Patent Publication Number: US-2023137550-A1

Title: Optical signal detection device

Description:
TECHNICAL FIELD 
     The disclosure relates to an optical signal detection device. 
     BACKGROUND ART 
     Nucleic acid amplification reaction well known as polynucleotide chain reaction (PCR) includes repeated cycles of double-stranded DNA denaturation, annealing of the oligonucleotide primers to DNA templates, and extension/elongation of the primers with the DNA polymerase (Mullis et al., U.S. Pat. Nos. 4,683,195, 4,683,202, and 4,800,159; Saiki et al., (1985) Science 230, 1350-1354). DNA denaturation is performed at about 95° C., and annealing and primer elongation are performed at a lower temperature ranging from 55° C. to 75° C. 
     The fluorescent material, which is an optical marker or label, included in the samples, emits fluorescence, which is an optical signal. The light source emits excitation light to the samples, and the fluorescent material excited by the excitation light emits the fluorescence. The light source may emit white light, and a filter may be disposed in the path of the excitation light in order to emit the excitation light of a specific wavelength to the samples. 
     In a high throughput device that simultaneously detects the same target nucleic acid in the plurality of the samples, the excitation light is irradiated to the plurality of the samples in various ways. For example, one light source unit may be configured to irradiate light to the entire sample holder in which the plurality of the samples are accommodated. In this case, since the angle of the excitation light irradiated to the sample is different according to the position in the sample holder, the signal for the same sample is deviated according to the position of the sample. 
     As another example, the light source unit may irradiate incident light onto each sample while moving on the sample holder. In this case, an error due to movement of the light source and an error due to individual measurement of the plurality of the samples may occur. First of all, there is a problem that the time required for measurement increases with each cycle. 
     Accordingly, there is a need to develop an optical signal detection device including the light source capable of providing the excitation light more efficiently and accurately to the plurality of the samples including a plurality of different optical labels. 
     DISCLOSURE OF INVENTION 
     Technical Problem 
     The present inventors have made intensive researches to develop a novel optical signal detection technology in which the light source unit maintains a stable excitation light path with respect to the sample holder, and at the same time, the deviation of the optical signal according to the sample position is reduced. As a result, the present inventors found that, in the case of detect the optical signal by a scheme where a dedicated individual light source unit is allocated to each sample area with respect to the sample holder divided into a plurality of sample areas and the plurality of filter units selectively filter the light of each light source unit to generate the optical signal, while maintaining the stable excitation light path, the deviation of the optical signal according to the sample position may be reduced. 
     In this background, a purpose of the present invention is to provide the optical signal detection device including a plurality of filter units which selectively filter light from the light source unit wherein one dedicated individual light source unit is allocated to each of the sample areas. 
     Solution to Problem 
     According to the embodiment, the present invention provides an optical signal detection device comprising: a sample holder configured to contain a plurality of samples wherein the sample holder is divided into a plurality of sample areas; a light source module configured to irradiate light to the plurality of sample areas wherein the light source module comprises a plurality of light source units comprising a first light source unit and a second light source unit, each of the plurality of light source units is arranged to irradiate light to different sample areas, and one dedicated individual light source unit is allocated to each of the sample areas; a filter module that filter light emitted from the light source unit wherein the filter module includes a plurality of filter units comprising a first filter unit and a second filter unit, when the first filter unit is configured to be positioned in an optical path of the first light source unit, the second filter unit is configured to be positioned in the optical path of the second light source unit, the filter module is configured to be movable so that the first filter unit may selectively filter light emitted from the first light source unit or the second light source unit; and a detection module configured to detect emission light emitted from the sample area. 
     Advantageous Effects of Invention 
     The optical signal detection device according to an embodiment measures the optical signal in such a way that each light unit of the plurality of light source units irradiates excitation light onto each sample area that is a part of the sample holder. Accordingly, with the device of the present invention, the difference in the amount of light depending on the position of the sample may be reduced, compared to a device that irradiates the entire sample holder with light with a single light source unit, so that the variation of signal value according to the position between samples can be reduced. 
     In addition, the optical signal detection device according to an embodiment may be configured such that an individual light source unit is allocated to each sample area to irradiate light, and the light emitted from at least two light source units may be simultaneously filtered by each filter unit, and the filter unit may be able to move between the plurality of the light source units. As a result, each of the sample areas is sequentially irradiated with light in a wavelength range provided by each filter unit, so that a plurality of optical labels included in one sample may be sequentially detected. In addition, since the plurality of the filter units are allocated to filter light from the plurality of the light source units at the same time, thereby retaining the above advantages over the device that irradiates the entire sample holder with light with the single light source unit, the time required for measurement may not increase. 
     The light source units of the optical signal detection device according to an embodiment do not move between the sample areas, and the dedicated individual light source unit is allocated to each sample area to irradiate light. Therefore, compared to a device that measures an optical signal while the light source unit moves, it is possible to stably maintain the optical path, thereby enabling a stable measurement with high reproducibility. 
     When the optical signal detection device according to an embodiment includes a plurality of thermally independent reaction regions, the reaction proceeds according to an independent protocol in the thermally independent reaction regions. Therefore, the time to detect the optical signal in each reaction region is independently determined. In the optical signal detection device according to an embodiment, since the plurality of the light source units and the filter units may independently detect the optical signal for each sample area, the detection of optical signal can be efficiently performed in an device that performs an independent reaction protocol for each reaction regions. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG.  1    is a view for describing a device for detecting an optical signal; 
         FIG.  2    is a view illustrating a light source module and a filter module according to an embodiment; 
         FIGS.  3 A to  3 C  are views illustrating a light source unit and a sample area according to an embodiment.  FIG.  3 A  shows the light source module including four light source units.  FIG.  3 B  shows a sample holder including four sample areas.  FIG.  3 C  explains the relative arrangement of the light source module and the sample holder; 
         FIGS.  4 A and  4 B  are views for explaining a light source module including two light source units and a filter module including two filter units according to an embodiment; 
         FIGS.  5 A to  5 C  are views for explaining a light source module including four light source units and a filter module including four filter units corresponding thereto according to an embodiment.  FIG.  5 A  shows the light source module including four light source units.  FIG.  5 B  shows the filter module including four filter units.  FIG.  5 C  explains the relative arrangement of the light source module and the filter module; 
         FIG.  6    is a view illustrating that a plurality of filter units according to an embodiment move to sequentially filter light emitted from a plurality of light source units; 
         FIGS.  7 A and  7 B  is a view illustrating that a plurality of filter units according to an embodiment move to filter excitation light irradiated to the same sample area of a sample holder according to an embodiment; 
         FIG.  8    is a view illustrating a device including a filter module and a light source module according to an embodiment; 
         FIG.  9    is a schematic diagram of an device including a light source module, a filter module, a detection module, and a sample holder according to an embodiment; and 
         FIG.  10    is a view illustrating a filter module including a plurality of filter units, a filter support, and a reference hole according to an embodiment. 
     
    
    
     MODE FOR THE INVENTION 
     Hereinafter, some embodiments of the present disclosure will be described in detail with reference to the accompanying illustrative drawings. In designating elements of the drawings by reference numerals, the same elements will be designated by the same reference numerals although they are shown in different drawings. Further, in the following description of the present disclosure, a detailed description of known functions and configurations incorporated herein will be omitted in the situation in which the subject matter of the present disclosure may be rendered rather unclear thereby. 
     In addition, terms, such as first, second, A, B, (a), (b) or the like may be used herein when describing components of the present disclosure. Each of these terminologies is not used to define an essence, order or sequence of a corresponding component but used merely to distinguish the corresponding component from other component(s). In the case that it is described that a certain structural element “is connected to”, “is coupled to”, or “is in contact with” another structural element, it should be interpreted that another structural element may “be connected to”, “be coupled to”, or “be in contact with” the structural elements as well as that the certain structural element is directly connected to or is in direct contact with another structural element. 
     Optical Module and Signal Detection Device with Rotating Light Source and Filter 
       FIG.  1    is a view for describing a device for detecting an optical signal. 
     Referring to  FIG.  1   , the optical signal detection device  10  includes a light source module  200 , a sample holder  100 , a filter module  300 , and a detection module  400 . The optical signal detection device  10  may further include a beam splitter  600 . 
     The optical signal detection device  10  refers to a device that detects an optical signal generated from a sample. The optical signal may be a luminescent signal, a phosphorescent signal, a chemiluminescent signal, a fluorescent signal, a polarized fluorescent signal, or other colored signal. The optical signal generated from the sample may be, for example, a fluorescent signal. The optical signal may be an optical signal generated in response to an optical stimulus applied to the sample. 
     The light source module  200  and the filter module  300  supply an appropriate optical stimulus to the sample, and the detection module  400  detects an optical signal generated from the sample in response thereto. The sample holder  100  positions the sample at a predetermined position so that the optical stimulus reaches the sample and the optical signal generated from the sample reaches the detection module  400 . In addition, the sample holder  100  may perform a process for detecting the optical signal from the sample, such as temperature control of the sample, if necessary. 
     The optical signal generated in the sample may be, for example, an optical signal that is generated depending on the properties of the target analyte, such as activity, amount, or presence (or absence), specifically presence (or absence). The size or change of the optical signal serves as an indicator qualitatively or quantitatively indicating the property of the target analyte, specifically the presence or absence of the target analyte. The target analyte may be, for example, a target nucleic acid sequence or a target nucleic acid molecule including the same. Accordingly, the optical signal detection device according to an embodiment may be a target nucleic acid sequence detection device. 
     The light source module  200  emits light to excite an optical label included in the sample. The light source module  200  includes a plurality of light source units  210 . Light emitted by the light source unit  210  may be referred to an excitation light. The light emitted by the sample may be referred to an emission light. The path of the excitation light emitted from the light source unit  210  may be referred to an excitation path. The path of the emission light emitted from the sample may be referred to an emission path. 
     The light source unit  210  may include a light source element  215 . One light source unit  210  may include one or more light source elements  215 . In one example, the light source element  215  may be a light emitting diode (LED) including an organic LED, an inorganic LED, and a quantum dot LED, and a laser unit including a tunable laser, a He—Ne laser, and an Ar laser. According to one embodiment, the light source element  215  may be the LED. 
     The filter module  300  filters light emitted from the light source module  200  so that light in a specific wavelength range reaches the sample. The filter module  300  includes a plurality of filter units  310 . The filter unit  310  includes one or more filters. 
     The beam splitter  600  reflects and transmits light incident from the light source unit  210 . Light transmitted through the beam splitter  600  reaches the sample holder  100 . The beam splitter  600  reflects and transmits light emitted from the sample. The beam splitter  600  may be configured such that light reflected by the beam splitter  600  reaches the detection module  400 . 
     The sample holder  100  accommodates a sample. The sample of the present invention comprises all substances capable of being accommodated in the optical signal detection device  10  of the present invention and becoming subject to the optical signal detection reaction. 
     For example, the samples include biological samples (e.g., cells, tissues, and body fluids) and non-biological samples (e.g., food, water and soil), and the biological samples are, for example, viruses, bacteria, tissues, cells, blood (whole blood, plasma and serum), lymph, bone marrow, saliva, sputum, swab, aspiration, milk, urine, feces, eye fluid, semen, brain extract, cerebrospinal fluid, joint fluid, Thymus fluid, bronchial lavage fluid, ascites and amniotic fluid. 
     In addition, a processed product obtained by processing the biological sample or the non-biological sample are also included in the sample of the present invention. 
     Such the processed product includes, for example, a processed product obtained by physically or chemically processing the biological sample or a non-biological sample such as heat treatment, ultrasonic treatment, acid, and base treatment to expose an active ingredient such as nucleic acid. 
     In addition, the processed product comprises an extract isolated from the biological sample and the non-biological sample as well as the biological sample and the non-biological sample itself. For example, when a nucleic acid is isolated from the sample and used in a detection reaction, the isolated nucleic acid is also included in the sample of the present invention. In this case, the sample may be subjected to a nucleic acid extraction process known in the art (see Sambrook, J. et al., Molecular Cloning. A Laboratory Manual, 3rd ed. Cold Spring Harbor Press (2001)). The nucleic acid extraction process may vary depending on the type of sample. 
     In addition, when the extracted nucleic acid is RNA, a reverse transcription process for synthesizing cDNA may be additionally performed (Sambrook, J. et al., Molecular Cloning. A Laboratory Manual, 3rd ed. Cold Spring. Harbor Press (2001)), and a synthetic product obtained by this process, such as cDNA, is also included in the processed product. 
     In addition, clones or nucleic acid amplification products obtained by an amplification method in which the extracted nucleic acid or cDNA obtained therefrom is directly amplified by a method such as PCR, or by transforming the microorganism to cultivate the microorganism and then extracting the nucleic acid, is also included in the processed product. 
     In addition, mixtures containing the above-described biological sample, the above-described non-biological sample, or the above-described processed product thereof and an additive for optical signal detection that may be performed in the optical signal detection device  10  are also included in the scope of the sample of the present invention. The additive may include, not limited thereto, for example, a reaction solution, a buffer, a stabilizer, an enzyme, a salt, a nucleic acid fragment, dNTP, a detection probe, an optical label, a polymer bead for support or separation, and a resin, etc. 
     The sample holder  100  may be configured to accommodate a plurality of samples. In one example, the plurality of the samples are not necessarily limited to a set of samples derived from different sources. Specifically, the plurality of the samples are not limited to a plurality of samples that are distinguished from each other. For example, when various tests are performed in separate tubes using a blood sample collected from one patient, each solution contained in each tube is a separate sample. When nucleic acid is extracted from a blood sample collected from one patient and applied to a plurality of reaction sites that are distinguished from each other, each of the extracted solution applied to each reaction site is separate sample. 
     In this way, the samples applied to the reaction sites where the distinct optical signal detection reactions may proceed are separate samples that are distinguished from each other. 
     Accordingly, according to an embodiment, the sample holder  100  may be configured to include a plurality of reaction sites. 
     The sample holder  100  may be configured to directly accommodate a plurality of samples or configured to accommodate a reaction vessel containing samples. The reaction vessel of the present invention includes a reaction vessel capable of holding one sample. In addition, the reaction vessel of the present invention includes a reaction vessel capable of containing a plurality of samples separately. In addition, the reaction vessel of the present invention includes a reaction vessel in which a plurality of distinct nucleic acid probes are fixed, such as a DNA array chip. 
     The sample holder  100  may be a conductive material. When the sample holder  100  contacts the reaction vessels, heat may be transferred from the sample holder  100  to the reaction vessel. For example, the sample holder  100  may be made of a metal such as aluminum, gold, silver, nickel, or copper. Alternatively, a separate configuration other than the sample holder  100  may directly supply energy to the reaction vessel to control the temperature of the samples in the reaction vessel. In this case, the sample holder  100  accommodates the reaction vessels, but may be configured not to transfer heat to the reaction vessel. 
     An example of the sample holder  100  is a thermal block. The thermal block may include a plurality of holes or wells, and reaction vessels may be positioned in the holes or wells. 
     Another example of the sample holder  100  is a heating plate. The heating plate is a form in which a thin metal is brought into contact with a plate containing a sample. It may be operated by heating the plate by passing an electric current through a thin metal. 
     Another example of the sample holder  100  is an accommodating portion capable of accommodating one or more chips or cartridges. An example of the cartridge is a fluid cartridge comprising a flow channel. 
     The sample holder  100  may be configured to accommodate a plurality of samples, and a reaction for detection such as a nucleic acid amplification reaction may occur by controlling the temperature of the plurality of the samples. For example, when the sample holder  100  is a thermal block in which a plurality of wells are formed, the sample holder  100  is composed of one thermal block, and all wells of the thermal block may be not configured to be thermally independent from each other. In this case, the temperatures of all wells in which samples are accommodated in the sample holder  100  are the same, and the temperature of the accommodated samples may not be adjusted according to different protocols. 
     As another example, the sample holder  100  may be configured to control a temperature of some of the samples accommodated in the sample holder  100  according to different protocols. In other words, the sample holder  100  may include two or more thermally independent reaction regions. Each reaction region may be thermally independent. No heat is transferred from one reaction region to another. For example, there may be an insulating material or air gap between the reaction regions. The temperature of each of the reaction regions may be controlled independently. For each of the reaction regions, a reaction protocol including reaction temperature and time may be individually set, and each of the reaction regions may perform a reaction according to an independent reaction protocol. Since the reaction proceeds in the reaction regions according to an independent protocol, the light detection time points in the reaction regions are independent of each other. 
     The detection module  400  detects a signal. Specifically, the detection module  400  detects fluorescence signal, which is an optical signal generated from samples. The detection module  400  includes a detection unit  410 . The detection unit  410  includes a detector that detects light. 
       FIG.  2    is a view illustrating a light source module and a filter module according to an embodiment. 
     As shown in  FIG.  2   , the light source module  200  includes a plurality of light source units  210 . Specifically, the light source module  200  includes a plurality of light source units  210  including a first light source unit  210   a  and a second light source unit  210   b.  In addition, the filter module  300  includes a first filter unit  310   a  and a second filter unit  310   b.    
     The light generated from the light source module  200  is filtered by the filter module  300  to reach the sample. Accordingly, the filter units  310   a  and  310   b  are positioned under each of the light source units  210   a  and  210   b.    
     According to an embodiment, the plurality of the light source units  210  may be light source units that emit light having the same wavelength properties. This means, for example, that the plurality of the light source units  210  emit light of the same wavelength range, and that the same amount of light emitted for each wavelength range. The same wavelength properties is meant to include substantially the same wavelength properties as well as exactly the same wavelength properties. The light source units that emit light having the same wavelength properties means the light source units that when the light generated from the two light source units is irradiated on the same optical label through the same filter, the same type of emitted light is generated from the optical label with the same amount of light. Specifically, the fact that the plurality of the light source units have substantially the same wavelength properties means that the amount of light or the deviation of the wavelength range of the plurality of the light source units is within 20%, 15%, or 10%. 
     For example, when the first light source unit  210   a  emits light in the visible wavelength range, the second light source unit  210   b  may also be configured to emit light in the visible wavelength range. In addition, for example, when the first light source unit  210   a  emits light in the first wavelength range and the second wavelength range, the second light source unit  210   b  may be also configured to emit light in the first wavelength range and the second wavelength range. In addition, the first light source unit  210   a  and the second light source unit  210   b  may be configured to have the same amount of light in the first wavelength range and the same amount of light in the second wavelength range. 
     According to one embodiment, the light source unit may include one or more light source elements. The number of light source elements included in the light source unit of the present invention may be, for example, one. In this case, one light source element may be one light source unit.  FIG.  3 A  shows a light source module including four light source units  210  each including one light source element.  FIG.  4 A  shows a light source module  200  including a light source unit including a plurality of light source elements  215 .  FIG.  4    illustrates that each of the light source units  210   a  and  210   b  includes four light source elements  215 , the number of light source elements included in the light source unit is not limited to one embodiment. Alternatively, the light source unit may include 1000, 500, 100, 50, 40, 30, 20 or less light source elements. 
       FIGS.  3 A to  3 C  are views illustrating a light source unit and a sample area according to an embodiment.  FIG.  3 A  shows the light source module including four light source units.  FIG.  3 B  shows a sample holder including four sample areas.  FIG.  3 C  shows the relative arrangement of the light source module and the sample holder. 
     As shown in  FIG.  3 B , the sample holder  100  may be divided into a plurality of sample areas  120 . 
     In an embodiment, the sample area  120  refers to an area on the sample holder  100  where an optical signal detection reaction is performed by the same light source unit  210  for a sample located in the same sample area. In other words, the sample area of an embodiment refers to a group of reaction sites in which the optical signal detection reaction proceeds by the same light source unit among the plurality of reaction sites included in the sample holder  100 . In other words, the sample area  120  is an area divided by irradiation area of the excitation light of the light source unit  210 . 
     When the sample holder  100  includes two or more thermally independent reaction regions, each sample area  120  is not defined over two or more reaction regions but is included in one reaction region or may be defined to be the same area as one reaction region. 
     When the sample area  120  is defined as described above, the optical signal detection may be performed by the light source unit and the filter unit different from each other in the two or more thermally independent reaction regions in which the light detection time points are independent from each other. According to an embodiment, the sample holder may include two or more reaction regions thermally independent from each other, and each of the sample areas may be defined to be included in any one of the two or more reaction regions thermally independent from each other. 
       FIG.  3 B  shows an example in which the sample holder  100  is divided into four sample areas  120   a,    120   b,    120   c,  and  120   d,  but the sample holder and the sample area are not limited thereto. The sample holder may be, for example, a sample holder including 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 sample areas. 
     According to one embodiment, the number of reaction sites included in each of the sample areas  120  may be the same. In other words, the sample areas  120  may have the same number of samples that may be accommodated in each sample area. For example, as shown in  FIG.  3 B , each sample area  120  may include 16 reaction sites. The number of reaction sites that may be included in each sample area  120 , that is, the number of samples that may be accommodated in each sample area is not particularly limited, and may be, for example, 2, 3, 4, 5, 6, 7, 8, 9 or more, and 1000, 900, 800, 700, 600, 500, 400, 384, 300, 200, 100, 96, 48, 32, 24, 16 or less. 
     Each light source unit of the plurality of the light source units is arranged to irradiate light to different sample areas. 
     The light source module may be configured that the plurality of the light source units included in the light source module are disposed to irradiate light to different sample areas. In the optical signal detection device  10  of an embodiment, not all reaction sites of the sample holder receive light by the same light source unit, but the plurality of the light source units irradiate light respectively onto the plurality of group of reaction sites. As a result, the deviation of the amount of light according to the position of the sample positioned in the sample holder is reduced, thereby reducing the deviation of the signal according to the position between the samples. 
       FIG.  3 A  is a view illustrating a light source module  200  according to one embodiment. The light source module  200  may include four light source units  210   a  to  210   d.    FIG.  3 B  is a view illustrating a sample holder  100  according to one embodiment. The sample holder  100  may include four sample areas  120   a  to  120   d.    
       FIG.  3 C  shows the arrangement of the light source module  200  with respect to the sample holder  100  in order to describe the sample areas  120   a  to  120   d  to which light is irradiated by each light source unit  210   a  to  210   d  of the light source module  200 . 
     Referring to  FIG.  3 C , the first light source unit  210   a  is disposed to irradiate light to the first sample area  120   a,  and the second light source unit  210   b  is disposed to irradiate light to the second sample area  120   b.  In addition, the third light source unit  210   c  and the fourth light source unit  210   d  are also disposed to irradiate light to the third sample area  120   c  and the fourth sample area  120   d,  respectively. 
     In addition, one dedicated individual light source unit is allocated to each of the sample areas. As shown in  FIG.  3 C , the first light source unit  210   a  is disposed to irradiate light to the first sample area  120   a,  and is configured not to irradiate light to other sample areas. In addition, the first sample area  120   a  is configured such that light emitted from the first light source unit  210   a  is irradiated, and light emitted from other light source units is not irradiated. 
     When one light source unit moves to irradiate light to two or more sample areas, it is difficult to maintain the same light path for one sample area at all times, and thus an error may occur. In addition, even when the light source unit is fixed without moving, if two or more light source units are configured to irradiate light to one sample area, excitation light passing through different filters is simultaneously irradiated to the same sample area so that crosstalk may occur. In addition, in order to avoid the risk of crosstalk, each light source unit must sequentially irradiate light to the sample unit and sequentially detect optical signals. Therefore, an increase in time required for optical signal detection is inevitable. 
     In the case where a dedicated individual light source unit is allocated to each sample area to irradiate light, as in the optical signal detection device  10 , since the light source module does not need to move in relation to the sample holder, it is easy to maintain an elaborate light path. In addition, since each light source unit does not irradiate light to an area other than the allocated sample area, the plurality of the light source units are able to simultaneously irradiate light, thereby enabling rapid optical signal detection. 
     The number of the light source units included in the light source module may be, for example, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, or 24. 
     According to an embodiment, in the optical signal detection device  10 , the number of the light source units and the number of the sample areas may be the same. The optical signal detection device  10  may include a plurality of light source modules. In this case, the total number of the light source units included in the plurality of the light source modules and the number of the sample areas may be the same. As long as each light source unit irradiates light to different sample areas, and one dedicated individual light source unit is allocated to each sample area, the the optical signal detection device  10  may include a plurality of light source modules. 
     The optical signal detection device  10  includes a filter module  300 . The filter module  300  filters light emitted from the light source unit  210 . The filtration may mean selectively passing light in a specific wavelength range among the light emitted from the light source unit or selectively blocking light in a specific wavelength range. The “selectively passing light” may mean passing 50%, 60%, 70%, 80%, or 90% or more of the amount of light in the desired wavelength range. The “selectively blocking light” may mean blocking without passing 50%, 60%, 70%, 80%, or 90% or more of the amount of light in the target wavelength range. 
     The filter module  300  selectively passes light of a specific wavelength range among the light emitted from the light source unit to irradiate the sample. As a result, only a specific optical label among the optical labels included in the sample generates an optical signal. 
     The optical label may be an optical label selected from the group consisting of Cy2™, YO-PRO™-1, YOYO™-1, Calcein, FITC, FluorX™, Alexa™, Rhodamine 110, Oregon Green™ 500, Oregon Green™ 488, RiboGreen™, Rhodamine Green™, Rhodamine 123, Magnesium Green™, Calcium Green™, TO-PRO™-1, TOTO1, JOE, BODIPY530/550, Dil, BODIPY TMR, BODIPY558/568, BODIPY564/570, Cy3™ Alexa™ 546, TRITC, Magnesium Orange™, Phycoerythrin R&amp;B, Rhodamine Phalloidin, Calcium Orange™, Pyronin Y, Rhodamine B, TAMRA, Rhodamine Red™, Cy3.5™, ROX, Calcium Crimson™, Alexa™ 594, Texas Red, Nile Red, YO-PRO™-3, YOYO™-3, R-phycocyanin, C-Phycocyanin, TO-PRO™-3, TOTO3, DiD Di1C(5), Cy5™, Thiadicarbocyanine, Cy5.5, HEX, TET, Biosearch Blue, CAL Fluor Gold 540, CAL Fluor Orange 560, CAL Fluor Red 590, CAL Fluor Red 610, CAL Fluor Red 635, FAM, Fluorescein, Fluorescein-C3, Pulsar 650, Quasar 570, Quasar 670 and Quasar 705. In particular, the label may be an optical label selected from the group consisting of FAM, CAL Fluor Red 610, HEX, Quasar 670, and Quasar 705. 
     The filter module  300  includes a plurality of filter units  310 . Referring to  FIG.  4 B , the filter module  300  may include a first filter unit  310   a  and a second filter unit  310   b.  Referring to  FIG.  5 B , the filter module  300  may include four filter units  310   a  to  310   d.    
     Each of the filter units includes a filter. Each of the filter units includes a filter that passes light in a wavelength range capable of excitation of at least one of the optical labels. The filter included in the filter unit may be a bandpass filter. The bandpass filter refers to a filter that selectively transmits light in a predetermined wavelength range. The wavelength range of light passing through the bandpass filter is referred to as a passband of the filter. The passband may be displayed in the form of a wavelength range. A filter including a specific passband means a filter that passes light having a wavelength included in the specific passband. For example, the first filter unit  310   a  may be a filter of a first passband, and the second filter unit  310   b  may be a filter of a second passband. Each of the first passband and the second passband may include a wavelength range of light capable of exciting a specific optical label. 
     The specific type of the optical label is as described above. In particular, the optical label may be an optical label selected from the group consisting of FAM, CAL, Fluor Red 610, HEX, Quasar 670, and Quasar 705. 
     The first filter unit  310   a  and the second filter unit  310   b  may pass light capable of exciting different optical labels. Accordingly, according to an embodiment, the passbands of the first filter unit  310   a  and the second filter unit  310   b  may not overlap each other. The filter units included in the filter module  300  may be disposed to selectively excite different optical labels. Accordingly, according to an embodiment, the passbands of the filter units included in the filter module may be different from each other. 
     Referring back to  FIG.  2   , the filter module  300  is configured to be movable so that each of the filter units  310   a  and  310   b  may selectively filter light emitted from the light source units  210   a  and  210   b.  To this end, the optical signal detection device  10  may include a filter support  320 . The plurality of filter units  310  may be disposed on the filter support  320 . The filter units  310  may be fixed to the filter support  320 . In one embodiment, the filter support  320  is configured to be movable. The filter units  310  fixed to the filter support  320  are moved by the movement of the filter support  320 . Although the filter support  320  is shown in a circular shape in  FIG.  2   , the shape of the filter support  320  is not limited thereto, and may have various shapes such as a circle, an ellipse, and a square. 
     According to one embodiment, the optical signal detection device  10  may include a moving means capable of moving the plurality of the filter units  310 . The filter support  320  may be configured to be movable by the moving means  330 . The moving means  330  may be, for example, a motor. The motor may be, for example, an AC motor, a DC motor, a step motor, a servo motor, or a linear motor, and preferably a step motor. 
     The moving means  330  may move the filter support  320  through a connection shaft  340 , for example. The movement may be, for example, a rotation movement that rotates about the connection shaft  340 . For example, the connection shaft  340  for transmitting the power of the motor  330  to the filter support  320  may be configured to connect the motor  330  and the filter support  320 . Both ends of the connection shaft  340  may be directly connected to the filter support  320  and the motor  330  to transmit power. Alternatively, one end of the connection shaft  340  may be connected to the filter support  320 , and the other end may be indirectly connected to the motor  330  through other power transmission means such as gears, belts, and pulleys. The position of the moving means  330  is not particularly limited. For example, as shown in  FIG.  2   , when the light source module  200  is positioned between the moving means  330  and the filter support  320 , the light source module  200  may be formed with a through hole  230  through which the connection shaft  340  may pass. 
     The filter module includes a plurality of filter units including a first filter unit and a second filter unit. When the first filter unit is positioned in an optical path of the first light source unit, the second filter unit is configured to be positioned in the optical path of the second light source unit. The optical path of the first light source unit refers to the path through which the light passes from the first light source unit to the sample area. 
     In other words, when the first filter unit is in a position capable of filtering light irradiated from the first light source unit to the sample area, the second filter unit is configured to be in a position capable of filtering light irradiated from the second light source unit to the sample area. 
     In addition, according to an embodiment, the plurality of the filter units may be disposed such that the plurality of the light source units irradiate light to each sample area through different filter units. 
       FIGS.  5 A to  5 C  are views for explaining a light source module including four light source units and a filter module including four filter units corresponding thereto according to an embodiment.  FIG.  5 A  shows a light source module including four light source units  210   a  to  210   d  including a first light source unit  210   a  and a second light source unit  210   b.    FIG.  5 B  shows a filter module including four filter units  310   a  to  310   d  including a first filter unit  310   a  and a second filter unit  310   b.    FIG.  5 C  is a view in which the light source module  200  and the filter module  300  are stacked in order to explain the relative arrangement of the light source module  200  and the filter module  300 . As shown in  FIG.  5 C , when the first filter unit  310   a  is positioned to selectively filter the light emitted from the first light source unit  210   a,  the second filter unit  310   b  may be positioned in a place that may selectively filter the light emitted from the second light source unit  210   b.    
     As described above, according to one embodiment, the plurality of the filter units are are arranged in the filter support such that at least two or more filter units  310   a  to  310   d  are simultaneously positioned in different optical paths of the light source units  210   a  to  210   d.  With this arrangement, the optical signal detection device  10  may simultaneously irradiate light filtered to a specific wavelength range to two or more sample areas. 
     In addition, the filter module  300  includes a plurality of filter units including a first filter unit  310   a  and a second filter unit  310   b.  The first filter unit  310   a  may be configured to be movable to selectively filter light emitted from the first light source unit  210   a  and the second light source unit  210   b.  In other words, the filter units  310  may be configured to move between the light source units  210 . The movement method is not particularly limited, and may be, for example, rotational movement. 
     The filter module  300  according to an embodiment as shown in  FIG.  5    may be configured to be rotatable. Accordingly, the first filter unit  310   a  positioned on the first light source unit  210   a  may move to a position where the second light source unit  210   b  is positioned. Accordingly, the filter module  300  may be configured to be movable so that the first filter unit  310   a  may selectively filter the light emitted from the first light source unit  210   a  or the second light source unit  210   b.  By the movement, all light source units  210   a,    210   b,    210   c,    210   d  included in the light source modules  200  may selectively emit, to the sample, light in the wavelength range determined by the filter units  310   a,    310   b,    310   c,    310   d.    
     The positions of the filter units  310  may be synchronously changed by the movement of the filter support  320 . According to an embodiment, the filter unit  310  located in each light source unit  210  may be synchronously replaced by the movement of the filter support  320  in the optical signal detection device  10 . 
     As shown in  FIG.  6   , for example, when the filter support  320  includes four filter units  310   a,    310   b,    310   c,    310   d,  at least two filter units may be positioned in the light paths of different light source units. Specifically, a first filter unit  310   a  is disposed in the first light source unit  210   a,  a second filter unit  310   b  is disposed in the second light source unit  210   b,  a third filter unit  310   c  is disposed in the third light source unit  210   c , and a fourth filter unit  310   d  is disposed in the fourth light source unit  210   d.    
     When the filter support  320  rotates and the filter units move, the fourth filter unit  310   d  is disposed in the first light source unit  210   a,  the first filter unit  310   a  is disposed in the second light source unit  210   b,  the second filter unit  310   b  is disposed in the third light source unit  210   c,  and the third filter unit  310   c  is disposed in the fourth light source unit  210   d.    
     When the filter support  320  rotates again and the filter units move, the third filter unit  310   c  is disposed in the first light source unit  210   a,  and the fourth filter unit  310   d  is disposed in the second light source unit  210   b,  the first filter unit  310   a  is disposed in the third light source unit  210   c,  and the second filter unit  310   b  is disposed in the fourth light source unit  210   d.    
     In this way, the filter unit  310  allocated to each light source unit  210  may be synchronously replaced by the movement of the filter support  320 . 
     In order to synchronously replace the filter units  310  as described above, the filter support  320  includes n filter units  310 , and, the filter support  320  is rotated 360/n degrees at a time by the moving means  330 , according to an embodiment. The n may be a natural number of 2 or more. In one embodiment, the filter support  320  may include two filter units  310 , and the filter support  320  may be rotated 180 degrees at a time. In another example, the filter support  320  includes three filter units  310 , and the filter support  320  may be rotated 120 degrees at a time. The filter support  320  may include four filter units  310 , and the filter support  320  may be rotated 90 degrees at a time.  FIG.  6    shows that the filter support  320  including the four filter units  310  rotates 90 degrees at a time, so that the filter units  310  allocated to each light source unit  210  are synchronously replaced. 
     By this synchronous movement, excitation light corresponding to the wavelength range of each filter unit  310  may be sequentially irradiated to every sample area. 
       FIGS.  7 A and  7 B  are views illustrating a positional relationship between the filter module  300  having the plurality of the filter units  310  and the plurality of the sample areas. As one of various structures for allowing the excitation light generated by the light source unit (not shown) to pass through the filter unit  310  to reach the sample area, each filter unit  310  may be configured to face the sample area directly. In other words, each filter unit  310  may be positioned above each sample area  120  of the sample holder. 
       FIG.  7 A  shows a filter module having two filter units to filter excitation light irradiated to two sample areas. According to the structure of  FIG.  7 A , by rotation of the filter module, two excitation lights having different wavelength regions may be sequentially irradiated to each sample area. 
       FIG.  7 B  shows a filter module having four filter units to filter excitation light irradiated to four sample areas. Excitation light in four wavelength ranges may be irradiated to each of the sample regions  120   b  by four filter units. 
     In the structure of  FIG.  7 A , two types of optical signals may be detected in all sample areas by measuring two times. In the structure of  FIG.  7 B , four types of optical signals may be detected in all sample areas by measuring four times. Even in a conventional device that measures an optical signal using excitation light in a single wavelength range for the entire sample holder, four measurements are required to detect four types of optical signals. As described above, the optical signal detection device  10  may maintain the processing speed equivalent to that of the conventional device while reducing the deviation of the signal according to the position of the sample by dividing the sample holder and arranging the light source. 
       FIG.  8    is a view illustrating a device including a filter module and a light source module according to an embodiment. 
       FIG.  8 A  shows an optical signal detection device according to an embodiment. The optical signal detection device includes a light source module including a plurality of light source units for irradiating light to a sample holder, and a filter module spaced apart from the light source module. 
     The apparatus of the present invention includes a support plate  390  to which a light source module and a moving module are fixed. 
     The light source module includes a light source support  220  and a plurality of light source units  210  fixed to the light source support  220 . The plurality of the light source units  210  are allocated to irradiate light to a plurality of sample areas of the sample holder. The light source module is configured by being fixed to the lower surface of the support plate  390 . 
       FIG.  8 B  shows a light source module according to an embodiment. The light source module includes four light source units. The light source unit includes a light source element  215  and a power supply unit  216 . A through hole  230  is formed in the center of the light source module so that the connection shaft  340  connecting the filter support and the moving means may pass therethrough.  FIG.  8 B  is a cross-sectional view in which the connection shaft  340  connecting the first pulley and the filter support  320  to the through hole  230  and a fixing member fixing the connection shaft to the filter support  320  are disposed. 
     Referring to  FIGS.  8 A and  8 C , the filter module  300  includes the filter support  320  and a plurality of filter units  310 . The plurality of the filter units  310  are filter units corresponding to the plurality of light source units, and the filter unit  310  is configured to filter excitation light irradiated from the light source unit  210 . The filter support  320  is configured to be rotatable about the connection shaft  340 . Specifically, one end of the connection shaft  340  is connected to the center of the filter support  320 , and the connection shaft  340  passes through the through hole  230  of the light source module  200  and is fixed to the first pulley  350 . The first pulley  350  is positioned on the upper surface of the support plate  390 . 
     Accordingly, a second through hole  391  may be formed in the support plate  390  to fix the connection shaft  340  to the first pulley  350 . A second through hole  391  may be configured to have a bushing structure or a bearing structure supporting the outer surface of the connection shaft  340  so as to rotate with respect to the support plate  390  together with a connection shaft  340  corresponding to the second through hole  391 . Such a structure enables the support plate  390  to support the first pulley  350  to enable stable rotation. 
     The first pulley may be configured to rotate in connection with the second pulley  360  connected to the motor  330  through the pulley belt  370 . The second pulley  360  is configured such that the rotation axis of the second pulley and that of the first pulley  350  are parallel, and the central axis of the second pulley  360  is connected to a motor, which is a moving means  330 . 
     The first pulley  350  and the second pulley  360  may be timing pulleys on which threads are formed. The pulley belt may be a timing belt in which threads corresponding to the threads of the first pulley  350  and the second pulley  360  are formed. 
     According to one embodiment, the optical signal detection device  10  may further include a tension pulley  380 . The tension pulley  380  serves to maintain a constant tension of the pulley belt  370  by supporting the pulley belt  370  shouldered between the first pulley  350  and the second pulley  360  in a pressed state. 
     In the optical signal detection device  10 , the pulley-timing belt-pulley method is an example of a method of transmitting power required for rotation of a filter module, and power transmission may also be carried out in a direct coupling method of a motor and filter module, a gear-gear method, a gear-chain-gear method, and a pulley-belt-pulley method. 
       FIG.  9    is a schematic diagram of a device including a light source module, a filter module, a detection module, and a sample holder according to an embodiment. 
     Referring to  FIG.  9   , the detection module  400  detects an optical signal emitted from a sample accommodated in a sample holder. The optical label is excited by the excitation light irradiated from the light source module  200  through the filter module  300  to the sample, and the optical signal is emitted from the optical label. The optical signal may be received by the detection module  400 . In this process, the optical path of the excitation light may be refracted by, for example, the beam splitter  600  so that the the excitation light may reach the detection module  400 . When the detection module  400  is in a linear path of the optical path, the optical signal may be received without the use of the beam splitter  600 . 
     The sample holder  100  may include two or more reaction regions  100   a  and  100   b  that are thermally independent from each other, and each reaction region may be defined as a different sample area. Specifically, the first reaction region  100   a  defined as the first sample area proceeds an optical signal detection reaction by the first light source unit  210   a,  and the second reaction region  100   b  defined as the second sample area proceeds the optical signal detection reaction by the second light source unit  210   b.  Therefore, even if each of the reaction regions proceeds a reaction according to an independent protocol, since each of the light source units is independently positioned, optical signals may be detected at an optimum reaction time respectively. 
       FIG.  9    is shown to include one filter module, but the optical signal detection device is not limited thereto. According to an embodiment, the the optical signal detection device may include a sample holder including a reaction sites arranged in 8×12, and the reaction sites arranged in 4×4 as one sample area in the sample holder. A total of 6 sample areas are defined separately, and the optical signal detection device may include a light source module including 6 light source units arranged in each sample area. In addition, in order to arrange the filter units in the optical paths of the six light source units, the optical signal detection device may include two filter modules including four filter units. 
     According to one embodiment, the filter module may further include a first additional filter unit. The first additional filter unit may be disposed so that when the first filter unit and the second filter unit are respectively positioned in the optical path of the first light source unit and the optical path of the second light source unit, the first additional filter unit is not positioned in the optical path of other light source units. 
     The filter module may include a plurality of filter units including a first filter unit and a second filter unit. When the first filter unit is positioned in the optical path of the first light source unit, the second filter unit is configured to be positioned in the optical path of the second light source unit. Filter units satisfying the above rules may be classified into one group, which is referred to as a first group. In other words, the first group is a group of filter units arranged such that when one filter unit among the plurality of the filter units belonging to the first group is positioned in the light path of one light source unit, at least one other filter unit belonging to the first group is positioned in the optical path of at least one different light source unit. 
     All of the filter units included in the filter module of an embodiment may be arranged to satisfy the above rule. In this case, the optical signal detection efficiency for the entire sample area may increase. However, when it is necessary to irradiate the sample area with light of a larger number of wavelength range, the filter module must include an additional filter unit in addition to the filter units that are disposed in accordance with the above rules and are synchronously replaced. 
     When one of the filter units of the first group is positioned in the optical path of the light source unit, such an additional filter unit may not be arranged to be positioned in the optical path of another light source unit at the same time. Therefore, the additional filter unit may be disposed in accordance with rules different from the filter units of the first group. According to an embodiment, the filter module  300  includes a plurality of filter units classified into a first group, and may further include one or more filter units not classified into the first group. 
       FIG.  5    shows an embodiment of a filter module comprising a first group of filter units.  FIG.  10    shows a filter module  300  including a filter unit of the first group and a first additional filter unit not classified into the first group, unlike  FIG.  5   . The filter module shown in  FIG.  10    includes four filter units  310   a  to  310   d  classified into a first group. As shown in  FIG.  5   , the four filter units of the first group are disposed on the filter support  320  so that two or more filter units are simultaneously positioned in different optical paths of the light source units  210   a  to  210   d.  In addition, the filter module  300  shown in  FIG.  10    includes a first additional filter unit  310   e.  When the first additional filter unit  310   e  is positioned in the optical path of one light source unit  210 , the first group of filter units  310   a  to  310   d  may not be positioned in any optical path of the unit  210 . 
     According to an embodiment, the filter module may include a plurality of additional filter units not classified into the first group, and a plurality of additional filter units not classified into the first group may be arranged to be classified into a second group. The second group is a group of filter units arranged such that when one filter unit among the plurality of the additional filter units belonging to the second group is positioned in the light path of one light source unit, at least one other additional filter unit belonging to the second group is positioned in the optical path of at least one different light source unit. 
     The first additional filter unit is also arranged to be positioned in the optical paths of the light source units in which the filter units divided into the first group are positioned by the movement of the filter module  300 , so that light of a desired wavelength range may be irradiated to the sample area. 
     Accordingly, according to one embodiment, a plurality of filter units including the first filter unit and the second filter unit may be disposed in rotational symmetry with respect to one axis of symmetry, and the first additional filter unit may be disposed such that a distance between the plurality of filter units including the filter unit and the second filter unit and the axis of symmetry may be the same as the distance between the first additional filter unit and the axis of symmetry. The distance may be, for example, a distance between the center point of each filter unit and the axis of symmetry. 
     Referring to  FIG.  10   , the first additional filter unit  310   e  may be disposed such that a distance between the first additional filter unit  310   e  and the connection shaft  340  corresponding to the axis of symmetry may be the same as a distance between the first group of filter units  310   a - 310   d  and the connection shaft  340 . According to such arrangement of the plurality of filter units, the plurality of the filter units are rotated around a symmetry axis, so that both the first group of filter units and the first additional filter units may be sequentially disposed in the light paths of the light source units. 
     According to an embodiment, the filter module  300  may include a reference hole  325 . The reference hole  325  may be formed in the filter support  320  of the filter module  300 . 
     According to one embodiment, the reference hole  325  may be arranged to be positioned in the optical path of at least one light source unit of the plurality of light source units  210  by the movement of the filter support  320 . 
     When the reference hole  325  is positioned in the optical path of one light source unit  210  by the movement of the filter support  320 , the light of the light source unit  210  passing through the reference hole  325  is detected. Therefore, the reference position of the filter support  320  may be configured, and the filter support  320  may position the filter units  310  at an accurate position. 
     According to one embodiment, the reference hole  325  may be configured to pass light in all wavelength ranges. The reference hole  325  may be, for example, an empty space, or may include a transparent film through which light of all wavelengths may pass. 
     According to an embodiment, the reference hole  325  may include a filter that passes light in a specific wavelength range. In this case, the filter may be a filter that passes light having a wavelength range different from that of the filter units  310  of the filter module  300 . 
     The size of the reference hole  325  is not particularly limited, but may be the same as or smaller than the size of the filter unit. 
     The detection module  400  detects an optical signal by generating an electric signal according to the intensity of the optical signal. 
     Like the light source module  200 , the detection module  400  may be disposed at a fixed position to maintain an accurate optical path with respect to the sample holder  100 . 
     According to an embodiment, the detection module  400  may include a detection unit  410  and a detection filter unit  420 . In one embodiment, the detection unit  410  may be a plurality of detection units  410 , each detection unit including a detector, and may be arranged to detect the emission light of each sample area. 
     The detection filter unit  420  may be disposed in front of the detection unit  410 . The detection filter unit  420  may include a detection filter, and a detection filter disposed in front of the detection unit  410  may be changed according to a wavelength of emitted light. The detection filter of the detection module is a filter for selectively passing emission light emitted from the optical label included in the sample. When the detector detects light in a wavelength range other than the emitted light emitted from the optical label included in the sample, the optical signal may not be accurately detected. The detection filter makes it possible to accurately detect a target by selectively passing emission light emitted from an optical label. 
     The detection unit  410  may include a detector  411 . The detector  411  is arranged to detect the emission light emitted from the optical label included in the sample. The detector may detect the amount of light for each wavelength by dividing the wavelength of light, or may detect the total amount of light regardless of the wavelength. Specifically, the detector  411  may be, for example, a photodiode, a photodiode array, a photo multiplier tube (PMT), a CCD image sensor, a CMOS image sensor, an avalanche photodiode (APD), or the like. 
     The detector  411  is arranged to detect the emitted light emitted from the optical label included in the sample. 
     According to one embodiment, the detector  411  may be disposed to be located in the emission light paths  520   a  and  520   b  generated from the sample holder. Specifically, the detector  411  may be disposed toward the sample holder  100  so that the emission light generated from the sample may directly reach the detector  411 , or the detector  411  may be disposed toward the reflector or the optical fiber such that the emission light may reach the detector  411  through the reflector or the optical fiber. As an example, as in the case of  FIG.  9   , the detector  411  may be disposed toward the beam splitter  600  from which the emission light is reflected. 
     According to an embodiment, the detector may be a plurality of detectors. In this case, the plurality of detectors  411   a  and  411   b  may be configured to detect emission light generated in a predetermined area of the sample holder, respectively. Referring to  FIG.  9   , the first detector  411   a  is configured to detect the emission light  520   a  emitted from the first sample area  100   a  of the sample holder, and the second detector  411   b  is configured to detect the emission light  520   b  emitted from the second sample of the sample holder. According to one embodiment, the optical signal detection device may detect a plurality of signals in the first sample area  100   a  of the sample holder, and the plurality of signals may be also detected in the second sample area  100   b  of the sample holder. 
       FIG.  9    shows that a plurality of detection modules  400  each include a detector  411 , but the optical signal detection device according to an embodiment is not limited thereto, and as shown in  FIG.  8 A , a plurality of detectors  411  may be disposed in the detection module and detect the emission light emitted from each different sample area. 
     In addition, the terms such as “include”, “consist of” or “have” described above mean that the corresponding component may be included unless otherwise stated, excluding other components such that they should be interpreted as being able to further include other components. All terms, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art, unless otherwise defined. Generally used terms, such as terms defined in the dictionary, should be interpreted as being consistent with the meaning in the context of the related technology, and are not interpreted as ideal or excessively formal meanings unless explicitly defined in the present invention. 
     The examples described herein may be expanded to individual elements and concepts described herein, independently from other concepts, ideas, or systems and may be combined with elements cited anywhere in the present invention. Although some examples have been described in detail with reference to the accompanying drawings, the concept is not limited to such examples. Thus, the scope of the concept is intended to be defined by the appended claims and their equivalents. Further, specific features described individually or as some examples may be combined with other features described individually or other examples although not specifically mentioned for the specific features. Thus, the absence of a description of such combination should not be interpreted as excluding such combination from the scope of the present invention. 
     While embodiments of the disclosure have been described above, it will be easily appreciated by one of ordinary skill in the art that the scope of the disclosure is not limited thereto. Thus, the scope of the disclosure is defined by the appended claims and equivalents thereof. 
     CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority from Korean Patent Application No. 10-2020-0039501, filed on Mar. 31, 2020, in the Korean Intellectual Property Office, the disclosure of which is incorporated herein by reference in its entirety.