Patent Application
20070280854
With reference to
The housing 11 has a cover 11A which has an upper wall region which is opposite the measurement part 20 and of a front wall region bordering it, and which opens a chip insertion part 12 by being pivoted around an axis which runs in the widthwise direction. At the position next to the cover 11A in the widthwise direction, on the top side of the housing 11, is the operator panel 13 which has a display panel part 13A.
The measurement part 20, as is shown in
On the bottom wall of the centrifugal rotor 25 is a direction reversing gear 27 with an outer diameter which is smaller than the radius of the centrifugal rotor 25 and which is supported to be able to rotate around an axis which is parallel to the center C of the axis of rotation of the centrifugal rotor 25. On the top side of this gear 27, there is a suitable holder component comprising the chip holding part 26 which is positioned on the outer peripheral edge of the centrifugal rotor 25.
The measurement part 20 can have several chip holding parts 26. In this embodiment, the chip holding parts 26 are formed from direction reversing gears 27 with the same arrangement at opposite positions between which the middle C of the axis of rotation is located in order to maintain the concentric running-balancing of the centrifugal rotor 25 in the proper state.
On the lower wall of the cover hood 22, in the centrifugal rotor 25 and in the direction reversing gear 27 comprising the chip holding part 26, in the state in which the microchip 60 is held fast in the chip holding part 26, at the positions in the radial direction in which a measurement cell 63 of the microchip 60 is positioned, apertures are formed for feeding light 22A, 25A (see,
On the upper side and the lower side of the cover hood 22, there is partially a flat heating apparatus 35 for maintaining the temperature within the measurement chamber 21 for analytic testing, for example, at a constant temperature of 37° C. The output is controlled based on the temperature determined, for example, using a thermistor 36.
Furthermore, on the upper wall of the cover hood 22, a window 29 for reading bar codes is formed and is used to read information by means of a bar code reader 37 located above the measurement chamber 21, this information being indicated, for example, by a bar code 65 which is located in the chip insertion opening 28 and in the microchip 60, and this information being characteristic of the microchip 60.
The measurement part 20 of the biochemical analysis device 10 has a chip direction reversal device 30 which forms a rotary driving device which is independent of the driving device which drives the centrifugal rotor 25 in rotation for adjusting the position of the microchip 60 held in the chip holding part 26. This chip direction reversal device 30 comprises a driving gear 33 which engages the direction reversing gear 27 of the chip holding part 26 and which is pivotally located with respect to the drive shaft 24A of the centrifugal motor 24, for example, over a ball bearing 32 or the like, and of a chip direction reversal motor 31 as a driving source for rotary driving of this driving gear 33.
As is described below, in the biochemical analysis device 10 in accordance with the invention, the operation of measurement of the light intensity of the test liquid within the measurement cell 63 of the microchip 60 is carried out in the state in which rotation of the centrifugal rotor 25 is stopped. It is therefore necessary to adjust the stop position of the centrifugal rotor 25 with high precision. Therefore, a coder 38 is coupled to the centrifugal motor 24 for rotational driving of the centrifugal rotor 25. For light intensity measurement operation, the stop position of the centrifugal rotor 25 is adjusted based on the signal from the encoder 38.
It is advantageous for the total pulse number P per rotation of the encoder 38 to be set such that the following relation is satisfied. In this way, for light intensity measurement operation, deviation of the stop position of the measurement cell 63 can be reduced to a negligible amount, i.e., high reproducibility can be obtained and the required measurement precision can be reliably maintained.
As is shown, for example, in
(Formula) 1/10>[r·tan(360°/P)]/D2
where r [mm] is the distance between the center C of the axis of rotation of the centrifugal rotor 25 and the center of the measurement cell 63 in the radial direction of the microchip 60 which is seated on the centrifugal rotor 25 and D [mm] is the diameter of the aperture for feeding light which limits the amount of light such that the beam diameter of the light from the light source 40 is limited to the beam diameter of the light which is finally fed into the measurement cell 63 (in this example, D2 is the diameter of the aperture 27A for light feed which is formed in the direction reversing gear 27). The beam diameter of the light from the light source 40 is, in any case, greater than the minimum value D1 of the cross sectional diameter (dimension of inside diameter) of the measurement cell 63 of the microchip 60 and also the diameter D2 of the aperture 27A for light feeding of the direction reversing gear 27.
Furthermore, as is shown in
(Formula) 1/10>[r·tan(360°/P)]/D1
if D=D1, the amount of light is limited by the outer peripheral edge of the measurement cell 63 of the microchip 60 such that the beam diameter of the light from the light source 40 is limited to the beam diameter of the light which is finally fed into the measurement cell 63.
The light source 40 in this biochemical analysis device 10 consists of the light source 41 of a discharge lamp which emits light in the wavelength range of UV radiation to the IR region, a lens 42 for making parallel the light emitted from the light source 41 and for its emission, and an optical filter 43. Furthermore, an air cooling fan 44 is provided for cooling the discharge lamp during lamp operation. For example, a xenon lamp, a mercury lamp, a halogen lamp with a high color temperature or the like can be used as the discharge lamp of the light source 41.
In this biochemical analysis device 10, for example, there is a reflection mirror 45 opposite the light feed opening 22A of the cover hood 22 of the measurement chamber 21. The light from the light source 41 is fed from the bottom side of the measurement chamber 21 such that it passes through within the measurement cell 63 of the microchip 60 in the vertical direction.
The light detector 50 has a light receiving apparatus 51 which comprises, for example, a concave diffraction grating photometer with several wavelengths which can measure several wavelengths at the same time. The light which has been transmitted from the inside of the measurement cell 63 is fed into the light receiving apparatus 51, for example, by the optical fiber 25 which is attached to the aperture 22B and which has an end mounted on the upper wall of the cover hood 22.
The microchip 60 which is used in the above described biochemical analysis device 10, as is shown, for example, in
In this microchip 60 several, for example, seven, measurement cells 63 are formed spaced apart from one another in the state in which the centrifugal rotor 25 is held fast in the chip holding part 26, at positions on the same circle periphery as the center C of the axis of rotation of the centrifugal rotor 25. They each have a narrow shape with an extremely large dimension (length) in the direction of thickness compared to the cross sectional diameter (inside diameter) so that a relatively great length of the optical path of the transmitted light which is required for measurement of the absorbance is ensured.
The arrangement of the measurement cell 63 is shown below using one specific example. For example, the inside diameter is 1 mm, the length is 10 mm and the volume (amount of the test liquid to be tested) is roughly 10 microliters.
In
Operation of the above described biochemical analysis device 10 is described below using an example of the analysis of human blood.
As is shown in
If the biochemical analysis device 10 is operated by pressing a starting button, the information which is characteristic of the microchip 60, such as the measurement conditions and the like, which is indicated by the bar code 65 of the microchip 60, is read by a bar code reader 37. Based on this information, the operating conditions of the biochemical analysis device 10 are set. Moreover, it is assessed whether the amount of blood necessary for analytic measurement which has been injected into the microchip 60 is sufficient, and in the case of a sufficient amount of blood, an analytic test of the blood is run. If it is ascertained that the amount of blood is insufficient, an error message is delivered.
Analytic testing comprises a pretreatment process for producing the test liquid according to the test samples (detection object components) and the process of measuring the light intensity for measuring the absorbance of the test liquids (device process) which were obtained by this pretreatment process.
The pretreatment process is carried out during rotary driving of the centrifugal rotor 25 using centrifugal force which acts on the microchip 60, and comprises the following:
separate treatment for separating the sample liquid from the sample;
distribution treatment for dividing the sample liquid into the respective measurement cell 63;
weighing treatment for metering of a certain amount of sample liquid;
mix and reaction treatment for mixing of the sample liquid with a reagent, reaction and production of the test liquid; and
liquid transport treatment for transporting the produced test liquid to the respective measurement cell 63.
The pretreatment process is described specifically below. As is shown in
Next, the plasma (sample liquid) which was obtained by separate treatment flows through the passage from the divided cell to the distribution region by rotary driving of the centrifugal rotor 25 with a given rpm and by the action of centrifugal force. The plasma is divided among the respective measurement cells 63 in the distribution region.
In the state in which the rotation of the centrifugal rotor 25 is stopped, a chip direction reversal process is carried out to change the direction (position) of the microchip 60. Afterwards, the centrifugal rotor 25 is rotationally driven with a given rpm, and the centrifugal force acts, by which the plasma flows through the passage from the distribution region to the weighing region. In the weighing region, weighing treatment is performed for metering of a certain amount of plasma.
Afterwards, in the state in which the rotation of the centrifugal rotor 25 is stopped, a chip direction reversal process is carried out to change the direction (position) of the microchip 60. Afterwards, the centrifugal rotor 25 is rotationally driven with a given rpm, and the centrifugal force acts to cause a certain amount of plasma to flow through the passage from the weighing region to the mixing cell. In the mixing cell, mix and reaction treatment is carried out in which the plasma is mixed with reagent, caused to react and the test liquid (reaction liquid) is produced. In this connection, in the mix and reaction treatment, for example, the plasma can also be mixed with several reagents and reacted. In this case, a given time for the reaction with the premixed reagent can be ensured, a reaction liquid can be produced, the chip direction reversal process can be carried out, and afterwards, the reaction liquid can be mixed with the reagent and caused to react.
Afterwards, in the state in which rotation of the centrifugal rotor 25 is stopped, a chip direction reversal process is carried out to change the direction (position) of the microchip 60. Then, the centrifugal rotor 25 is rotationally driven with a given rpm, and the centrifugal force acts, by which the plasma flows through the passage from the mixing cell to the measurement cell 63, the measurement cell 63 being filled with it.
In the above described processes, for example, in cases of determination of diseases of patients and the like, it is necessary to take measurements at several test samples so that the respective corresponding measurement cell 63 is filled with several test liquids which have been obtained by reactions with different types of reagents. In this embodiment, a microchip 60 with seven measurement cells 63 is used so that analytic measurements with respect to seven test samples can be carried out at the same time.
In the mixing reaction treatment, a reagent can be used which is used in a conventional biochemical analysis device and which is selected according to the target test samples (detection object component).
The respective treatment conditions in pretreatment are described below using one example.
For example:
the rpm of the centrifugal rotor 25 in separate treatment is 3000 rpm;
the treatment time is 120 sec;
the rpm of the centrifugal rotor 25 in distribution treatment is 1000 rpm;
the treatment time is 30 sec;
the rpm of the centrifugal rotor 25 in weighing treatment is 1000 rpm;
the treatment time is 30 sec;
the rpm of the centrifugal rotor 25 in mix and reaction treatment is 1500 rpm; and
the treatment time (excluding the reaction time) is 40 sec.
After carrying out the above described series of pretreatments, for each measurement cell 63 which has been filled with the produced test liquid, the light intensity is measured. Positioning is performed, for example, such that light from the light source 40 is fed into the measurement cell which is positioned on the outermost side of the microchip 60 (which is positioned on the right end in
The data which have been determined by the light detector 61 contain a fluctuation by brief scattering of the light source 41 and a fluctuation by long-term drift of a few dozen minutes to a few hours based on the service life and the thermal properties of the light source 41. In a biochemical analysis, such as, for example, blood analysis or the like, the change of the absorbance during a relatively short time of a few minutes is measured so that, in particular, a fluctuation as a result of brief scattering is regarded as disadvantageous.
However, for example, if a xenon lamp is used as the light source 41, it does not happen that only a certain wavelength fluctuates, but fluctuation takes place essentially in the entire wavelength range with an essentially identical width. In the case of a biochemical analysis for each reagent, the absorption wavelength and wavelengths without absorption are known beforehand. By simultaneous measurement of the amount of light without absorption (reference light) and the amount of measurement light, the fluctuation by brief scattering of the light source 41 which is contained in the data with respect to the measurement light can be balanced (corrected) by data relating to the reference light, and the absorbance of the test liquid within the measurement cell 63 can be measured with high precision.
The light intensity is measured by repeating a process several times in which, for example, for all measurement cells, the light intensity is measured successively, the light intensity measurement during a given time per measurement cell being called the treatment unit. This means that, when the measurement of absorbance per cell is completed, the centrifugal rotor 25 is rotationally driven. By adjusting the amount of motion thereof based on a signal from the encoder 38, positioning control is exercised such that light from the light source 40 is fed into the adjacent measurement cell which is to be subjected to light intensity measurement. Rotation of the centrifugal rotor 25 is stopped. In this state, the light intensity is measured. After such a light intensity measurement has been taken in succession for all measurement cells, for example, starting from the measurement cell which was subject to light intensity measurement first, the light intensity is measured a second time in succession.
By repeating this treatment a given number of times, several data (amount of measurement light and amount of reference light for each light intensity measurement) are acquired.
For the respective measurement cell 63, the absorbance of the measurement light for each light intensity measurement is computed by correction of the fluctuation of the light source 41 based on the absorbance of the reference light. Based on this result, the concentration of the detection object which is contained in the test liquid in the measurement cell 63 is computed. This data processing is performed for the test liquid in all measurement cells 63. The result thereof is displayed in a display part 13A, and moreover, is output by the printer 16A.
The treatment conditions of the light intensity measurement are illustrated below using one example. For example:
the time per treatment unit of a measurement cell is 1 sec.;
the time which is necessary per light intensity measurement for all seven measurement cells is roughly 15 sec., and
the light intensity is measured 20 times for one measurement cell.
The measurement light which is used in the light intensity measurement process is one of twelve wavelengths of, for example, 340 nm, 405 nm, 450 nm, 480 nm, 505 nm, 546 nm, 570 nm, 600 nm, 660 nm, 700 nm, 750 nm, and 800 nm (10 nm) according to the detection object. As reference light, a wavelength outside of the wavelength selected for the measurement light is selected.
In a test of γ-GTP it is, for example, necessary for the reference light to have a wavelength without absorption by benzoic acid which is produced in the course of a reaction with plasma, and this wavelength should be longer than roughly 500 nm (in the table shown below, 570 μm). Table 1 below shows combinations of the wavelength of the measurement light (main wavelength) to the wavelength of the reference light (secondary wavelength) using a specific example, which correspond to analysis samples (detection object components).
The biochemical analysis device 10 with the above described arrangement measures the light intensity in the state in which the centrifugal rotor 25 is stopped. In this way, the amount of light which is incident in the measurement cell 63 of the microchip 60 can be adequately ensured so that the absorbance can be measured with high precision and thus high analysis accuracy can be obtained even if the measurement cell 63 is irradiated with light without sufficient intensity.
Furthermore, in light intensity measurement, because the stop position of the centrifugal rotor 25 which holds the microchip 60 fast is adjusted based on the signal from the encoder 38 with a pulse number which is set such that a certain relation is satisfied, the stop position of the measurement cell 63 of the microchip 60 can be adjusted with high precision, and moreover, with high reproducibility, so that an amount of light sufficient for measuring absorbance can be reliably fed into the measurement cell 63. As a result the base line of the analysis device can be stabilized in the state in which the fluctuation width is small. Thus, high measurement precision can be ensured, and therefore, high analysis accuracy with a CV value of, for example, at most 10% can be obtained.
Therefore, the device is extremely useful for analysis of test samples such as, for example, γ-GTP and the like, for which the difference between the normal value and the anomalous value is small, for which the amount of change of absorbance is small and for which extremely small fluctuations must be determined.
Furthermore, the light detector 50 is made such that light with several wavelengths can be measured at the same time. Because the reference light with wavelengths outside the measurement light for analyzing the detection object component which is contained in the test fluid is measured with the measurement light at the same time with respect to its light intensity, the fluctuation of the amount of light of the light source 41 is corrected and the absorbance is measured. Therefore, the amount of light of the UV radiation is greater than for a conventionally used halogen lamp. It is nearer a point light source than a conventionally used halogen lamp. On the other hand, use of a discharge lamp, such as a xenon lamp with a somewhat lower stability or the like is enabled, by which the fluctuation of the amount of light of the light source can be corrected by the single beam method. As a result, the analysis device can be made smaller and the costs reduced.
One embodiment of the invention was described above; but, the invention is not limited to the above described embodiment, rather various modifications can be made.
In the biochemical analysis device in accordance with the invention, for example, the number of chip holding parts formed in the measurement chamber, the specific arrangement and the directions of rotation of the centrifugal rotor and of the chip holding part and the like as well as the respective treatment condition in the analytic measurement are not especially limited, but suitable changes can be made according to the purpose.
In the above described embodiment, an arrangement was described in which the measurement cell of the microchip which is held by the above described chip holding part is irradiated with light from the light source from one side in the direction of the axis of rotation of the centrifugal rotor and the test liquid in the measurement cell is subjected to light intensity measurement. However, the measurement cell of the microchip can also be irradiated with light from the light source from the direction perpendicular to the axis of rotation of the centrifugal rotor (transverse direction to the centrifugal rotor).
Furthermore, the specific arrangement of the microchip used in the biochemical analysis device in accordance with the invention, such as, for example, the number of measurement cells and the like, is not limited to the above described embodiment.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-151397 | May 2006 | JP | national |
