WO2009054647A2 - Portable analyzing apparatus based on pcr - Google Patents

Portable analyzing apparatus based on pcr Download PDF

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Publication number
WO2009054647A2
WO2009054647A2 PCT/KR2008/006109 KR2008006109W WO2009054647A2 WO 2009054647 A2 WO2009054647 A2 WO 2009054647A2 KR 2008006109 W KR2008006109 W KR 2008006109W WO 2009054647 A2 WO2009054647 A2 WO 2009054647A2
Authority
WO
WIPO (PCT)
Prior art keywords
processing unit
sample processing
analyzing apparatus
unit
thin film
Prior art date
Application number
PCT/KR2008/006109
Other languages
French (fr)
Other versions
WO2009054647A3 (en
Inventor
Min-Su Lee
Young-Ki Lee
Dong-Hoon Lee
Sang-Won Seo
Original Assignee
Seed Biochips Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Seed Biochips Co., Ltd. filed Critical Seed Biochips Co., Ltd.
Publication of WO2009054647A2 publication Critical patent/WO2009054647A2/en
Publication of WO2009054647A3 publication Critical patent/WO2009054647A3/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/08—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0819—Microarrays; Biochips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
    • G01N2035/00099—Characterised by type of test elements
    • G01N2035/00158—Elements containing microarrays, i.e. "biochip"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00346—Heating or cooling arrangements
    • G01N2035/00356—Holding samples at elevated temperature (incubation)
    • G01N2035/00366—Several different temperatures used

Definitions

  • the present invention relates to a potable analyzing apparatus based on polymerase chain reaction (PCR). More particularly, the present invention relates to a PCR-based portable analyzing apparatus which is compact-sized and portable for a point- of-care-testing (POCT) use, and driven with low power consumption, and which provides fast analysis and efficient fluorescence measurement without requiring an expensive imaging element.
  • PCR polymerase chain reaction
  • the currently- available POCT diagnostic kits are generally based on antibody or organic molecule.
  • the advance of gene diagnostic technology has recently enabled a shift from the previous diagnostic principles which are based on the interaction between organic molecules to a method of amplifying genes with polymerase chain reaction (PCR) and detecting a specific source of infection such as virus or bacteria, or harmful minute organisms at higher accuracy and sensitivity. Therefore, the PCR, which enables amplification of the genes, has been recognized as the core step of the gene diagnosis.
  • PCR polymerase chain reaction
  • the reaction detecting apparatus which is an essential device in gene diagnosis of the POCT approach, is hardly compact-sized or portable.
  • the reason that the conventional reaction detecting apparatus is unsuitable for POCT approach is mainly due to the use of expensive imaging detector such as charge coupled device (CCD) or complementary metal-oxide semiconductor (CMOS) element to measure a plurality of samples at high sensitivity, since this element generally complicates the related signal processing system and increases element price. Accordingly, manufacture cost increases, and the apparatus is unsuitable for the POCT approach.
  • CCD charge coupled device
  • CMOS complementary metal-oxide semiconductor
  • the present invention has been made to overcome the above-mentioned problems occurring in the prior art, and accordingly, it is an object of the present invention to provide a portable analyzing apparatus based on a polymerase chain reaction (PCR), which is compact-sized and portable for a point-of-care-testing (POCT) use, and which is driven with low power consumption and fabricated with minimized cost.
  • PCR polymerase chain reaction
  • POCT point-of-care-testing
  • a portable analyzing apparatus based on PCR which is capable of focusing fluorescence into a light detector efficiently without a loss, without requiring an expensive imaging detector such as a charge coupled device (CCD) or a complementary metal-oxide semiconductor (CMOS) element even when a sample on a lab-on-a-chip (LOC) has a plurality of rod patterns.
  • CCD charge coupled device
  • CMOS complementary metal-oxide semiconductor
  • a portable analyzing apparatus which includes a sample processing unit to perform a biochemical reaction using an injected sample; a thin film thermoelectric element arranged in a manner in which a first surface thermally contacts with the sample processing unit and includes terminals to receive a supply of variable power; and a control unit to precision-control temperature of the first surface by supplying the variable power to the thin film thermoelectric element through the terminals, and provide the sample processing unit with temperature which is necessary for the biochemical reaction.
  • the portable analyzing apparatus may further include a conductive layer interposed between the sample processing unit and the thin film thermoelectric element to transfer heat.
  • the portable analyzing apparatus may further include a heat radiating plate arranged on a second surface of the thin film thermoelectric element to radiate heat generated from the second surface to the outside.
  • the portable analyzing apparatus may further include a heat radiating fan arranged on a lower portion of a second surface of the thin film thermoelectric element to radiate heat generated from the second surface to the outside.
  • the portable analyzing apparatus may further include a temperature sensor to measure temperature of the sample processing unit or a first surface of the thin film thermoelectric element.
  • the biochemical reaction may be a polymerase chain reaction (PCR).
  • the sample processing unit may be a thin film biochip.
  • the sample processing unit may include a substrate, one or more micro chambers formed therein to perform biochemical reaction, and valve holes arranged at both ends of each of the micro chambers.
  • the sample processing unit may further include a pre-processing unit to preliminary process the sample to be suitable for the biochemical reaction.
  • Only the micro chambers may thermally contact with the thin film thermoelectric element.
  • the substrate may be made from plastic, and the micro chambers may be arranged in parallel relationship.
  • the portable analyzing apparatus may further include a main body to house therein the sample processing unit, the thin film thermoelectric element and the control unit, and wherein the thin film thermoelectric element is slidingly movable out of the main body so that when the thin film thermoelectric element is exposed out of the main body, the sample processing unit is loaded on the thin film thermoelectric element.
  • the portable analyzing apparatus may further include an alarming unit to provide an alarming message if an operating signal is received before the sample processing unit is loaded on the thin film thermoelectric element.
  • the portable analyzing apparatus may further include an optical detecting unit arranged above the sample processing unit or the thin film thermoelectric element, and vertically movable with respect to the sample processing unit or the thin film thermoelectric element.
  • the sample processing unit may include a substrate, one or more micro chambers formed therein to perform biochemical reaction, and valve holes arranged at both ends of each of the micro chambers, and the optical detecting unit include a pinch valve capable of closing the valve holes so that the pinch valve opens and closes the valve holes in accordance with the vertical movement of the optical detecting unit.
  • the optical detecting unit may include a buffer unit to apply a constant level of pressure to different each of the sample processing unit.
  • the optical detecting unit may include a light source to emit a uniform light beam; an excitation light transmitting unit to transfer the light beam emitted from the light source to the sample processing unit; an emission light reducing unit to receive a fluorescence signal emitted from a fluorescence mark of the sample processing unit and output a fluorescence signal in an asymmetrically-reduced form; and a fluorescence detecting unit to detect a fluorescence signal output from the emission light reducing unit.
  • the light source may be a light emitting diode (LED) array or a LED matrix.
  • LED light emitting diode
  • the asymmetric reduction of the emission light reducing unit may have a different reduction rate in a first direction from that in a second direction, in which the first direction is the direction in which a fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
  • the emission light reducing unit may include one or more of: a dichroic mirror to change a direction of a fluorescence signal emitted from the sample processing unit; a secondary lens unit to process the fluorescence signal; a secondary optical filter to filter the fluorescence signal according to an individual wavelength; and a fluorescence signal converting unit to convert the fluorescence signal into an asymmetrically- reduced form.
  • the fluorescence signal converting unit may include a semi-cylindrical lens or a prism.
  • the fluorescence detecting unit may include one or more photodiodes, and the photodiodes correspond to micro chambers on a one-to-one basis.
  • the control unit may include a reaction analyzing unit to receive a result of detection and perform analysis on the sample.
  • the portable analyzing apparatus may further include a data transmitting unit to transmit a result of detection or analysis by wired or wireless communication.
  • the PCR-based portable analyzing apparatus is compact-sized and portable for a point-of-care-testing (POCT) use, and driven with low power consumption and fabricated with minimized cost.
  • POCT point-of-care-testing
  • the PCR-based portable analyzing apparatus greatly improves a biochemical reaction speed such as PCR speed and thus enables realization of the POCT approach.
  • the PCR-based portable analyzing apparatus is capable of focusing fluorescence into a light detector efficiently without a loss, without requiring an expensive imaging detector such as a charge coupled device (CCD) or a complementary metal-oxide semiconductor (CMOS) element even when a sample on a lab-on-a-chip (LOC) has a plurality of rod patterns.
  • CCD charge coupled device
  • CMOS complementary metal-oxide semiconductor
  • the PCR-based portable analyzing apparatus is capable of minimizing light loss and thus accomplishing uniform light beam profile without requiring a separate optical component, by employing a light emitting diode (LED) array mixing, and also capable of dealing adaptively with the changes in a sample pattern on a lab-on-a-chip, by employing a low-power consuming and low-heat generating light emitting diode (LED) array to maintain a constant lighting pattern and using a mask to provide lighting.
  • LED light emitting diode
  • the PCR-based portable analyzing apparatus provides the result of analysis on a biochemical reaction at the site of the biochemical reaction, and is capable of transmitting the result of reaction or analysis by wired or wireless communication.
  • FIG. 1 is a block diagram of a portable analyzing apparatus based on a polymerase chain reaction (PCR), according to a preferred embodiment of the present invention.
  • PCR polymerase chain reaction
  • FIG. 2 is a perspective view of a PCR-based portable analyzing apparatus according to a preferred embodiment of the present invention.
  • FIG. 3 is a perspective view illustrating a situation where a loading unit of the PCR- based portable analyzing apparatus of FIG. 2 is exposed to the outside.
  • FIG. 4 is a cross-section view of the temperature adjusting unit according to a preferred embodiment of the present invention.
  • FIG. 5 is a cross-section view of the temperature adjusting unit according to another preferred embodiment of the present invention.
  • FIG. 6 is a perspective view of the temperature adjusting unit according to yet another preferred embodiment of the present invention.
  • FIG. 7 is a plan view of the sample processing unit according to a preferred embodiment of the present invention.
  • FIG. 8 is a cross-section view provided to illustrate relationship between the optical detecting unit and the sample processing unit according to a preferred embodiment of the present invention.
  • FIG. 9 illustrates the structure of the optical detecting unit according to a preferred embodiment of the present invention.
  • FIG. 10 schematically illustrates the manner of operating the emission light reducing unit of the optical detecting unit according to a preferred embodiment of the present invention.
  • FIG. 53 FIG.
  • FIG. 11 illustrates in detail the light source of the optical detecting unit according to a preferred embodiment of the present invention.
  • FIG. 12 is a block diagram of the control unit according to a preferred embodiment of the present invention, in which the main components according to the present invention are emphasized for convenient explanation.
  • FIG. 1 is a block diagram of a portable analyzing apparatus based on a polymerase chain reaction (PCR), according to a preferred embodiment of the present invention.
  • PCR polymerase chain reaction
  • the PCR-based portable analyzing apparatus 100 includes a sample processing unit
  • the sample processing unit 102 performs biochemical reaction using an injected sample.
  • the 'biochemical reaction' is not limited to a specific type of reaction, but includes all biochemical reactions that require temperature control.
  • the biochemical reaction may preferably be the polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • a template DNA which is a target to be amplified
  • DNA oligonucleotides also called DNA primers
  • heat-stable DNA polymerase and a sample containing dNTP are prepared.
  • the amplification technique generally consists of three or two temperature varying cycles, which will be explained below.
  • the first step i.e., the denaturation step heats the sample at a high temperature to separate double- stranded DNA into single-stranded DNA.
  • the annealing step cools the sample after the denaturation at an appropriate temperature to cause the single- stranded DNA and the primers to assemble with each other into a partially double-stranded DNA-primer synthesis.
  • the third step i.e., the polymerization step keeps the sample after annealing at an optimum temperature so that the primer in the DNA-primer synthesis extends according to the polymerization of the DNA polymerase to replicate a nascent single-stranded DNA which is complementary to the template DNA.
  • the polymerization step keeps the sample after annealing at an optimum temperature so that the primer in the DNA-primer synthesis extends according to the polymerization of the DNA polymerase to replicate a nascent single-stranded DNA which is complementary to the template DNA.
  • the temperature adjusting unit 104 performs high precision control of the temperature of the sample processing unit 102 by thermally contacting with the sample processing unit 102.
  • the phrase 'thermally contacts' or 'thermally contacting' refers to a situation where two elements are arranged to allow uni- or bi-directional heat transmission. Accordingly, the two elements may be arranged in contact or at distance with a third heat conductive material interposed therebetween.
  • the optical detecting unit 106 detects reaction profile or result of the sample processing unit 102 optically.
  • the optical detecting unit 106 may be arranged above the sample processing unit 102 or the temperature adjusting unit 104 and movable with respect to the sample processing unit 102 or the temperature adjusting unit 104 vertically.
  • the control unit 108 controls the overall operation of the apparatus including the temperature adjusting unit 104, the optical detecting unit 106 and the power unit 110.
  • the control unit 108 provides a thin film thermoelectric element (not illustrated) with a variable power to thus provide the sample processing unit 102 with the temperature which is necessary for biochemical reaction, by precisely controlling the temperature of the thermoelectric element.
  • the power unit 110 supplies power to the overall apparatus such as the temperature adjusting unit 104, the optical detecting unit 106, and the control unit 108.
  • the sensor 112 measures temperature of the sample processing unit 104 or the temperature adjusting unit 104 and transmits the measurement to the control unit 108, to thus enable more precise temperature control.
  • FIG. 2 is a perspective view of a PCR-based portable analyzing apparatus according to a preferred embodiment of the present invention
  • FIG. 3 is a perspective view illustrating a situation where a loading unit of the PCR-based portable analyzing apparatus of FIG. 2 is exposed to outside.
  • the PCR-based portable analyzing apparatus includes a main body 202, a loading unit 204, and a vertically- movable unit 206 to move the optical detecting unit 106 vertically.
  • the main body 202 houses therein the sample processing unit 102, the temperature adjusting unit 104, the optical detecting unit 106, the control unit 108, the power unit 110 and the sensor 112.
  • the loading unit 204 may be formed as a part or entirety of the temperature adjusting unit 104.
  • the loading unit 204 is slidingly movable out of the main body 202, and when the loading unit 204 is in the exposed position where the loading unit 204 is moved out of the main body 202, the sample processing unit 102 may be loaded on the loading unit 204.
  • the vertically-movable unit 206 moves the optical detecting unit 106 vertically, with respect to the sample processing unit 102 or the temperature adjusting unit 104.
  • FIG. 4 is a cross-section view of the temperature adjusting unit according to a preferred embodiment of the present invention.
  • the temperature adjusting unit includes a conductive layer 402, a thermoelectric element 404, and a heat-radiating plate 406.
  • the conductive layer 402 is interposed between the sample processing unit 102 and the thin film thermoelectric element 404 to transfer heat between the two elements.
  • a heat-conductive metal may preferably be used.
  • the thin film thermoelectric element 404 is arranged in a manner in which the first surface thermally contacts with the sample processing unit 102 and includes terminals (not illustrated) to receive the variable power, and the second surface thermally contacts with the heat-radiating plate 406.
  • the control unit 108 supplies the variable power to the thin film thermoelectric element 404 via the terminals, to thereby precision-control the temperature of the first surface and provide the temperature that is necessary for the biochemical reaction of the sample processing unit 102.
  • the heat-radiating plate 406 is arranged on the second surface of the thin film thermoelectric element 404 to radiate the heat generated from the second surface.
  • the heat-radiating plate 406 may be formed in a shape to increase a contact area with the external air.
  • the heat-radiating plate 406 may have a comb-like cross section as illustrated in FIG. 4.
  • FIG. 5 is a cross-section view of the temperature adjusting unit according to another preferred embodiment of the present invention.
  • the temperature adjusting unit according to another exemplary embodiment of the present invention has the similar structure as that of the temperature adjusting unit of FIG. 4, except for the addition of a first heat-conductive grease layer 408a interposed between the conductive layer 402 and the thermoelectric element 404, and a second heat-conductive grease layer 408b interposed between the thermoelectric element 404 and the heat-radiating plate 406.
  • FIG. 6 is a perspective view of the temperature adjusting unit according to yet another preferred embodiment of the present invention.
  • the temperature adjusting unit according to yet another exemplary embodiment of the present invention has the similar structure as that of the temperature adjusting unit of FIG. 4, except for the addition of an input heat-radiating fan 410a and an output heat-radiating fan 410b.
  • the input heat-radiating fan 410a and the output heat-radiating fan 410b are arranged below the second surface of the thin film thermoelectric element 404, for example, arranged at a certain portion of the heat-radiating plate 406 to radiate the heat generated from the second surface or the heat-radiating plate 406 to outside and thus further improve cooling efficiency.
  • a power in certain direction is applied to the thin film thermoelectric element 404 which thermally contacts with the sample processing unit 102, to heat the first surface of the thin film thermoelectric element 404 and thereby increase temperature of the sample processing unit 102, while a power in opposite direction is applied to cool down the first surface of the thin film thermoelectric element 404 and thereby decrease temperature of the sample processing unit 102.
  • the heat generated from the first or the second surface is discharged outside efficiently, due to the heat- radiating plate 406 and the heat-radiating fans 410a, 410b.
  • the sample processing unit 102 is formed as a thin film chip, and heat transmission efficiency is maximized between the sample processing unit 102 and the temperature adjusting unit 104 using the thin film thermoelectric element. As a result, the temperature of the sample processing unit 102 is controlled efficiently, and time for biochemical reaction, particularly, the time for PCR is reduced significantly.
  • FIG. 7 is a plan view of the sample processing unit according to a preferred embodiment of the present invention.
  • the sample processing unit 102 is a thin film biochip.
  • the sample processing unit 102 includes a substrate 714, a sample entrance port 704 formed therein, a sample pre-processing unit 706, a micro chamber 708 to perform biochemical reaction, particularly the PCR, valve holes 710a, 710b arranged at both ends of the micro chamber, a post-reaction sample storage unit (not illustrated), and a sample discharge port 712.
  • the micro chamber 708 to perform biochemical reaction particularly, the
  • thermoelectric element 404 directly and thermally contacts with the temperature adjusting unit 104, particularly, the thin film thermoelectric element 404.
  • micro chamber 708 to perform biochemical reaction particularly, the PCR
  • the micro chamber 708 to perform biochemical reaction may be provided in plural numbers, and the plurality of micro chambers may be arranged in parallel relationship.
  • FIG. 8 is a cross-section view provided to illustrate relationship between the optical detecting unit and the sample processing unit according to a preferred embodiment of the present invention.
  • the optical detecting unit 106 is arranged above the sample processing unit 102.
  • the optical detecting unit 106 is connected to a vertically- movable unit 802 to move in accordance with the vertical movement of the vertically- movable unit 802 vertically with respect to the sample processing unit 102, and optically detects profile or result of the reaction occurring in the sample processing unit 102.
  • the sample processing unit 102 includes the micro chamber 708 to perform biochemical reaction, and the valve holes 710a, 710b which are arranged at both ends of the micro chamber 708.
  • the optical detecting unit 106 includes pinch valves 804a, 804b to close the valve holes 710a, 710b.
  • the pinch valves 804a, 804b open and close the valve holes 710a, 710b.
  • valve holes 710a, 710b, and the pinch valves 804a, 804b help to prevent discharge of the content of the micro chamber 708, in case that the temperature of the micro chamber 708 rises rapidly and causes the content of the micro chamber 708 to expand.
  • the optical detecting unit 106 includes buffer units 806a, 806b to apply a certain level of pressure to the sample processing unit 102.
  • the buffer units 806a, 806b be a spring or a piston.
  • the portable analyzing apparatus includes the buffer units 806a, 806b, the pinch valves 804a, 804b are capable of applying unvaried level of pressure to the valve holes 710a, 710b even if there are changes due to external causes, such as the height difference or displacement from original position due to long use of the sample processing unit 102.
  • micro chamber 708 can be formed in a variety of shapes, it is preferable that the micro chamber 708 is formed in a rod shape in which vertical side is longer than horizontal side.
  • a rod-like micro chamber can have capillary phenomenon which will facilitate and thus optimize the flow of minute fluid.
  • FIG. 9 illustrates the structure of the optical detecting unit according to a preferred embodiment of the present invention.
  • the optical detecting unit includes a sample processing unit 914, a light source 902, an excitation light transmitting unit 904, 906, 908, 912, an emission light reducing unit 916, 918, 920, 922, and a fluorescence detecting unit 924.
  • the micro chambers may preferably be arranged in parallel relationship.
  • a micro chamber to detect positive reaction, another chamber to detect negative reaction, and another chamber to detect reaction on the sample may be formed in parallel relationship.
  • the micro chambers may preferably be formed in rod- like shape having longer vertical sides than the horizontal sides.
  • the light source 902 emits a uniform light beam.
  • the light source 902 may include a light emitting diode (LED) array or a LED matrix.
  • LED light emitting diode
  • LED matrix a light emitting diode
  • LED light emitting diode
  • LED matrix a light emitting diode
  • LED light emitting diode
  • a beam homogenizer or a light pipe is used to regulate the light beam profile. While the conventional method can obtain uniform light beam profile, the method also has shortcomings. That is, the above device is expensive, increases light path and thus takes large volume of space and causes additional light loss. Accordingly, the conventional method is inappropriate for the POCT application.
  • the present invention overcomes the above-mentioned shortcomings by employing an economic, low-power consuming device such as a LED array as the light source 902 to regulate a light beam profile. Therefore, the device for fluorescence measurement according to the present invention can be compact-sized, economical, and generates less heat.
  • the excitation light transmitting unit 904, 906, 908, 912 transmits the light beam emitted from the light source 902 to the sample processing unit 914.
  • the excitation light transmitting unit 904, 906, 908, 912 includes a mask 904 having identical pattern to the micro chamber of the sample processing unit 914, a primary optical filter 906 to filter excitation light beams from the light source 904 according to individual wavelengths, and a primary lens unit 908, 912 to process the excitation light beam from the light source 902.
  • the emission light reducing unit 916, 918, 920, 922 receives fluorescence signal emitted from the fluorescent mark of the sample processing unit 914 and outputs a fluorescence signal in the asymmetrically-reduced form.
  • the fluorescence signal in the asymmetrically-reduced form may have a different reduction rate in the first direction from that in the second direction, in which the first direction is the direction in which the fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
  • the emission light reducing unit includes a dichroic mirror 910 to change a direction of the fluorescence signal emitted from the sample processing unit 914, a secondary lens unit 916 to process the fluorescence signal, a secondary optical filter 920 to filter the fluorescence signal according to individual wavelength, and a fluorescence signal converting unit 922 to convert the fluorescence signal into an asymmetrically-reduced signal form.
  • the fluorescence signal converting unit 922 may be a semi-cylindrical lens or a prism. It is possible to vary the reduction rate and the asymmetric reduction rate of the fluorescence signal converting unit 922 according to the size of the chamber, and the rate of horizontal to vertical lengths of the chamber.
  • the fluorescence detecting unit 924 detects fluorescence signal output from the emission light reducing unit 916, 918, 920, 922.
  • the fluorescence detecting unit 924 includes one or more photodiodes, which may preferably correspond to the micro chambers of the sample processing unit 914 on a one-to-one basis.
  • the photodiode may preferably be the economic type which includes an amplifier therein.
  • a sample is injected into the sample processing unit 914 to undergo a series of biochemical reactions.
  • a series of processes are performed as explained below to analyze the result of the reactions.
  • the light source 902 emits a uniform light beam, and the excitation light of the light source 902 is transmitted to the reaction chamber of the sample processing unit 914.
  • the uniform light beam may preferably be formed by a LED array or a LED matrix.
  • the excitation light is passed through the mask 904 having a corresponding pattern to the reaction chamber, then through the filter 906, the dichroic mirror 910, and the lens units 908, 912, before being applied to the reaction chamber of the sample processing unit 914.
  • the fluorescence signal emitted from the reaction chamber of the sample processing unit 914 changes direction at the dichroic mirror 910 in sequence, to be transmitted to the lens unit 916, the filters 918, 920, and the fluorescence signal converting unit 922.
  • the fluorescence signal of the sample processing unit is received using the signal converting unit 922, which may be a semi-cylindrical lens or a prism, and as a result, a fluorescence signal in an asymmetrically -reduced form is output.
  • the fluorescence signal in the asymmetrically-reduced form may have a different reduction rate in the first direction from that in the second direction, in which the first direction is the direction in which the fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
  • the fluorescence signal in the asymmetrically-reduced form is detected.
  • the detection may preferably be performed using a photodiode that corresponds to the micro chamber of the sample processing unit 914.
  • FIG. 10 schematically illustrates the manner of operating the emission light reducing unit of the optical detecting unit according to a preferred embodiment of the present invention.
  • a reference numeral 1002 denotes the emission light reducing unit, and particularly, the reference numeral 1002 denotes a signal converting unit.
  • the signal converting unit 1002 converts an input fluorescence signal 1004 into an output fluorescence signal 1006 by asymmetrically reducing the input fluorescence signal 1004.
  • the input fluorescence signal 1010 may be converted and output as a undesirable output fluorescence signal 1020 or a desirable output fluorescence signal 1030.
  • the input fluorescence signal 1010 includes three fluorescence signals 1010a, 1010b, 1010c of the rod-shaped chamber.
  • the undesirable output fluorescence signal 1020 has the length (Lf) and widths (Wf, df) in symmetrically-reduced form, in which case a high- sensitive and expensive CCD or CMOS is required.
  • the desirable output fluorescence signal 1030 obtained using the signal converting unit 1002 according to the exemplary embodiment of the present invention has the asymmetrically-reduced form, and thus has greatly reduced length (Lf), but the widths (Wf, df) that are barely reduced.
  • the output signals 1030a, 1030b, 1030c are detectable by an individually corresponding low-price photo diode 1032, 1034, 1036.
  • FIG. 11 illustrates in detail the light source of the optical detecting unit according to a preferred embodiment of the present invention.
  • the light source includes a substrate 1102, and a LED array or matrix 1106.
  • a light beam emitted from the LED array or matrix 1106 is uniformized through interference with each other and thus form a uniform beam region 1110 before passing through the mask 1104.
  • the uniformized beam then passes through the mask 1104 and the lens unit 1108.
  • the present invention utilizes an economic, and low-brightness and low-power consuming light source 902 such as LED array to obtain uniformized light beam, and thus provides advantages such as compactness, economic price, and reduced heat generation and power consumption.
  • FIG. 12 is a block diagram of the control unit according to a preferred embodiment of the present invention, in which the main components according to the present invention are emphasized for convenient explanation.
  • control unit 108 is connected to an external organization by a wired or wireless communication network 1214, and controls the overall apparatus such as the temperature adjusting unit 104, the optical detecting unit 106, and the power unit 110.
  • the control unit 108 includes a temperature control unit 1202, a PCR performing unit 1204, a reaction analyzing unit 1206, a data transmitting unit 1208, and an alarming unit 1210.
  • the temperature control unit 1202 causes the temperature adjusting unit 104 to maintain a preset temperature based on feedback control using a sensor such as temperature sensor.
  • the PCR performing unit 1204 provides the temperature control unit 1202 with temperature profile information that is necessary for the PCR, to change the temperature of the temperature adjusting unit 104.
  • the reaction analyzing unit 1206 receives the result of detection and performs analysis on the sample.
  • the data transmitting unit 1208 transmits the result of detection or result of analysis by wired or wireless communication.
  • the alarming unit 1210 provides an alarming message if an operating signal is received before the sample processing unit 102 is loaded on the thin film thermoelectric element 404.

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Abstract

A polymerase chain reaction (PCR)-based portable analyzing apparatus is provided, which is compact-sized and portable for a point-of-care-testing (POCT) use, and which provides greatly improved PCR speed and thus enables POCT, and which is capable of collecting fluorescence efficiently without requiring an expensive imaging element and adaptively dealing with changes in a sample pattern. The portable analyzing apparatus includes a sample processing unit to perform a biochemical reaction using an injected sample, a thin film thermoelectric element arranged in a manner in which a first surface thermally contacts with the sample processing unit and includes terminals to receive a supply of variable power, and a control unit to precision-control temperature of the first surface by supplying the variable power to the thin film thermoelectric element through the terminals, and provide the sample processing unit with temperature which is necessary for the biochemical reaction.

Description

Description
PORTABLE ANALYZING APPARATUS BASED ON PCR
Technical Field
[1] The present invention relates to a potable analyzing apparatus based on polymerase chain reaction (PCR). More particularly, the present invention relates to a PCR-based portable analyzing apparatus which is compact-sized and portable for a point- of-care-testing (POCT) use, and driven with low power consumption, and which provides fast analysis and efficient fluorescence measurement without requiring an expensive imaging element. Background Art
[2] Recently, attempts have continuously been made to make real-time analysis in detecting harmful material or diagnosing a disease near the site of a patient. These attempts led to development of a point-of-care-testing (POCT) system which detects source of disease or contamination of harmful material within a short time.
[3] The currently- available POCT diagnostic kits are generally based on antibody or organic molecule. Meanwhile, the advance of gene diagnostic technology has recently enabled a shift from the previous diagnostic principles which are based on the interaction between organic molecules to a method of amplifying genes with polymerase chain reaction (PCR) and detecting a specific source of infection such as virus or bacteria, or harmful minute organisms at higher accuracy and sensitivity. Therefore, the PCR, which enables amplification of the genes, has been recognized as the core step of the gene diagnosis.
[4] For example, active attempts are made to apply the above technology to the diagnosis and management of viral diseases which are the main threats to the agro-livestock health. In order to diagnose and manage the agro-livestock diseases efficiently, it is important that the disease is detected at the site of outbreak. However, the current agro- livestock disease diagnosis and management system is inconvenient and inefficient since it is required to transfer sample or specimen from the site to the analyzing facility where the scientific specialists or analyzing equipments of the lab diagnose and analyze the sample, and then to notify the result of analysis to a separate management facility for management.
[5] It is very important to detect and act on the viral diseases right at the site of outbreak, since virus spreads fast. Therefore, a device must be developed, which can perform diagnosis and analysis efficiently at the disease site and automatically transmit the result of analysis on real-time basis, without requiring that the sample or specimen be transferred to an analyzing facilities to be diagnosed and analyzed. [6] However, there still is a long way to go to develop a portable PCR apparatus to diagnose genes at the disease site. Furthermore, since a conventional PCR apparatus lacks ability to control temperature precisely and rapidly, which is essential ability to the PCR process, the PCR processing time is lengthy and real-time diagnosis is practically impossible.
[7] Furthermore, the reaction detecting apparatus, which is an essential device in gene diagnosis of the POCT approach, is hardly compact-sized or portable. The reason that the conventional reaction detecting apparatus is unsuitable for POCT approach is mainly due to the use of expensive imaging detector such as charge coupled device (CCD) or complementary metal-oxide semiconductor (CMOS) element to measure a plurality of samples at high sensitivity, since this element generally complicates the related signal processing system and increases element price. Accordingly, manufacture cost increases, and the apparatus is unsuitable for the POCT approach.
[8]
Disclosure of Invention Technical Problem
[9] The present invention has been made to overcome the above-mentioned problems occurring in the prior art, and accordingly, it is an object of the present invention to provide a portable analyzing apparatus based on a polymerase chain reaction (PCR), which is compact-sized and portable for a point-of-care-testing (POCT) use, and which is driven with low power consumption and fabricated with minimized cost.
[10] It is another object of the present invention to provide a portable analyzing apparatus based on PCR, which greatly improves a biochemical reaction speed such as PCR speed and thus enables realization of the POCT approach.
[11] It is yet another object of the present invention to provide a portable analyzing apparatus based on PCR, which is capable of focusing fluorescence into a light detector efficiently without a loss, without requiring an expensive imaging detector such as a charge coupled device (CCD) or a complementary metal-oxide semiconductor (CMOS) element even when a sample on a lab-on-a-chip (LOC) has a plurality of rod patterns.
[12] It is yet another object of the present invention to provide a portable analyzing apparatus based on PCR, which is capable of minimizing light loss and thus accomplishing uniform light beam profile without requiring a separate optical component, and maintaining a constant lighting pattern and dealing adaptively with the changes in a sample pattern on a lab-on-a-chip. Technical Solution
[13] In order to accomplish these and other objects of the present invention, there is provided a portable analyzing apparatus, which includes a sample processing unit to perform a biochemical reaction using an injected sample; a thin film thermoelectric element arranged in a manner in which a first surface thermally contacts with the sample processing unit and includes terminals to receive a supply of variable power; and a control unit to precision-control temperature of the first surface by supplying the variable power to the thin film thermoelectric element through the terminals, and provide the sample processing unit with temperature which is necessary for the biochemical reaction. [14] The portable analyzing apparatus may further include a conductive layer interposed between the sample processing unit and the thin film thermoelectric element to transfer heat. [15] The portable analyzing apparatus may further include a heat radiating plate arranged on a second surface of the thin film thermoelectric element to radiate heat generated from the second surface to the outside. [16] The portable analyzing apparatus may further include a heat radiating fan arranged on a lower portion of a second surface of the thin film thermoelectric element to radiate heat generated from the second surface to the outside. [17] The portable analyzing apparatus may further include a temperature sensor to measure temperature of the sample processing unit or a first surface of the thin film thermoelectric element.
[18] The biochemical reaction may be a polymerase chain reaction (PCR).
[19] The sample processing unit may be a thin film biochip.
[20] The sample processing unit may include a substrate, one or more micro chambers formed therein to perform biochemical reaction, and valve holes arranged at both ends of each of the micro chambers. [21] The sample processing unit may further include a pre-processing unit to preliminary process the sample to be suitable for the biochemical reaction. [22] Only the micro chambers may thermally contact with the thin film thermoelectric element. [23] The substrate may be made from plastic, and the micro chambers may be arranged in parallel relationship. [24] The portable analyzing apparatus may further include a main body to house therein the sample processing unit, the thin film thermoelectric element and the control unit, and wherein the thin film thermoelectric element is slidingly movable out of the main body so that when the thin film thermoelectric element is exposed out of the main body, the sample processing unit is loaded on the thin film thermoelectric element. [25] The portable analyzing apparatus may further include an alarming unit to provide an alarming message if an operating signal is received before the sample processing unit is loaded on the thin film thermoelectric element.
[26] The portable analyzing apparatus may further include an optical detecting unit arranged above the sample processing unit or the thin film thermoelectric element, and vertically movable with respect to the sample processing unit or the thin film thermoelectric element.
[27] The sample processing unit may include a substrate, one or more micro chambers formed therein to perform biochemical reaction, and valve holes arranged at both ends of each of the micro chambers, and the optical detecting unit include a pinch valve capable of closing the valve holes so that the pinch valve opens and closes the valve holes in accordance with the vertical movement of the optical detecting unit.
[28] The optical detecting unit may include a buffer unit to apply a constant level of pressure to different each of the sample processing unit.
[29] The optical detecting unit may include a light source to emit a uniform light beam; an excitation light transmitting unit to transfer the light beam emitted from the light source to the sample processing unit; an emission light reducing unit to receive a fluorescence signal emitted from a fluorescence mark of the sample processing unit and output a fluorescence signal in an asymmetrically-reduced form; and a fluorescence detecting unit to detect a fluorescence signal output from the emission light reducing unit.
[30] The light source may be a light emitting diode (LED) array or a LED matrix.
[31] The asymmetric reduction of the emission light reducing unit may have a different reduction rate in a first direction from that in a second direction, in which the first direction is the direction in which a fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
[32] The emission light reducing unit may include one or more of: a dichroic mirror to change a direction of a fluorescence signal emitted from the sample processing unit; a secondary lens unit to process the fluorescence signal; a secondary optical filter to filter the fluorescence signal according to an individual wavelength; and a fluorescence signal converting unit to convert the fluorescence signal into an asymmetrically- reduced form.
[33] The fluorescence signal converting unit may include a semi-cylindrical lens or a prism.
[34] The fluorescence detecting unit may include one or more photodiodes, and the photodiodes correspond to micro chambers on a one-to-one basis.
[35] The control unit may include a reaction analyzing unit to receive a result of detection and perform analysis on the sample.
[36] The portable analyzing apparatus may further include a data transmitting unit to transmit a result of detection or analysis by wired or wireless communication.
Advantageous Effects
[37] The following effects are accomplished with the PCR-based portable analyzing apparatus according to the present invention.
[38] First, the PCR-based portable analyzing apparatus according to the present invention is compact-sized and portable for a point-of-care-testing (POCT) use, and driven with low power consumption and fabricated with minimized cost.
[39] Second, the PCR-based portable analyzing apparatus according to the present invention greatly improves a biochemical reaction speed such as PCR speed and thus enables realization of the POCT approach.
[40] Third, the PCR-based portable analyzing apparatus according to the present invention is capable of focusing fluorescence into a light detector efficiently without a loss, without requiring an expensive imaging detector such as a charge coupled device (CCD) or a complementary metal-oxide semiconductor (CMOS) element even when a sample on a lab-on-a-chip (LOC) has a plurality of rod patterns.
[41] Fourth, the PCR-based portable analyzing apparatus according to the present invention is capable of minimizing light loss and thus accomplishing uniform light beam profile without requiring a separate optical component, by employing a light emitting diode (LED) array mixing, and also capable of dealing adaptively with the changes in a sample pattern on a lab-on-a-chip, by employing a low-power consuming and low-heat generating light emitting diode (LED) array to maintain a constant lighting pattern and using a mask to provide lighting.
[42] Fifth, the PCR-based portable analyzing apparatus according to the present invention provides the result of analysis on a biochemical reaction at the site of the biochemical reaction, and is capable of transmitting the result of reaction or analysis by wired or wireless communication. Brief Description of Drawings
[43] FIG. 1 is a block diagram of a portable analyzing apparatus based on a polymerase chain reaction (PCR), according to a preferred embodiment of the present invention.
[44] FIG. 2 is a perspective view of a PCR-based portable analyzing apparatus according to a preferred embodiment of the present invention.
[45] FIG. 3 is a perspective view illustrating a situation where a loading unit of the PCR- based portable analyzing apparatus of FIG. 2 is exposed to the outside.
[46] FIG. 4 is a cross-section view of the temperature adjusting unit according to a preferred embodiment of the present invention.
[47] FIG. 5 is a cross-section view of the temperature adjusting unit according to another preferred embodiment of the present invention. [48] FIG. 6 is a perspective view of the temperature adjusting unit according to yet another preferred embodiment of the present invention. [49] FIG. 7 is a plan view of the sample processing unit according to a preferred embodiment of the present invention. [50] FIG. 8 is a cross-section view provided to illustrate relationship between the optical detecting unit and the sample processing unit according to a preferred embodiment of the present invention. [51] FIG. 9 illustrates the structure of the optical detecting unit according to a preferred embodiment of the present invention. [52] FIG. 10 schematically illustrates the manner of operating the emission light reducing unit of the optical detecting unit according to a preferred embodiment of the present invention. [53] FIG. 11 illustrates in detail the light source of the optical detecting unit according to a preferred embodiment of the present invention. [54] FIG. 12 is a block diagram of the control unit according to a preferred embodiment of the present invention, in which the main components according to the present invention are emphasized for convenient explanation.
Best Mode for Carrying out the Invention
[55] The present invention will be explained in detail below with reference to the accompanying drawings. [56] FIG. 1 is a block diagram of a portable analyzing apparatus based on a polymerase chain reaction (PCR), according to a preferred embodiment of the present invention. [57] Referring to FIG. 1, the PCR-based portable analyzing apparatus 100 according to the preferred embodiment of the present invention includes a sample processing unit
102, a temperature adjusting unit 104, an optical detecting unit 106, a control unit 108, a power unit 110, and a sensor 112. [58] The sample processing unit 102 performs biochemical reaction using an injected sample. [59] According to an aspect of the present invention, the 'biochemical reaction' is not limited to a specific type of reaction, but includes all biochemical reactions that require temperature control. For example, the biochemical reaction may preferably be the polymerase chain reaction (PCR). [60] As the DNA amplification technique, the PCR consists of basic operations which will be explained below. First, a template DNA, which is a target to be amplified, DNA oligonucleotides (also called DNA primers) which are complementary to the targeted region of each single strand of the target DNA, heat-stable DNA polymerase and a sample containing dNTP are prepared. By repeating temperature cycles to sequentially vary temperatures of the sample, the DNA sequence of the targeted region of the template DNA is amplified.
[61] The amplification technique generally consists of three or two temperature varying cycles, which will be explained below. The first step, i.e., the denaturation step heats the sample at a high temperature to separate double- stranded DNA into single-stranded DNA. As the second step, the annealing step cools the sample after the denaturation at an appropriate temperature to cause the single- stranded DNA and the primers to assemble with each other into a partially double-stranded DNA-primer synthesis. The third step, i.e., the polymerization step keeps the sample after annealing at an optimum temperature so that the primer in the DNA-primer synthesis extends according to the polymerization of the DNA polymerase to replicate a nascent single-stranded DNA which is complementary to the template DNA. As the above explained three cycles are repeated 20-40 times, DNA are replicated between two primers, amounting to DNA amplification by several hundred million-fold or above.
[62] The temperature adjusting unit 104 performs high precision control of the temperature of the sample processing unit 102 by thermally contacting with the sample processing unit 102.
[63] Herein, the phrase 'thermally contacts' or 'thermally contacting' refers to a situation where two elements are arranged to allow uni- or bi-directional heat transmission. Accordingly, the two elements may be arranged in contact or at distance with a third heat conductive material interposed therebetween.
[64] The optical detecting unit 106 detects reaction profile or result of the sample processing unit 102 optically. The optical detecting unit 106 may be arranged above the sample processing unit 102 or the temperature adjusting unit 104 and movable with respect to the sample processing unit 102 or the temperature adjusting unit 104 vertically.
[65] The control unit 108 controls the overall operation of the apparatus including the temperature adjusting unit 104, the optical detecting unit 106 and the power unit 110. The control unit 108 provides a thin film thermoelectric element (not illustrated) with a variable power to thus provide the sample processing unit 102 with the temperature which is necessary for biochemical reaction, by precisely controlling the temperature of the thermoelectric element.
[66] The power unit 110 supplies power to the overall apparatus such as the temperature adjusting unit 104, the optical detecting unit 106, and the control unit 108.
[67] The sensor 112 measures temperature of the sample processing unit 104 or the temperature adjusting unit 104 and transmits the measurement to the control unit 108, to thus enable more precise temperature control.
[68] FIG. 2 is a perspective view of a PCR-based portable analyzing apparatus according to a preferred embodiment of the present invention, and FIG. 3 is a perspective view illustrating a situation where a loading unit of the PCR-based portable analyzing apparatus of FIG. 2 is exposed to outside.
[69] Referring to FIGs. 2 and 3, the PCR-based portable analyzing apparatus according to the present invention includes a main body 202, a loading unit 204, and a vertically- movable unit 206 to move the optical detecting unit 106 vertically.
[70] The main body 202 houses therein the sample processing unit 102, the temperature adjusting unit 104, the optical detecting unit 106, the control unit 108, the power unit 110 and the sensor 112.
[71] The loading unit 204 may be formed as a part or entirety of the temperature adjusting unit 104. The loading unit 204 is slidingly movable out of the main body 202, and when the loading unit 204 is in the exposed position where the loading unit 204 is moved out of the main body 202, the sample processing unit 102 may be loaded on the loading unit 204.
[72] The vertically-movable unit 206 moves the optical detecting unit 106 vertically, with respect to the sample processing unit 102 or the temperature adjusting unit 104.
[73] FIG. 4 is a cross-section view of the temperature adjusting unit according to a preferred embodiment of the present invention.
[74] Referring to FIG. 4, the temperature adjusting unit according to an exemplary embodiment of the present invention includes a conductive layer 402, a thermoelectric element 404, and a heat-radiating plate 406.
[75] The conductive layer 402 is interposed between the sample processing unit 102 and the thin film thermoelectric element 404 to transfer heat between the two elements. Although there is no specific limit on the types of material which can be used to form the conductive layer 402, a heat-conductive metal may preferably be used.
[76] The thin film thermoelectric element 404 is arranged in a manner in which the first surface thermally contacts with the sample processing unit 102 and includes terminals (not illustrated) to receive the variable power, and the second surface thermally contacts with the heat-radiating plate 406.
[77] The control unit 108 supplies the variable power to the thin film thermoelectric element 404 via the terminals, to thereby precision-control the temperature of the first surface and provide the temperature that is necessary for the biochemical reaction of the sample processing unit 102.
[78] The heat-radiating plate 406 is arranged on the second surface of the thin film thermoelectric element 404 to radiate the heat generated from the second surface. The heat-radiating plate 406 may be formed in a shape to increase a contact area with the external air. For example, the heat-radiating plate 406 may have a comb-like cross section as illustrated in FIG. 4. [79] FIG. 5 is a cross-section view of the temperature adjusting unit according to another preferred embodiment of the present invention.
[80] Referring to FIG. 5, the temperature adjusting unit according to another exemplary embodiment of the present invention has the similar structure as that of the temperature adjusting unit of FIG. 4, except for the addition of a first heat-conductive grease layer 408a interposed between the conductive layer 402 and the thermoelectric element 404, and a second heat-conductive grease layer 408b interposed between the thermoelectric element 404 and the heat-radiating plate 406.
[81] By adding the heat-conductive grease layers 408a, 408b as illustrated in FIG. 5, the heat conductivity between the components is further improved.
[82] FIG. 6 is a perspective view of the temperature adjusting unit according to yet another preferred embodiment of the present invention.
[83] Referring to FIG. 6, the temperature adjusting unit according to yet another exemplary embodiment of the present invention has the similar structure as that of the temperature adjusting unit of FIG. 4, except for the addition of an input heat-radiating fan 410a and an output heat-radiating fan 410b.
[84] The input heat-radiating fan 410a and the output heat-radiating fan 410b are arranged below the second surface of the thin film thermoelectric element 404, for example, arranged at a certain portion of the heat-radiating plate 406 to radiate the heat generated from the second surface or the heat-radiating plate 406 to outside and thus further improve cooling efficiency.
[85] Flows of air 412a, 412b are formed in a certain direction due to the input and output heat-radiating fans 410a, 410b.
[86] In the PCR-based portable analyzing apparatus according to the present invention, a power in certain direction is applied to the thin film thermoelectric element 404 which thermally contacts with the sample processing unit 102, to heat the first surface of the thin film thermoelectric element 404 and thereby increase temperature of the sample processing unit 102, while a power in opposite direction is applied to cool down the first surface of the thin film thermoelectric element 404 and thereby decrease temperature of the sample processing unit 102. During this process, the heat generated from the first or the second surface is discharged outside efficiently, due to the heat- radiating plate 406 and the heat-radiating fans 410a, 410b.
[87] Accordingly, in the PCR-based portable analyzing apparatus according to the present invention, the sample processing unit 102 is formed as a thin film chip, and heat transmission efficiency is maximized between the sample processing unit 102 and the temperature adjusting unit 104 using the thin film thermoelectric element. As a result, the temperature of the sample processing unit 102 is controlled efficiently, and time for biochemical reaction, particularly, the time for PCR is reduced significantly. [88] FIG. 7 is a plan view of the sample processing unit according to a preferred embodiment of the present invention.
[89] Referring to FIG. 7, the sample processing unit 102 according to the preferred embodiment of the present invention is a thin film biochip.
[90] The sample processing unit 102 includes a substrate 714, a sample entrance port 704 formed therein, a sample pre-processing unit 706, a micro chamber 708 to perform biochemical reaction, particularly the PCR, valve holes 710a, 710b arranged at both ends of the micro chamber, a post-reaction sample storage unit (not illustrated), and a sample discharge port 712.
[91] Preferably, the micro chamber 708 to perform biochemical reaction, particularly, the
PCR, directly and thermally contacts with the temperature adjusting unit 104, particularly, the thin film thermoelectric element 404.
[92] Although there is no limit on the materials that can be used to form the substrate 714 of the sample processing unit 102, it is preferable that plastic is used.
[93] Furthermore, the micro chamber 708 to perform biochemical reaction, particularly, the PCR, may be provided in plural numbers, and the plurality of micro chambers may be arranged in parallel relationship.
[94] FIG. 8 is a cross-section view provided to illustrate relationship between the optical detecting unit and the sample processing unit according to a preferred embodiment of the present invention.
[95] Referring to FIG. 8, the optical detecting unit 106 is arranged above the sample processing unit 102. The optical detecting unit 106 is connected to a vertically- movable unit 802 to move in accordance with the vertical movement of the vertically- movable unit 802 vertically with respect to the sample processing unit 102, and optically detects profile or result of the reaction occurring in the sample processing unit 102.
[96] As explained above, the sample processing unit 102 includes the micro chamber 708 to perform biochemical reaction, and the valve holes 710a, 710b which are arranged at both ends of the micro chamber 708.
[97] Meanwhile, the optical detecting unit 106 includes pinch valves 804a, 804b to close the valve holes 710a, 710b. In accordance with the vertical movement of the optical detecting unit 106, the pinch valves 804a, 804b open and close the valve holes 710a, 710b.
[98] The valve holes 710a, 710b, and the pinch valves 804a, 804b help to prevent discharge of the content of the micro chamber 708, in case that the temperature of the micro chamber 708 rises rapidly and causes the content of the micro chamber 708 to expand.
[99] Referring back to FIG. 8, the optical detecting unit 106 includes buffer units 806a, 806b to apply a certain level of pressure to the sample processing unit 102. Although not limiting, the buffer units 806a, 806b be a spring or a piston.
[100] Since the portable analyzing apparatus according to the present invention includes the buffer units 806a, 806b, the pinch valves 804a, 804b are capable of applying unvaried level of pressure to the valve holes 710a, 710b even if there are changes due to external causes, such as the height difference or displacement from original position due to long use of the sample processing unit 102.
[101] Although the micro chamber 708 according to the present invention can be formed in a variety of shapes, it is preferable that the micro chamber 708 is formed in a rod shape in which vertical side is longer than horizontal side. A rod-like micro chamber can have capillary phenomenon which will facilitate and thus optimize the flow of minute fluid.
[102] It is very preferable to collect the whole fluorescence patterns generated in the rod- shaped micro chamber to the light detector, instead of sampling a certain portion for measurement, in order to detect the existence of a target material or biochemical reaction that may occur in the micro chamber.
[103] To this end, it may be possible to reduce the rod- like fluorescence patterns for measurement using a magnification optical system. However, this method requires that a matrix sensor capable of multi-channel detection, such as charge coupled device (CCD) or complementary metal oxide semiconductor (CMOS), be employed to detect signals from a plurality of channels. If the device such as CCD or CMOS is employed, it is necessary to employ complicated electric circuit structure and high-price array sensor to maintain high sensitivity, and since the volume of the system increases to house the additional component. It is inappropriate for POCT application.
[104] FIG. 9 illustrates the structure of the optical detecting unit according to a preferred embodiment of the present invention.
[105] Referring to FIG. 9, the optical detecting unit according to an exemplary embodiment of the present invention includes a sample processing unit 914, a light source 902, an excitation light transmitting unit 904, 906, 908, 912, an emission light reducing unit 916, 918, 920, 922, and a fluorescence detecting unit 924.
[106] The micro chambers may preferably be arranged in parallel relationship. For example, in order to detect a target within the sample, a micro chamber to detect positive reaction, another chamber to detect negative reaction, and another chamber to detect reaction on the sample, may be formed in parallel relationship.
[107] As explained above, the micro chambers may preferably be formed in rod- like shape having longer vertical sides than the horizontal sides.
[108] The light source 902 emits a uniform light beam. The light source 902 may include a light emitting diode (LED) array or a LED matrix. [109] In detecting fluorescence on LOC, emitting a uniform light beam plays a critical role. Conventionally, a beam homogenizer or a light pipe is used to regulate the light beam profile. While the conventional method can obtain uniform light beam profile, the method also has shortcomings. That is, the above device is expensive, increases light path and thus takes large volume of space and causes additional light loss. Accordingly, the conventional method is inappropriate for the POCT application.
[110] The present invention overcomes the above-mentioned shortcomings by employing an economic, low-power consuming device such as a LED array as the light source 902 to regulate a light beam profile. Therefore, the device for fluorescence measurement according to the present invention can be compact-sized, economical, and generates less heat.
[I l l] The excitation light transmitting unit 904, 906, 908, 912 transmits the light beam emitted from the light source 902 to the sample processing unit 914.
[112] The excitation light transmitting unit 904, 906, 908, 912 includes a mask 904 having identical pattern to the micro chamber of the sample processing unit 914, a primary optical filter 906 to filter excitation light beams from the light source 904 according to individual wavelengths, and a primary lens unit 908, 912 to process the excitation light beam from the light source 902.
[113] The emission light reducing unit 916, 918, 920, 922 receives fluorescence signal emitted from the fluorescent mark of the sample processing unit 914 and outputs a fluorescence signal in the asymmetrically-reduced form.
[114] The fluorescence signal in the asymmetrically-reduced form may have a different reduction rate in the first direction from that in the second direction, in which the first direction is the direction in which the fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
[115] The emission light reducing unit includes a dichroic mirror 910 to change a direction of the fluorescence signal emitted from the sample processing unit 914, a secondary lens unit 916 to process the fluorescence signal, a secondary optical filter 920 to filter the fluorescence signal according to individual wavelength, and a fluorescence signal converting unit 922 to convert the fluorescence signal into an asymmetrically-reduced signal form.
[116] The fluorescence signal converting unit 922 may be a semi-cylindrical lens or a prism. It is possible to vary the reduction rate and the asymmetric reduction rate of the fluorescence signal converting unit 922 according to the size of the chamber, and the rate of horizontal to vertical lengths of the chamber.
[117] The fluorescence detecting unit 924 detects fluorescence signal output from the emission light reducing unit 916, 918, 920, 922. [118] The fluorescence detecting unit 924 includes one or more photodiodes, which may preferably correspond to the micro chambers of the sample processing unit 914 on a one-to-one basis. The photodiode may preferably be the economic type which includes an amplifier therein.
[119] The operation of the optical detecting unit according to the exemplary embodiment of the present invention will be explained in greater detail below with reference to FIG. 9.
[120] First, a sample is injected into the sample processing unit 914 to undergo a series of biochemical reactions. Next, a series of processes are performed as explained below to analyze the result of the reactions.
[121] The light source 902 emits a uniform light beam, and the excitation light of the light source 902 is transmitted to the reaction chamber of the sample processing unit 914. The uniform light beam may preferably be formed by a LED array or a LED matrix.
[122] Accordingly, the excitation light is passed through the mask 904 having a corresponding pattern to the reaction chamber, then through the filter 906, the dichroic mirror 910, and the lens units 908, 912, before being applied to the reaction chamber of the sample processing unit 914.
[123] Next, the fluorescence signal emitted from the reaction chamber of the sample processing unit 914 changes direction at the dichroic mirror 910 in sequence, to be transmitted to the lens unit 916, the filters 918, 920, and the fluorescence signal converting unit 922.
[124] Accordingly, the fluorescence signal of the sample processing unit is received using the signal converting unit 922, which may be a semi-cylindrical lens or a prism, and as a result, a fluorescence signal in an asymmetrically -reduced form is output. The fluorescence signal in the asymmetrically-reduced form may have a different reduction rate in the first direction from that in the second direction, in which the first direction is the direction in which the fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
[125] Next, the fluorescence signal in the asymmetrically-reduced form is detected. The detection may preferably be performed using a photodiode that corresponds to the micro chamber of the sample processing unit 914.
[126] FIG. 10 schematically illustrates the manner of operating the emission light reducing unit of the optical detecting unit according to a preferred embodiment of the present invention.
[127] On top side of FIG. 10, a reference numeral 1002 denotes the emission light reducing unit, and particularly, the reference numeral 1002 denotes a signal converting unit. The signal converting unit 1002 converts an input fluorescence signal 1004 into an output fluorescence signal 1006 by asymmetrically reducing the input fluorescence signal 1004.
[128] As shown below the top side of FIG. 10, the input fluorescence signal 1010 may be converted and output as a undesirable output fluorescence signal 1020 or a desirable output fluorescence signal 1030. The input fluorescence signal 1010 includes three fluorescence signals 1010a, 1010b, 1010c of the rod-shaped chamber.
[129] The undesirable output fluorescence signal 1020 has the length (Lf) and widths (Wf, df) in symmetrically-reduced form, in which case a high- sensitive and expensive CCD or CMOS is required.
[130] On the contrary, the desirable output fluorescence signal 1030 obtained using the signal converting unit 1002 according to the exemplary embodiment of the present invention has the asymmetrically-reduced form, and thus has greatly reduced length (Lf), but the widths (Wf, df) that are barely reduced. In this case, it is advantageous since the output signals 1030a, 1030b, 1030c are detectable by an individually corresponding low-price photo diode 1032, 1034, 1036.
[131] FIG. 11 illustrates in detail the light source of the optical detecting unit according to a preferred embodiment of the present invention.
[132] Referring to FIG. 11, the light source includes a substrate 1102, and a LED array or matrix 1106. A light beam emitted from the LED array or matrix 1106 is uniformized through interference with each other and thus form a uniform beam region 1110 before passing through the mask 1104. The uniformized beam then passes through the mask 1104 and the lens unit 1108.
[133] As explained above, instead of one high-brightness LED and beam homogenizer or light pipe, which are expensive and take large space, the present invention utilizes an economic, and low-brightness and low-power consuming light source 902 such as LED array to obtain uniformized light beam, and thus provides advantages such as compactness, economic price, and reduced heat generation and power consumption.
[134] FIG. 12 is a block diagram of the control unit according to a preferred embodiment of the present invention, in which the main components according to the present invention are emphasized for convenient explanation.
[135] Referring to FIG. 12, the control unit 108 according to the preferred embodiment of the present invention is connected to an external organization by a wired or wireless communication network 1214, and controls the overall apparatus such as the temperature adjusting unit 104, the optical detecting unit 106, and the power unit 110. The control unit 108 includes a temperature control unit 1202, a PCR performing unit 1204, a reaction analyzing unit 1206, a data transmitting unit 1208, and an alarming unit 1210.
[136] The temperature control unit 1202 causes the temperature adjusting unit 104 to maintain a preset temperature based on feedback control using a sensor such as temperature sensor.
[137] The PCR performing unit 1204 provides the temperature control unit 1202 with temperature profile information that is necessary for the PCR, to change the temperature of the temperature adjusting unit 104.
[138] The reaction analyzing unit 1206 receives the result of detection and performs analysis on the sample.
[139] The data transmitting unit 1208 transmits the result of detection or result of analysis by wired or wireless communication.
[140] The alarming unit 1210 provides an alarming message if an operating signal is received before the sample processing unit 102 is loaded on the thin film thermoelectric element 404.
[141] While the invention has been shown and described with reference to certain embodiments to carry out this invention, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

Claims
[1] A portable analyzing apparatus, comprising: a sample processing unit to perform a biochemical reaction using an injected sample; a thin film thermoelectric element arranged in a manner in which a first surface thermally contacts with the sample processing unit and includes terminals to receive a supply of variable power; and a control unit to precisely control temperature of the first surface by supplying the variable power to the thin film thermoelectric element through the terminals, and provide the sample processing unit with temperature which is necessary for the biochemical reaction.
[2] The portable analyzing apparatus according to claim 1, further comprising a conductive layer interposed between the sample processing unit and the thin film thermoelectric element to transfer heat.
[3] The portable analyzing apparatus according to claim 1, further comprising a heat-radiating plate arranged on a second surface of the thin film thermoelectric element to radiate heat generated from the second surface to the outside.
[4] The portable analyzing apparatus according to claim 1, further comprising a heat radiating fan arranged on a lower portion of a second surface of the thin film thermoelectric element to radiate heat generated from the second surface to the outside.
[5] The portable analyzing apparatus according to claim 1, further comprising a temperature sensor to measure temperature of the sample processing unit or a first surface of the thin film thermoelectric element.
[6] The portable analyzing apparatus according to claim 1, wherein the biochemical reaction is a polymerase chain reaction (PCR).
[7] The portable analyzing apparatus according to claim 1, wherein the sample processing unit is a thin film biochip.
[8] The portable analyzing apparatus according to claim 1, wherein the sample processing unit comprises a substrate; one or more micro chambers formed therein to perform biochemical reaction; and valve holes arranged at both ends of each of the micro chambers.
[9] The portable analyzing apparatus according to claim 8, wherein the sample processing unit further comprises a pre-processing unit to preliminary process the sample to be suitable for the biochemical reaction.
[10] The portable analyzing apparatus according to claim 8, wherein only the micro chambers thermally contact with the thin film thermoelectric element.
[11] The portable analyzing apparatus according to claim 8, wherein the substrate is made from a plastic, and the micro chambers are arranged in parallel relationship.
[12] The portable analyzing apparatus according to claim 1, further comprising a main body to house therein the sample processing unit, the thin film thermoelectric element and the control unit, and wherein the thin film thermoelectric element is slidingly movable out of the main body so that when the thin film thermoelectric element is exposed out of the main body, the sample processing unit is loaded on the thin film thermoelectric element.
[13] The portable analyzing apparatus according to claim 1, further comprising an alarming unit to provide an alarming message if an operating signal is received before the sample processing unit is loaded on the thin film thermoelectric element.
[14] The portable analyzing apparatus according to claim 1, further comprising an optical detecting unit arranged above the sample processing unit or the thin film thermoelectric element, and vertically movable with respect to the sample processing unit or the thin film thermoelectric element.
[15] The portable analyzing apparatus according to claim 14, wherein the sample processing unit comprises a substrate, one or more micro chambers formed therein to perform biochemical reaction, and valve holes arranged at both ends of each of the micro chambers, and the optical detecting unit comprises a pinch valve capable of closing the valve holes so that the pinch valve opens and closes the valve holes in accordance with the vertical movement of the optical detecting unit.
[16] The portable analyzing apparatus according to claim 14, wherein the optical detecting unit comprises a buffer unit to apply a constant level of pressure to different each of the sample processing unit.
[17] The portable analyzing apparatus of claim 14, wherein the optical detecting unit comprises: a light source to emit a uniform light beam; an excitation light transmitting unit to transfer the light beam emitted from the light source to the sample processing unit; an emission light reducing unit to receive a fluorescence signal emitted from a fluorescence mark of the sample processing unit and output a fluorescence signal in an asymmetrically-reduced form; and a fluorescence detecting unit to detect a fluorescence signal output from the emission light reducing unit.
[18] The portable analyzing apparatus according to claim 17, wherein the light source comprises a light emitting diode (LED) array or a LED matrix.
[19] The portable analyzing apparatus according to claim 17, wherein the asymmetric reduction of the emission light reducing unit comprises a different reduction rate in a first direction from that in a second direction, in which the first direction is the direction in which a fluorescence signal is emitted from the sample processing unit, and the second direction is the direction perpendicular to the first direction.
[20] The portable analyzing apparatus according to claim 17, wherein the emission light reducing unit comprises one or more of: a dichroic mirror to change a direction of a fluorescence signal emitted from the sample processing unit; a secondary lens unit to process the fluorescence signal; a secondary optical filter to filter the fluorescence signal according to an individual wavelength; and a fluorescence signal converting unit to convert the fluorescence signal into an asymmetrically-reduced form.
[21] The portable analyzing apparatus according to claim 20, wherein the fluorescence signal converting unit comprises a semi-cylindrical lens or a prism.
[22] The portable analyzing apparatus according to claim 16, wherein the fluorescence detecting unit comprises one or more photodiodes, and the photodiodes correspond to micro chambers of the sample processing unit on a one-to-one basis.
[23] The portable analyzing apparatus according to claim 1, wherein the control unit comprises a reaction analyzing unit to receive a result of detection and perform analysis on the sample.
[24] The portable analyzing apparatus according to claim 1 or claim 23, further comprising a data transmitting unit to transmit a result of detection or analysis by wired or wireless communication.
PCT/KR2008/006109 2007-10-25 2008-10-16 Portable analyzing apparatus based on pcr WO2009054647A2 (en)

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