-south (NS) pole axis that is parallel to the north-south (NS) axis of the electromagnet. The magnet 10 is preferably oriented in the detection chamber 4 so that the end with the N pole is located at the end of the detection chamber proximal to the fill channel. Therefore, a known technique can be applied to move the magnet 10 to a specific end of the detection chamber 4. By magnetizing the material in strips, the magnet can be moved in the same direction when a voltage is applied to the electromagnet.

  FIG. 4 is a cross-sectional view of the measuring instrument 20 in which the device 1 shown in cross section is inserted. The measuring instrument 20 includes an induction coil 21 and at least one Hall effect sensor 24 configured to detect the position of the magnet in each detection chamber 4. The measuring instrument 20 also includes at least one optical sensor 22, 23. These optical sensors are preferably LED light sources and conventional phototransistors. The use of the optical sensor and the operation of the optical sensor will be described in detail later.

  According to one embodiment, coil 21 has a 70 ohm DC resistance and is driven by a 5V power supply.

  The coil 21 may have an open tube shape. The coil cross section may be any other shape. For example, a triangle, an ellipse, a rectangle, a rectangle, a circle, and the like may be used.

  In the configuration having a plurality of illustrated detection chambers, the Hall effect sensor 24 is provided for each detection chamber 4. The Hall effect sensor 24 is preferably arranged so that the midpoint of the detection area of the Hall effect sensor is aligned with one end of the magnet 10 when the magnet is in the center of the detection chamber 4. In addition, a heating element 42 and a temperature sensor 45 are provided adjacent to the detection chamber.

  The measuring instrument passes along each ventilation channel 5 when the device is inserted into the first optical sensor arranged to detect the sample body fluid passing through each inlet channel 3 of each detection chamber 4. A second optical sensor arranged to detect the sample body fluid to be detected. Alternatively, the second optical sensor may be arranged to detect sample body fluid passing along each ventilation channel 6.

  Usually, the magnetic field strength of the device 1 generated by the coil 21 is about 15 mT. This is a smaller magnetic field than prior art instruments, preferably reducing the power consumption of the device, reducing the device weight and running costs.

  FIG. 8 shows a functional block diagram of the control circuit of the measuring instrument 20. The microprocessor 40 receives inputs from each Hall effect sensor 24, each photosensor 22 and the temperature sensor 45. Microprocessor 40 is connected to amplifiers 43 and 44 that provide power to coil 21 and heating element 42, respectively. The microprocessor is further connected to the display 41. The display 41 may be used to show the measurement result to the user. The measurement result may be presented, for example, as a value of coagulation time or International Normalized Ratio (INR).

  The heating element 42 may include a resistance coil that generates heat when a current passes therethrough. The heating element may comprise a ceramic plate with an electrically resistive carbon ink printed on top. Such a heating element may have a resistance of 18 ohms. Alternatively, the heating element 42 may be a Peltier element. The Peltier element functions as a heat pump and is preferably connected to a heat sink.

  The heating element 42 preferably functions to heat the receiving hole of the device to a predetermined temperature monitored by the temperature sensor 45 before using the device and instrument for measurement. The temperature sensor 45 may comprise a conventional thermocouple array configured to measure infrared radiation emitted by the device. Thus, the thermocouple array is spaced from the device. The air gap may be about 3 mm. The thermocouple string outputs a voltage signal proportional to the temperature of the infrared source in the direction in which the thermocouple string is directed. Preferably, the temperature sensor 45 faces the device 1 rather than the heating element 42. Thus, the temperature sensor measures the temperature of the device, not the temperature of the heating element 42 that may be hotter or colder than the device 1. This reduces device temperature measurement errors caused by variables such as thermal delay, contact pressure, device flatness, etc., and maintains the temperature at a predetermined target value with an accurate feedback loop. Since the solidification time is temperature dependent, this allows more accurate determination of results.

  When the device and measuring instrument reach a predetermined temperature, the measuring instrument 20 displays an instruction on the display 41. This indication may be something like “ready for test”. Upon receiving this instruction, the user may introduce a body fluid sample into the device. If the ambient temperature in which the device and instrument are used is greater than a predetermined temperature, and if the heating element 42 is a Peltier element, a current of opposite polarity is applied to the Peltier element to cool the device and the device receiving hole. May be applied.

  The predetermined temperature depends on the nature of the test being performed. For the measurement of prothrombin time, the temperature is selected at 37 ° C.

  The operation of the device and measuring instrument will be described with reference to the measurement of the coagulation time of the body fluid sample. The device is inserted into the device receiving hole of the measuring instrument. In the sample application structure 2, a body fluid sample is placed in front of the device. Body fluid moves inside the device by capillary action. The body fluid is sucked up from the sample application structure 2 and enters each detection chamber 4 along each inlet channel 3. The sample body fluid continues to flow through each inlet channel 3, fills each detection chamber 4, and continues to flow through the vent channels 5, 6. When the body fluid in the ventilation channels 5 and 6 reaches the capillary breaks 7 and 8, respectively, the flow of the sample body fluid stops. By disposing the flow path at each corner of the detection chamber, the detection chamber can be completely filled while reducing the possibility of forming a gap. Thereby, a uniform coagulation detection result can be obtained.

  In a preferred embodiment, bodily fluids move through the device by capillary action. However, other standard means of transporting bodily fluids within the device, such as electro-osmotic flow, may be envisaged.

  As described above, an optical sensor is provided for detecting sample body fluid entry events and / or detection chamber full events. A sample body fluid entry event can be defined as a sample body fluid being detected in the filling channel of the device. A detection chamber full event can be defined as a sample body fluid being detected in at least one vent channel of the device.

  When the sample body fluid is detected in the inlet channel 3 of the device 1 (defined as a body fluid entry event), the measuring device 20 starts measuring time.

  When a body fluid entry event is detected, a filling signal is given to the coil 21 and a magnetic field having a constant polarity is created. As a result, the magnet 10 in the detection chamber 4 repels from the coil 21 and moves toward the sample application structure 2 of the device 1 as shown in FIG. By positioning this magnet in the filling stage, the detection chamber can be reproducibly filled with the body fluid sample. It is therefore advantageous to fix the magnet in a known position in order to obtain consistent filling characteristics for different tests. The fill signal lasts for 3 seconds, which is the time it is assumed that the detection chamber is full.

  After the filling signal, a mixed signal is given to the coil 21. The mixed signal generates an oscillating magnetic field having opposite polarities. The mixed signal preferably generates an oscillating magnetic field that oscillates at about 8 Hz around the coil 21. In order to reliably mix the body fluid sample and the reagent 11 shown in FIG. 2, the mixing signal is given for 5 seconds.

  After the mixed signal, a measurement signal is applied to the coil 21. The measurement signal generates an oscillating magnetic field with opposite polarities and initially oscillates at about half the frequency of a mixed newspaper. The mixed signal preferably generates an oscillating magnetic field around the coil 21 that initially oscillates at about 4 Hz. During the application of the measurement signal, the oscillation period of the magnetic field around the coil 21 is preferably increased by 15 milliseconds per cycle. An example of this method of applying power to the coil is shown schematically in FIG.

  As will be described in detail later, a measurement signal is provided to the coil 21 until a coagulation event is detected.

  When connected to a 5V power supply, a direct current of 71 mA flows through the coil 21. To reduce power consumption, the coil is operated with a frequency of 50 Hz and a duty cycle of 50%. This reduces the average current consumption to about 35 mA. Further, during any half cycle, the magnet is forced only during a portion of the half cycle. A current having a first polarity is applied during a portion of the first half cycle, followed by a current having a second polarity opposite to the first polarity during a portion of the second half cycle. For example, if the magnet is oscillating at 2 Hz, the half-cycle duration is 250 ms. During the first half cycle, a first polarity signal is applied to the coil for 100 ms. Subsequently, during the second half cycle, a signal of the second polarity is applied to the coil for 100 ms. Preferably, the first or second polarity signal is a pulsed voltage. The pulse duty cycle may be reduced to save power.

  The pulsing of currents in opposite directions is done by using an alternating voltage source. The AC voltage source may be a rectangular wave signal, a sine wave signal, or a triangular waveform signal.

  In order to detect the movement of the magnet, the signal output from each Hall effect sensor 24 of the measuring instrument 20 is processed as shown in FIG. The peak amplitude 31 of the signal output from each Hall effect sensor represents the movement of the tip of the magnet 10 when the magnet vibrates. The signal output indicates that the magnet reciprocates according to the magnetic field applied by the coil 21. Since the velocity of the magnetic body begins to decrease means that the fluid sample or blood has reached a clotting event, the amplitude and speed of the magnet motion, the corresponding peak amplitude, and / or the output signal from the Hall effect sensor Decreases in speed (32). The magnitude of the voltage after the occurrence of a coagulation event can also be an indicator of clot strength. Therefore, this value may be used to determine the coagulation strength of a particular body fluid sample. In addition, the device can be used to determine the clot dissolution rate by continuing to move the magnetic material back and forth in the sample after the coagulation event. If necessary, the magnetic field strength may be increased first to move the magnetic material through the sample.

  Each magnet 10 is magnetized along the longest axis in a direction parallel to the direction in which the magnet reciprocates when an alternating magnetic field is applied by the coil 21. Thus, the magnetic field measured in the length direction of the magnet is minimum at the center and maximum at both ends. As the position of the magnet in the detection chamber 4 changes, the output signal from the Hall effect sensor also changes. Therefore, the amount of displacement of the magnet in the detection chamber 4 can be determined by measuring the output signal from the Hall effect sensor 24. The relationship between the Hall effect sensor output signal and the magnet displacement becomes nonlinear when the magnet tip passes the Hall effect sensor 24. This non-linearity is taken into account during the measurement.

  The displacement is converted into a distance moved by subtracting the end position of the magnet, for example. Thus, the distance traveled by the magnet in a given cycle is directly measured. This value decreases as a clot occurs.

  The solidification event can be defined as the time when the magnet stops moving or when the magnet decelerates to a certain range. The clotting event can be easily determined by measuring the amplitude of the signal or by the change or rate of change in the signal amplitude. A bodily fluid sample or clot that prevents magnet movement can be defined as a predetermined decrease in the amplitude of the Hall effect sensor output signal from the average amplitude. The degree of amplitude change may be determined according to factors such as blood INR, the size and shape of the magnet, and the ratio or difference of the magnetic field strength of the magnet compared to the electromagnet. For example, a clotting event may be considered to have occurred when the signal amplitude is 70% of the average amplitude signal. The average amplitude signal is an average value of amplitude measurement values measured during a specific period (for example, measurement for the first 5 seconds).

  Alternatively, smoothing with a moving average may be applied to the magnet movement signal and the decrease in measured amplitude.

  FIG. 9 shows a flowchart of a method for operating the apparatus. The method includes detecting (71) a bodily fluid entry event using optical sensors 22,23. This causes the start of a coagulation timer (72) and the application of an initialization signal to the coil 21 (73). The clotting timer is implemented by the microprocessor 40. Either upon detection of a detection chamber full signal from another or the same light sensor 22, 23 (74) or at the end of a predetermined 3 second timeout (75), the device sends the mixed signal to coil 21. Apply for 5 seconds (76). After applying the mixed signal for 5 seconds (77), a measurement signal is applied to the coil (78) and the amplitude of the magnet movement is detected (79). A threshold is calculated from the measured magnet movement amplitude by multiplying the measured value by a ratio (eg, 70%) (80). A measurement signal is applied (78) until the apparatus detects a decrease in the magnet movement amplitude to a value below a threshold that defines the occurrence of a coagulation event (81). When a coagulation event is detected, the coagulation timer is stopped (82), the measurement signal is stopped, and the measured coagulation time is output by the device (83).

  FIG. 10 is a flowchart of a method for moving a magnet. In this method, the magnet is moved (91), the position of the magnet is detected (92), it is determined whether the detected position of the magnet is within a preferred range (93), and the detected position of the magnet is preferable. If not, the magnet is moved again (94).

  A method for manufacturing the device shown in FIG. 1 will be described. Lower layer 1 is preferably formed from polystyrene using injection molding techniques well known in the art. The exemplary lower layer is 40 mm long, 8 mm wide, and 0.8 mm thick. During molding, the lower layer is shaped to have a plurality of microstructures on the upper surface.

  The injection molded lower layer is processed in a plasma chamber. The plasma chamber creates a hydrophilic layer disposed on the upper surface and a lower microstructure.

  A commercially available thromboplastin solution is deposited in each detection chamber 4 in the lower layer. A thromboplastin solution may be deposited using a deposition station, such as that provided by Horizon Instruments (UK). Preferably, at least 0.4 μl of thromboplastin solution is deposited in each detection chamber 4. It will be apparent to those skilled in the art that several other well-known thromboplastin solutions are also suitable for use in this device.

  The deposited thromboplastin solution is dried by passing it through the heated chamber through a heated chamber for a total of 10 minutes at a temperature of about 65 ° C. for 4 minutes followed by a temperature of about 45 ° C. for 6 minutes.

  Following the deposition of the thromboplastin solution in each lower detection chamber 4 and subsequent drying, a neodymium magnet 10 is placed in each detection chamber 4 of the device 1.

  A lid is placed over the lower layer and attached. The lid is preferably a 125 μm thick polystyrene laminate and is preferably attached to the lower layer with an adhesive. Other methods can be used to attach the lid to the lower layer.

  Once the lid is bonded to the lower layer, a 25 W carbon dioxide laser is used to cut the lid material stack to remove excess lid material from the lower layer edge. The 25 W laser is also used to open a vent in the lid above the vents 7,8. During use, when introducing sample body fluid from the sample application structure 2 to the device, this vent allows air to escape from the detection chamber 4.

  The devices described herein provide various effects. The use of a strong magnetic material such as NdFe3B for each magnet 10 in the detection chamber 4 is advantageous for various reasons.

  First, the magnetic field generated by the electromagnetic coil 21 to generate a specific driving force for driving the magnet 10 in the body fluid sample in the detection chamber 4 may be small. Therefore, the coil 21 may be smaller and power consumption may be reduced, so that the power source of the measuring instrument 20 may be smaller. This is particularly advantageous in embodiments where the instrument 20 is portable and battery powered.

  Secondly, the stronger the magnet 10, the higher the signal intensity generated at the Hall effect sensor 24. Therefore, the signal-to-noise ratio of the Hall effect sensor output is reduced and the detection accuracy of the coagulation event is improved.

  When the Hall effect sensor 24 is placed in alignment with one end of the magnet 10 when the magnet is in the center of the detection chamber 4, the change in the magnetic field is maximized, and therefore the magnet moves from one end of the detection chamber 4 to the opposite end. Sometimes the output signal from the Hall effect sensor 24 is maximized. This advantageously improves the signal to noise ratio of the output signal by each Hall effect sensor 24. Hall effect sensors are usually placed as close as possible to the detection chamber to maximize the signal.

  The two detection chambers shown in FIG. 1 are separated by 4.8 mm when measured from the center of each chamber.

  When the two detection chambers are arranged adjacent to each other and sufficiently close to each other so that the magnetic fields of the respective magnets interact with each other, the magnet is stabilized and the detection chamber is operated when the magnetic field of the electromagnetic coil acts. Showed that the magnet could not be twisted. There are further advantages to placing the detection chambers close to each other. For example, the size of the device is made smaller and the size of the heating element is made smaller. However, if the detection chambers are too close to each other, the magnet in one detection chamber may interfere with the movement of the magnet in the other detection chamber, as shown in FIG. Interference of one magnet with the movement of the other magnet may appear when one magnet is attracted to the other, which creates friction between the magnet and the side wall of the detection chamber, hindering the movement of the magnet. It is done. Such interference can cause the detector to falsely indicate a clotting event. Therefore, there is a minimum separation between the two detection chambers. This minimum separation may be defined as the minimum distance necessary to prevent the magnets from substantially interfering with each other's movement and falsely presenting a coagulation event earlier than it actually is. it can. Ideally, the detection chamber is arranged so that each magnet does not interfere with the movement of the other. However, some interference is allowed as long as it does not affect the result of clotting time. The separation distance between the detection chambers may be determined by the magnetic field density of each magnet. The greater the magnetic field density, the greater the required separation. Therefore, there is an optimal separation range between the two detection chambers. If the detection chambers are too close, the magnets can interfere with each other's movement, and if the detection chambers are too far apart, the magnets can twist during use and require larger specimens and larger heating elements. Become. In a device with two detection chambers each containing a NdFe3B magnet with dimensions of 3 mm x 1 mm x 0.25 mm and a magnetic field strength of 50 mT at its tip, the magnets are properly A 4.8 mm separation was shown to be stable. At a separation distance of 4 mm from the center of each detection chamber, the magnets interfered with each other to a significant degree, indicating that they were inappropriate.

  The output signal from the magnetic field sensor is proportional to the magnetic strength. Therefore, the absolute position and / or moving speed of the magnet in the detection chamber can be derived from the output signal of the Hall effect sensor 24. In an alternative device, instead of driving the entire coil, only the amount of power required to move the magnet 10 from end to end of the detection chamber 4 can be input to the coil 21. The coil 21 is provided with a short duration signal for generating a short duration magnetic field. If the signal output from the Hall effect sensor does not indicate that the magnet is at the maximum value of the measurement, for example at one end of the detection chamber 4, another short duration signal is provided to the coil 21. When the body fluid sample has not solidified, the magnet 10 finally reaches the end of the detection chamber 4. Then, the above process may be repeated by providing the coil 21 with a short duration signal having the opposite polarity. Thus, only the minimum electric power for moving the magnet 10 is input to the coil 21. Advantageously, this reduces the power consumption of the meter 20. Furthermore, this type of measurement method can be used to determine the clotting time when INR is high or when clotting is weak. In this type of situation, providing a short duration pulse can increase the sensitivity of the device to detect clotting events. When the body fluid sample is solidified, the magnet 10 cannot cross the detection chamber 4. This is detected by the Hall effect sensor 24 as described above. Alternatively or in addition, the power supplied to the coil may be varied during the measurement.

  If excessive power is applied to the electromagnetic coil, excessive use of energy by the instrument occurs. This excessively consumes finite power such as a battery, thereby reducing the operation time and increasing the operation cost. Furthermore, by detecting the position of the magnet during vibration, only the minimum necessary energy needs to be given to the operation, saving battery power.

  In the embodiment described above, the polarity of the magnet 10 is known with respect to the orientation of the detection chamber 4. Thus, the polarity of the magnetic field that must be applied to the detection chamber to move the magnet to a predetermined position during filling is also known. In the modification, the polarity direction of the magnet 10 is not known. Therefore, a preliminary filling signal is given to the coil 21, and the position of the magnet 10 is detected by either the Hall effect sensor or the optical sensor. When the magnet is in the desired predetermined position, the fill signal is maintained as described above. If the magnet is in the desired predetermined position, the polarity of the filling signal is reversed and the position of the magnet 10 is detected again. If the detector does not detect that either or both of the magnets 10 are in the desired position, an error signal is generated.

  In the above embodiment, means for detecting the position of the magnetic body 10 in the detection chamber 4 is provided. In the modification, a means for detecting the movement of the magnetic body 10 is provided. During operation, the movement measured by the sensor is reduced due to changes in the viscosity of the body fluid sample caused by coagulation disturbances.

  Alternatively, at least one light sensor that is stationary may be used to detect the position of one or both of the magnets 10. In operation, a decrease in the frequency of change in the light transfer characteristics of the detection chamber 4 indicates a change in the viscosity of the body fluid sample caused by a coagulation disorder. The presence or absence of the magnet 10 at a predetermined position in the detection chamber 4 determines the optical signal measured by the optical sensor.

  Another arrangement of at least one photosensor will be described. An optical sensor arranged to detect light transmission may be provided in both the inlet channel 3 and the vent channel 5 for each detection chamber. Body fluid is detected in the inlet channel 3 at the first transmission decrease event, and body fluid is detected in the ventilation channel 5 at the second transmission decrease event. Therefore, by providing one optical sensor for the detection chamber, both the body fluid entry event and the detection chamber full event can be detected.

  Although specific examples of signals applied to coil 21 have been described above with respect to duty cycle and frequency, it should be noted that these signals are exemplary only. The duty cycle of the pulses applied to the coil must only be greater than 0% and depends on the coil and power source used. The frequency of the oscillating signals such as the mixed signal and measurement signal applied to the coil 21 is preferably between 1 Hz and 50 Hz.

  In the above embodiment, each detection chamber 4 includes a reagent 11. In a variant, two detection chambers 4 are provided, only one detection chamber 4 contains the reagent 11 and the other detection chamber 4 acts as a controller during the measurement process.

  In the above case, the coagulation time may be measured from the time of detection of the body fluid entry event (which may be defined as time 0). Another measurement of time 0 may be measured by programming the instrument 20 to have a preset delay taking into account the filling characteristics of the device 1.

  Alternatively, the instrument 20 may detect both a sample fluid entry event and a detection chamber filling event, and calculate time 0 according to a predetermined algorithm defined from the filling characteristics measured for the device 1. Good. As described above, detection of the detection chamber filling event may be used as a trigger for the transition from the application of the filling signal to the coil 21 to the application of the mixing signal instead of a fixed 3 seconds.

  Furthermore, the example of the reduction | decrease of the output signal from the Hall effect sensor 24 for determining the stop of the reciprocation of a magnet was shown as an example. Alternative methods for determining the stop of the reciprocation of the magnet are also available.

  A method is provided for determining a coagulation or coagulation characteristic of a body fluid sample that takes into account the initial viscosity of the body fluid sample as follows. That is, before the coagulation, the amplitude of movement of the magnet located in the body fluid sample is measured, and then the occurrence of a coagulation event is determined by detecting a decrease in the predetermined amplitude.

It is the schematic of the device used with a measuring device. It is a figure which shows the device in the XX cross section of FIG. It is a figure which shows the measuring device used with a device. It is sectional drawing of the device inserted in a measuring device. It is a figure which shows the two magnets arrange | positioned in a device. It is a figure which shows the method of the electric power given to the coil of a measuring device. It is a figure which shows the signal output from each of two Hall effect sensors during a coagulation test. It is a figure which shows the control circuit for measuring instruments. It is a flowchart which shows the operating method of an apparatus. It is a flowchart of the method of moving a magnet.

Claims (26)

  A method for determining a coagulation characteristic of a bodily fluid sample, comprising causing vibrations of at least one magnet, wherein the vibrations include a first vibration within a first frequency range over a first time period, and a second time period. And a second vibration in a second frequency range different from the first frequency range.   The method of claim 1, wherein the first frequency is greater than the second frequency.   3. The method according to claim 1, wherein the period of the second vibration is increased from the initial second frequency by a certain time increment for each pulse.   4. The method of claim 3, wherein the constant time increment per pulse is 0.15 milliseconds.   5. A method as claimed in any preceding claim, wherein the first frequency is between 5Hz and 12Hz.   6. A method according to any preceding claim, wherein the first frequency is between 7 Hz and 10 Hz.   7. A method as claimed in any preceding claim, wherein the first frequency is substantially 8H.   8. A method according to any preceding claim, wherein the first period is between 2 and 8 seconds.   9. A method according to any preceding claim, wherein the first time period is between 4 and 6 seconds.   10. A method according to any one of the preceding claims, wherein the first period is substantially 5 seconds.   11. A method as claimed in any preceding claim, wherein the second frequency is between 2Hz and 6Hz.   12. A method as claimed in any preceding claim, wherein the second frequency is between 3Hz and 5Hz.   13. A method as claimed in any preceding claim, wherein the second frequency is substantially 4Hz. A method for determining a coagulation characteristic of a body fluid sample in a device comprising a body fluid sample chamber and a magnet movable within the chamber, comprising:
Detect body fluid entry events,
Moving the magnet to a predetermined position over a first time period upon detection of a bodily fluid entry event.   15. The method of claim 14, wherein moving the magnet to a predetermined position over a first period includes applying a first polarity signal to the electromagnetic coil.   16. A method according to claim 14 or 15, wherein the first period is between 2 and 6 seconds.   16. A method according to claim 14 or 15, wherein the first period is between 2 and 4 seconds.   16. A method according to claim 14 or 15, wherein the first period is 3 seconds.   19. A method according to any of claims 14 to 18, wherein the first period ends upon detection of a detection chamber full event. A method for determining a coagulation characteristic of a body fluid sample in a device comprising a body fluid sample chamber and a magnet movable within the chamber, comprising:
Moving the magnet,
Detecting the position of the magnet,
Moving the magnet again in response to the result of the detecting step. A method for determining a coagulation characteristic of a body fluid sample in a device comprising a body fluid sample chamber and a magnet movable within the chamber, comprising:
Moving the magnet,
Detecting the position of the magnet,
Determining whether the detection position of the magnet is within a predetermined range;
Moving the magnet again according to the result of the determining step. A method for determining a coagulation characteristic of a body fluid sample in a device comprising a body fluid sample chamber and a magnet movable within the chamber, comprising:
Moving the magnet,
Detecting the position of the magnet,
Determining whether the detection position of the magnet is within a desired one of two preferred ranges;
If the magnet is not within the desired range, move the magnet again,
If the magnet is within a desired range, the method causes the magnet to vibrate between two preferred ranges by waiting for a predetermined period of time before moving the magnet again. A method for determining the coagulation characteristics of a body fluid sample, comprising:
The bodily fluid sample piece includes a bodily fluid sample and at least one magnet configured to vibrate therein;
Oscillating the at least one magnet;
Detecting vibrations of the at least one magnet;
Determining a coagulation event upon detecting that the amplitude of vibration of the at least one magnet has decreased to an amplitude below a threshold;
The threshold is determined by measuring the amplitude of vibration of the at least one magnet during the initial period of the vibration and defining a predetermined percentage of the measured average amplitude motion as the threshold. A method characterized by that.   The threshold is an average of a plurality of measurements of the amplitude of vibration of the at least one magnet during the initial period of the vibration, and a predetermined percentage of the measured average amplitude motion is defined as the threshold. 24. The method of claim 23, wherein the method is determined by defining.   25. A method according to claim 23 or 24, wherein the predetermined percentage is between 50% and 90%.   25. A method according to claim 23 or 24, wherein the predetermined percentage is between 65% and 75%.

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