Heat block and thermal cycler comprising same

Abstract

A heat block, according to the present invention, for performing a plurality of reactions has an upper surface and a lower surface, each having a length and a width, has a plurality of sample wells opened upward and formed on the upper surface, and has pores formed in the lower surface in a predetermined pattern, wherein the proportion of the area occupied by the pores is greater in a central region than in a peripheral region of the lower surface. Therefore, the pores are formed in the lower surface of the heat block so that the heat transferred from a thermoelectric element to the heat block can be alleviated from being locally concentrated on the lower surface, and heat uniformity can be improved by the effective control of heat transfer.

Description

Thermal block and thermal cycler including the same

[0001] The present invention relates to a thermal block for performing multiple reactions and a thermal cycler including the same.

[0002] With increasing health concerns and increasing life expectancy, the importance of nucleic acid-based in vitro molecular diagnostics, including accurate pathogen analysis and patient genetic analysis, is growing, and demand is on the rise. Nucleic acid-based molecular diagnostics involves extracting nucleic acids from a specimen sample and then confirming the presence of target nucleic acids within the extracted nucleic acids.

[0003] Polymerase chain reaction (PCR) is the most widely used nucleic acid amplification reaction, which involves repeated cycles of denaturation of double-stranded DNA, annealing of oligonucleotide primers to a DNA template, and extension of the primers by 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).

[0004] A typical real-time PCR (real-time polymerase chain reaction) device consists of a thermal cycler installed at the bottom where a nucleic acid amplification reaction occurs and an optics mechanism installed at the top that analyzes or monitors the nucleic acid amplification reaction in real time.

[0005] DNA denaturation occurs at approximately 95°C, while annealing and primer extension occur at temperatures lower than 95°C, typically between 55°C and 75°C. Therefore, thermal cyclers are designed to allow for repeated temperature increases and decreases in the heat block. Typically, thermal cyclers include a heat block capable of accommodating multiple reaction vessels. The heat block includes a sample well capable of accommodating the reaction vessels.

[0006] As the temperature of the heat block rapidly changes by the thermal cycler, a nucleic acid amplification reaction of samples contained in reaction vessels is performed. The heat provided to the heat block may be generated by a heat generating device, and the heat generated by the heat generating device may be discharged to the outside through a heat sink.

[0007] Additionally, the thermal cycler includes a device and control system capable of maintaining a uniform temperature in the sample wells, and a program capable of reading and comprehensively reporting the results obtained from multiple wells. A reaction plate, consisting of multiple tube-shaped reaction vessels connected together, has been developed and is used as the reaction vessel used in such a thermal cycler.

[0008] Typically, the heat blocks that house these reaction plates are made of metal for rapid heat conduction. However, metal has a high specific gravity and heat capacity, which necessitates the supply or removal of a large amount of energy to control the temperature of the heat block. To address this issue, US Pat. No. 7,955,573, US Pat. No. 7,632,464, and US Pat. No. 8,557,196 disclose methods for drilling holes in the side and top surfaces of the heat block.

[0009] This was intended to allow for faster temperature changes in the heat block by removing unnecessary parts of the heat block. However, this configuration presents another problem: a temperature difference between the reaction plates or reaction vessels accommodated in each well. More specifically, the heat generating element may be a Peltier element, and the heat generated from one side of the Peltier element is not uniform, resulting in a non-uniform temperature on one side of the heat block through which the heat is conducted. In particular, when heat is dissipated from the heat block through a heat sink, the edge portion (outer portion) of the heat block tends to cool more quickly. However, since the reaction efficiency at each stage of the PCR reaction may vary depending on the temperature, the temperature difference between the reaction vessels must be minimized.

[0010] In particular, when performing the same test on multiple samples using a PCR reaction, the persistent temperature difference between wells causes the amplification reaction to proceed with different efficiencies for each sample in different wells. Since the PCR reaction repeats the nucleic acid amplification reaction for dozens of cycles, and the nucleic acid strands produced in the previous cycle serve as templates for the next cycle, these differences in amplification efficiency that occur with each cycle can significantly affect the analysis results.

[0011] Therefore, there is a need to develop a new heat block and a thermal cycler including the same that minimizes the temperature difference between reaction plates or reaction vessels.

[0012] Against this backdrop, one embodiment of the present invention provides a novel heat block having a gap formed on the lower surface to minimize temperature deviation between reaction plates or reaction vessels.

[0013] Additionally, one embodiment of the present invention provides a novel heat block having a groove formed on the lower surface for efficient heat control.

[0014] Additionally, one embodiment of the present invention provides a thermal cycler including the heat block that improves thermal uniformity.

[0015] In order to achieve the above purpose, one aspect of the present invention provides a heat block for performing a plurality of reactions, the heat block having an upper surface and a lower surface having a length and a width, a plurality of sample wells open upwardly formed on the upper surface, a heat block having pores formed in a predetermined pattern on the lower surface, and a heat block characterized in that the ratio of the area occupied by the pores is larger in the central area than in the outer area of ​​the lower surface.

[0016] Additionally, the above-mentioned gap may be formed on the lower surface in the form of a trench.

[0017] Additionally, the gap may include a plurality of linear depressions arranged parallel to each other.

[0018] In addition, the plurality of linear depressions may include a central depression formed across the central region and peripheral depressions distributed on both sides based on the central depression.

[0019] Additionally, the peripheral depression may have a smaller width the farther away it is from the central depression.

[0020] Additionally, the peripheral depressions may be spaced apart from each other at wider intervals the farther away they are from the central depression.

[0021] Additionally, the central depression may have a smaller width than adjacent peripheral depressions among the peripheral depressions.

[0022] In addition, among the above peripheral depressions, the remaining peripheral depressions, excluding the adjacent peripheral depressions, may have a smaller width as they get farther away from the central depression.

[0023] Additionally, the remaining peripheral depressions may be spaced apart from each other by a wider gap the farther away they are from the adjacent peripheral depressions.

[0024] Additionally, the gap may include a plurality of linear depressions, at least some of which are arranged to intersect each other.

[0025] Additionally, the above-described predetermined pattern may include a point-symmetric pattern.

[0026] Additionally, the above-described predetermined pattern may include a line-symmetric pattern.

[0027] Additionally, the void may include a plurality of loop-shaped depressions having different perimeters.

[0028] Additionally, the void may include a linear depression that crosses the plurality of loop-shaped depressions and connects at least a portion of the outer region and the central region.

[0029] Additionally, the loop-shaped depressions may be distributed from the central region to the outer region while sharing the same center point.

[0030] Additionally, the void may include a plurality of depressions having a geometric cross-section.

[0031] Additionally, the plurality of recessed portions may include a plurality of circular recessed portions having a predetermined diameter.

[0032] Additionally, the plurality of circular depressions may be distributed radially based on the center point of the lower surface.

[0033] Additionally, the ratio of the area of ​​the gap to the total area of ​​the above surface can be set to improve the thermal uniformity of the heat block.

[0034] In addition, the lower surface may include a plurality of grooves formed at a shallower depth than the gap, and the grooves may be formed vertically across the lower surface and spaced apart at regular intervals.

[0035] Another aspect of the present invention provides a thermal cycler including the heat block, further including a thermoelectric element in thermal contact with at least a portion of a lower surface of the heat block, wherein a heat transfer rate between the heat block and the thermoelectric element varies depending on a gap distributed on the lower surface.

[0036] Additionally, the heat transfer rate between the heat block and the thermoelectric element may be smaller in the central region than in the outer region of the lower surface.

[0037] Additionally, a thermal transfer member interposed between the heat block and the thermoelectric element may be further included.

[0038] Another aspect of the present invention provides a thermal cycler comprising: a heat block for performing a plurality of reactions; a thermoelectric element in thermal contact with at least a portion of a lower surface of the heat block; and a thermal transfer member interposed between the heat block and the thermoelectric element, wherein the heat block has an upper surface and a lower surface having a length and a width, a plurality of sample wells open upwardly are formed on the upper surface, and gaps are formed in a predetermined pattern on the lower surface, and a ratio of an area occupied by the gaps is larger in a central area than in an outer area of ​​the lower surface, and a heat transfer rate between the heat block and the thermoelectric element is characterized in that the central area is smaller than the outer area of ​​the lower surface due to the gaps distributed on the lower surface.

[0039] According to one embodiment of the present invention, by forming a gap on the lower surface of the heat block, heat transferred from the thermoelectric element to the heat block can be alleviated from being locally concentrated on the lower surface, and heat uniformity can be improved by controlling the effective heat transfer in this way.

[0040] In addition, according to one embodiment of the present invention, a groove that serves as an insulating spacer between Peltier elements is additionally formed in addition to a gap on the lower surface of the heat block, thereby improving heat uniformity through more effective heat control.

[0041] The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the detailed description of the present invention or the composition of the invention described in the claims.

[0042] FIG. 1 is a perspective view showing the upper surface of a heat block according to one embodiment of the present invention.

[0043] Fig. 2 is a perspective view showing the lower surface of a heat block according to the first embodiment of the present invention.

[0044] Figures 3 and 4 are bottom views showing the lower surface of a heat block according to the first embodiment of the present invention.

[0045] FIG. 5 is a plan view showing the upper surface of a heat block according to the first embodiment of the present invention.

[0046] Fig. 6 is a cross-sectional view showing a cross-section cut along line A-A' of Fig. 5.

[0047] Fig. 7 is a perspective view showing the lower surface of a heat block according to a second embodiment of the present invention.

[0048] Fig. 8 is a perspective view showing the lower surface of a heat block according to a third embodiment of the present invention.

[0049] Fig. 9 is a front view showing the arrangement of a thermoelectric element and a heat block of a thermal cycler according to one embodiment of the present invention.

[0050] Fig. 10 is a cross-sectional view showing a cross-section cut along line B-B' of Fig. 9.

[0051] Fig. 11 is a perspective view showing the lower surface of a heat block according to the fourth embodiment of the present invention.

[0052] Fig. 12 is a plan view showing the lower surface of a heat block according to the fourth embodiment of the present invention.

[0053] Hereinafter, the present invention will be described in detail through examples and illustrative drawings. These examples are intended solely to illustrate the present invention more specifically. It will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, as they reflect the gist of the invention.

[0054] Additionally, when assigning reference numerals to components in each drawing, it should be noted that identical components are assigned the same numerals whenever possible, even if they appear on different drawings. Furthermore, when describing the present invention, if a detailed description of a related known configuration or function is deemed likely to obscure the gist of the present invention, the detailed description will be omitted.

[0055] Additionally, terms such as first, second, A, B, (a), (b), (i), and (ii) may be used to describe components of the present invention. These terms are only intended to distinguish the components from other components, and the nature, order, or sequence of the components are not limited by the terms. When a component is described as being "connected," "coupled," or "connected" to another component, it should be understood that the component may be directly connected or connected to the other component, but another component may be "connected," "coupled," or "connected" between each component.

[0056] Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings so that a person having ordinary skill in the art to which the present invention pertains can easily practice the present invention.

[0057] FIG. 1 is a perspective view showing the upper surface of a heat block (110) according to one embodiment of the present invention. The heat block (110) of the present invention is a heat block for performing a plurality of reactions, and is also known as a sample holder or a thermal block. The heat block (110) of the present invention may have a shape of a hexahedron, particularly a rectangular parallelepiped, having a constant height (thickness). In addition, it may have a block or plate shape. The heat block (110) according to one embodiment of the present invention has an upper surface (S) having a length and a width. T ) and under (S B ) (see Fig. 2) and has an upper surface (S T ) and under (S B ) are parallel to each other.

[0058] In this specification, the X-axis direction includes a direction such as the first direction or the length direction of the heat block (110), the Y-axis direction includes a direction such as the second direction or the width direction of the heat block (110), and the Z-axis direction includes an up-down direction such as the thickness of the heat block (110), the depth of the gap, or the height / depth of the sample well (111).

[0059] One heat block (110) is provided to accommodate one or more samples. The upper surface (S T ) may be formed with a plurality of sample wells (111) that are open toward the top. The sample wells (111) may directly accommodate a sample or accommodate a reaction vessel containing a sample. That the heat block (110) accommodates the sample reaction vessels may mean that the sample reaction vessels are placed in the plurality of sample wells (111) formed in the heat block (110) or in assigned positions on the heat block (110). The position of the reaction vessel may be guided and fixed by the sample wells (111). Accordingly, the sample may be positioned at a predetermined position by the sample wells (111).

[0060] Reaction vessels are used to accommodate the samples to be analyzed, and include various types of containers, such as tubes, vials, strips in which multiple single tubes are connected, plates in which multiple tubes are connected, microcards, chips, cuvettes, or cartridges.

[0061] As shown in Fig. 1, the upper surface (S T ) may have a shape that protrudes upward, but is not limited thereto. The sample well (111) may be formed in a shape similar to that of the reaction vessel described above to directly accommodate a sample, or may be formed in a shape that is easy to accommodate the reaction vessel. In addition, 96 sample wells (111) are formed in a regular arrangement in the heat block (110) illustrated in FIG. 1, but is not limited thereto.

[0062] According to one embodiment, a plurality of sample wells (111) in the heat block (110) are formed in a regular arrangement and may be formed in a matrix shape forming columns and rows. The sample wells may be formed in various shapes such as 16-wells in a 4 x 4 shape, 24-wells in a 6 x 4 shape, 32-wells in a 4 x 8 shape, 60-wells in a 5 x 12 shape, 90-wells in a 5 x 18 shape, 96-wells in an 8 x 12 shape, or 384-wells in a 16 x 24 shape, and are not limited thereto, but 16-well, 32-well, 96-well, or 384-well may be primarily used. The shape, size, etc. of the sample wells (111) may be determined to be suitable for the reaction vessel or sample to be accommodated.

[0063] The heat block (110) may be made of various materials, such as plastic, ceramic, glass, or metal. Preferably, the heat block (110) may be made of a material having thermal conductivity so that when heat is supplied to the heat block (110) from a heat source, the heat is directly or indirectly transferred to a sample contained in the heat block (110). For example, the heat block (110) may be made of iron, aluminum, gold, silver, nickel, copper, or an alloy containing one or more of these, or in some cases, may be made of plastic or ceramic.

[0064] Referring further to FIG. 2, one embodiment of the present invention is described below (S). B ) is described. Figure 2 shows the lower surface (S) of the heat block (110) according to the first embodiment of the present invention. B ) is a perspective view showing the lower surface (S). As shown in Fig. 2, B ) has a gap (112) formed in a predetermined pattern.

[0065] Here, the gap (112) is, B ) serves to locally reduce heat directly transferred to the heat block (110). The term "void" is used herein to denote an area of ​​the thermally conductive heat block (110) that remains open, i.e., an area that forms a discontinuity in the thermally conductive material and is generally filled with air. The "void" may be filled with air as an air gap, but in another embodiment may be filled with an insulating material.

[0066] Although expressed in the singular, the term "void" is used herein to encompass both a single extended unfilled area, such as a trench, as well as multiple distinct unfilled areas. The term "void" refers to the lower surface (S) of the heat block (110). B ), preferably means a recessed portion that is open only on the side facing the heat source, e.g., the thermoelectric device(s).

[0067] The thermal conductivity of the heat block (110) is determined by the material of the heat block (110), the unit area, and the heat transfer rate at the unit temperature difference. In practice, the lower surface (S) of the heat block (110) B ) is partially blocked from direct contact with the heat block (110) by the gap (112). Accordingly, the heat transferred from the heat source to the heat block (110) can be locally reduced in the area where the gap (112) is formed.

[0068] Here, the heat source may be, for example, a thermoelectric element as described below. In general, the thermal uniformity of a heat block is greatly affected by the performance and thermal properties of the thermoelectric element. In the present specification, the thermoelectric element includes a Peltier element or a thermoelectric cooler (TEC). In particular, the thermal uniformity of a heat block may vary depending on the shape, number, and / or arrangement of the Peltier elements.

[0069] Generally, the primary factor determining the thermal uniformity of a heat block is the temperature difference between its corners and center. In thermal systems, heat loss at boundaries, known as the "edge effect," causes thermal imbalances. Specifically, as the thermoelectric element repeatedly heats and cools, more heat is lost at the corners of the heat block, leaving the center of the heat block warmer than the corners.

[0070] A heat block (110) according to one embodiment of the present invention is designed in consideration of the thermal properties of such a thermoelectric element, and the gap (112) is formed on the lower surface (S B ) is characterized by a higher density distribution in the central region than in the outer region. Here, the "central region" means the lower region (S B ) means an area including the center point of the heat block (110). According to the present invention, the lower surface (S) of the heat block (110) B) prevents heat from accumulating more in the center of the heat block (110), thereby improving heat uniformity. That is, by the gap (112) that serves to prevent heat accumulation in the center region of the heat block (110), the temperature gradient of the entire heat block (110) can be reduced to an acceptable level.

[0071] In addition, in the present invention (S B ) is set to improve the thermal uniformity of the heat block (110). For example, the area ratio of the gap (112) is set to the total area of ​​the lower surface (S B ) may be 12.5% ​​or more and less than 50% of the total area.

[0072] As shown in Fig. 2, the gap (112) according to the first embodiment of the present invention is in the form of a trench (S B ) may be formed. At this time, the gap (112) may include a plurality of linear depressions arranged parallel to each other, and the linear depressions may be formed symmetrically with respect to a center line passing through the center point. In addition, the linear depressions may be formed to have a wider width as they get closer to the center line.

[0073] Referring further to Fig. 3, the characteristics of the linear depressions (112a to 112g) along with the central region and the outer region are described. Fig. 3 shows the lower surface (S) of the heat block (110) according to the first embodiment of the present invention. B ) is a bottom view. In Fig. 3, the dotted rectangle represents a boundary line defining a central area and an outer area, and the inner area of ​​the dotted rectangle is referred to as the “central area” and the outer area of ​​the dotted rectangle is referred to as the “outer area”.

[0074] In this specification, the "central region" refers to a region including the center point of the heat block (110), and the "outer region" refers to a region other than the center point. That is, the "outer region" refers to the lower surface (S) of the heat block (110). B) means an area closer to the edge of the heat block (110) than the central area. In this specification, the terms "central area" and "outer area" are used to refer to the area (S B ) is explained by distinguishing between relatively close or far areas based on the center point.

[0075] Referring first to Fig. 3, a more detailed description will be given. As shown in Fig. 3, the central region is the lower surface (S) of the heat block (110). B ) is depicted as a dotted rectangle.

[0076] More specifically, the central region may be the inner region of the region indicated by the dotted rectangle whose vertex is a point located a first distance (d1) away from the center point of the heat block (110), and the outer region may be any other region. The first distance (d1) may be the maximum straight-line distance from the center point to the boundary point of the central region.

[0077] As illustrated in Fig. 3, the central region may be set to have a symmetrical shape. More specifically, it may have a symmetrical shape based on a center line in the X-axis direction passing through the center point and a center line in the Y-axis direction.

[0078] In addition, the second distance (d2) is the distance from the center point of the heat block (110) to the bottom of the heat block (110) (S B ) may be the distance to the vertex of the central region. At this time, the first diagonal distance (d1) defining the central region is smaller than the second distance (d2).

[0079] According to one embodiment of the present invention, the ratio of the area occupied by the linear depressions (112a to 112g) formed is larger in the central area than in the outer area. That is, the gap (112) is formed on the lower surface (S B) are distributed with a higher density in the central region than in the outer region. This characteristic applies to all cases where the first distance (d1) defining the dotted rectangle is smaller than the second distance (d2).

[0080] Referring further to FIG. 4, another example is further described in which the first distance (d1) defining the dotted rectangle is smaller than the second distance (d2). In FIG. 4, as in FIG. 3, the lower surface (S) of the heat block (110) according to the first embodiment of the present invention B ) is a low-level view.

[0081] As illustrated in Fig. 4, the central region may be set to include not only the center point but also some of the edges of the heat block (110). For example, the central region may include the lower surface (S) of the heat block (110). B ) and may include a portion of two mutually parallel sides among the four sides of the edge. The first distance (d1) and the second distance (d2) in Fig. 4 are also the same as those described for Fig. 3, and the first distance (d1) is smaller than the second distance (d2).

[0082] In another embodiment, the central region may be set as a circle or an oval rather than a dotted rectangle, but is not limited thereto. When the central region is set as a circle or an oval, the maximum diameter of the circle or oval is set as the first distance (d1), and the second distance (d2) is set as the lower surface (S) of the heat block (110), as in FIG. 3. B ) can be the distance from the center point to the vertex. Here, too, the first distance (d1) is smaller than the second distance (d2).

[0083] In this way, the first distance (d1) is the lower surface (S) of the heat block (110). B ) can be defined as the maximum distance or diameter in a geometric shape defining the central area from the center point of the heat block (110). In addition, the second distance (d2) is defined as the distance from the lower surface (S) of the heat block (110). B) may be the distance from the center point to the vertex. The central region formed so that the first distance (d1) is smaller than the second distance (d2) may be set differently depending on the shape, number, arrangement, and thermal properties of the thermoelectric elements used when the heat block (110) is heated and / or cooled. For example, the lower surface (S) of the present invention B ) The ratio of the outer area to the central area can be set in various ways, ranging from 1:9 to 9:1.

[0084] Next, the first embodiment of the present invention will be further described with reference to FIGS. 5 and 6. FIG. 5 is a plan view showing the upper surface of a heat block according to the first embodiment of the present invention. FIG. 6 is a cross-sectional view showing a cross-section taken along line A-A' of FIG. 5.

[0085] As shown in FIGS. 5 and 6, the lower surface (S) of the heat block (110) B ) is formed with linear depressions (112a to 112g) dug to a certain depth. The depth of the linear depressions (112a to 112g) is B ) and top surface (S T ) is smaller than the thickness between the sample wells, and in particular, it is preferable that the depth be set so as to secure a certain distance from the plurality of sample wells (111) that are open upward on the upper surface.

[0086] For example, the depth of the linear depressions (112a to 112g) may be about 0.5 mm. In this case, the lower surface (S B ) and the bottom (the deepest point of the part where the reaction vessel is accommodated) in the sample well (111) is preferably 0.5 mm or more. More preferably, the bottom (S B ) and the bottom of the sample well (111) is preferably greater than 0.5 mm. Accordingly, the linear depressions (112a to 112g) and the sample well (111) can be prevented from communicating with each other or damaging the durability of the heat block (110).

[0087] The plurality of linear depressions (112a to 112g) according to the first embodiment of the present invention may include a central depression (112d) formed across a central region and peripheral depressions (112a, 112b, 112c, 112e, 112f, 112g) distributed on both sides of the central depression (112d). At this time, the peripheral depressions (112a, 112b, 112c, 112e, 112f, 112g) may have a smaller width as they get farther away from the central depression (112d). In addition, the peripheral depressions (112a, 112b, 112c, 112e, 112f, 112g) may be spaced apart from each other at a wider interval as they get farther away from the central depression (112d).

[0088] The peripheral depressions (112a, 112b, 112c, 112e, 112f, 112g) according to the first embodiment of the present invention may be distributed in a line-symmetrical pattern with respect to the central depression (112d). For example, the two peripheral depressions (112a and 112g) distributed on the outside may have a shape that is symmetrical to each other. Similarly, the two peripheral depressions (112c and 112e) distributed on the inside may also have a shape that is symmetrical to each other.

[0089] In another embodiment, a pattern of voids (112) may be formed such that two or more central depressions are formed between which the center point of the heat block (110) is located, and the remaining peripheral depressions are distributed around the central depression. In another embodiment, the pattern of voids (112) may include a plurality of linear depressions, at least some of which are arranged to intersect.

[0090] Next, a heat block (110) according to a second embodiment of the present invention will be described with reference to FIG. 7. FIG. 7 shows the lower surface (S) of the heat block (110) according to the second embodiment of the present invention. B) is a perspective view. As shown in Fig. 7, the gap (112) is formed in a trench shape and may include a plurality of loop-shaped depressions having different perimeters.

[0091] Additionally, the gap (112) according to the second embodiment of the present invention may further include a linear depression that crosses a plurality of loop-shaped depressions and connects at least a portion of the outer region and the central region. In this case, the loop-shaped depressions may be distributed from the central region to the outer region while sharing the same center point.

[0092] According to the pattern of the gap (112) according to the second embodiment of the present invention, loop-shaped depressions are densely distributed in the central region, and linear depressions are formed across them. By reducing the heat transferred through the central region by the loop-shaped depressions, heat is prevented from accumulating more in the central region of the heat block (110), thereby improving heat uniformity. In particular, when six bar-type thermoelectric elements are arranged in parallel in a thermal cycler, heat can be prevented from accumulating in the heat block (110) at a position corresponding to the center of each thermoelectric element by these linear depressions.

[0093] Next, a heat block (110) according to a third embodiment of the present invention will be described with reference to FIG. 8. FIG. 8 shows the lower surface (S) of the heat block (110) according to the third embodiment of the present invention. B ) is a perspective view. As shown in Fig. 8, in the heat block (110) according to the third embodiment of the present invention, the gap (112) is formed as a circular depression.

[0094] The above circular depression may have a predetermined diameter and has a lower surface (S B) can be radially distributed based on the center point of the heat block (110). Furthermore, the gaps (112) can be formed in a point-symmetrical pattern based on the center point of the heat block (110). At this time, some of the plurality of depressions can be spaced apart from each other at a constant interval, and other parts can be formed so that the intervals become wider as they spread out toward the outer region.

[0095] In another embodiment of the present invention, the circular recesses may have different diameters. For example, a plurality of circular recesses distributed in the central region may have a larger diameter, while a plurality of circular recesses distributed in the peripheral region may have a relatively smaller diameter. In another embodiment of the present invention, the void (112) may include a plurality of recesses having a geometric cross-section other than a circular one. Here, the geometric cross-section refers to a cross-section having a shape such as a polygon, a streamline, or a circular loop.

[0096] In another embodiment of the present invention, the void (112) comprises a plurality of recessed portions having a geometric cross-section, and the lower surface (S) of the heat block (110) B ) can be formed in a pattern that is line-symmetrical about a centerline passing through the center point of the plurality of depressions. For example, a plurality of depressions can be formed such that the depressions closer to the center point have a larger area and the area decreases toward the outer region, and these can be formed in a line-symmetrical pattern. In another embodiment, these can be formed in a line-symmetrical and / or point-symmetrical pattern.

[0097] In the first to third embodiments of the present invention illustrated in FIGS. 2 to 8, the gaps (112) are designed in various patterns, but are not limited thereto. According to the present invention, the thermal uniformity of the heat block (110) can be improved by designing other patterns in which the gaps (112) are distributed at a higher density in the central region than in the peripheral region. That is, according to the present invention, it is possible to design a pattern having a heat transfer rate in the central region and a heat transfer rate in the peripheral region that are optimized to minimize the temperature difference between the corners and the central portion of the heat block (110).

[0098] Next, the thermoelectric element (120) in the thermal cycler according to one embodiment of the present invention will be further described with reference to FIGS. 9 and 10. FIG. 9 is a front view illustrating the arrangement of the thermoelectric element and the heat block of the thermal cycler according to one embodiment of the present invention. FIG. 10 is a cross-sectional view taken along the line B-B' of FIG. 9.

[0099] A thermal cycler according to one embodiment of the present invention is a thermal cycler to which a heat block (110) according to embodiments of the present invention is applied, and may be provided in a detection device for detecting a target analyte in a sample. As illustrated in FIG. 9, in the thermal cycler according to one embodiment of the present invention, a thermoelectric element (120) may be disposed closely to the heat block (110) and may be in thermal contact with at least a portion thereof. The thermoelectric element (120) illustrated in FIG. 9 may be a six-bar type Peltier element.

[0100] As previously explained, the thermal uniformity of a typical heat block can be affected by the performance and thermal properties of the thermoelectric element. A key factor determining thermal uniformity is the temperature difference between the corners and center of the heat block. Specifically, as the thermoelectric element repeatedly heats and cools, more heat is lost at the corners of the heat block, resulting in the center of the heat block remaining warmer than the corners.

[0101] As shown in Fig. 10, the heat transfer rate between the heat block (110) and the thermoelectric element (120) is changed by the gap (112). The lower surface (S) of the heat block (110) B ) formed in the heat block (110) prevents more heat from accumulating in the central region of the heat block (110), thereby improving heat uniformity. In other words, the heat transfer rate between the heat block (110) and the thermoelectric element (120) is B ) may have a smaller central area than the outer area. That is, the temperature gradient of the entire heat block (110) can be reduced to an acceptable level by the gap (112) that serves to prevent heat accumulation in the central area of ​​the heat block (110).

[0102] Specifically, the thermoelectric element (120) may be provided between the heat block (110) and the heat sink (not shown). The thermoelectric element (120) may generate heat flux at the junction of dissimilar materials using the Peltier effect. In addition, the thermoelectric element (120) may function as a heat pump by transferring heat to the heat block (110) or taking heat away from the heat block (110). In this case, the thermoelectric element (120) may be used for thermal cycling that repeats heating and cooling.

[0103] In a thermal cycler, a plurality of such thermoelectric elements (120) may be arranged adjacent to each other, and a thermal block (110) according to an embodiment of the present invention may be arranged thereon. For example, six bar-type Peltier elements may be arranged in parallel to divide the thermal zones of the thermal block (110) into at least six. In addition, by independently controlling each Peltier element, the temperature of the corresponding thermal zone can be individually controlled.

[0104] At this time, more or larger pores (112) are formed closer to the central region than to the peripheral region. Therefore, as mentioned above, the pores (112) located in the central region have a higher spatial density or individual size than the peripheral region, and the area in direct or indirect thermal contact with the thermoelectric element(s) (112) is smaller.

[0105] In one embodiment of the present invention, a thermal transfer member (not shown) may be further provided between the thermoelectric element (120) and the heat block (110). The thermal transfer member is provided with a material having high thermal conductivity, and may be provided with a tape, pad, film, or adhesive. For example, the thermal transfer member may be acrylic foam, PET, a graphite pad, or copper foil, and the material may be selected by considering adhesive strength, heat resistance, conductivity, and flame retardancy.

[0106] Next, a heat block (110) according to a fourth embodiment of the present invention will be described with further reference to FIGS. 11 and 12. FIG. 11 illustrates a lower surface (S) of a heat block (110) according to a fourth embodiment of the present invention. B ) is a perspective view showing the lower surface (S) of the heat block (110) according to the fourth embodiment of the present invention. B ) is a floor plan.

[0107] As shown in Fig. 11, the gap (112) according to the fourth embodiment of the present invention is formed in a trench shape (S) similar to the second embodiment of the present invention. B ) may be formed. At this time, the gap (112) may include a plurality of linear depressions arranged parallel to each other in the X-axis direction, and the linear depressions may be formed symmetrically with respect to a center line passing through the center point.

[0108] In addition, the heat block (110) according to the fourth embodiment of the present invention has a lower surface (S B), it may include a groove (113) formed in the Y-axis direction. The grooves (113) may be formed in multiple numbers between the thermoelectric elements thermally connected to the heat block (110). These grooves (113) are formed on the lower surface (S) of the heat block (110) at a depth shallower than the gap (112). B ) can be formed by being spaced apart at regular intervals while vertically stretching. At this time, the groove (113) is formed in the heat block (110) at a predetermined depth, and the gap (112) can be formed deeper than the groove (113). That is, the grooves (113) are arranged so as to space out the Peltier elements, thereby reducing the thermal influence of the thermoelectric elements on each other.

[0109] In a thermal cycler according to one embodiment of the present invention, a thermoelectric element (120) may be disposed closely with a heat block (110) to be in thermal contact with at least a portion thereof. Here, the thermoelectric elements may be six bar-type Peltier elements. Accordingly, for example, when six bar-type thermoelectric elements are disposed side by side in the thermal cycler, a groove (113) may be formed on both sides of each thermoelectric element. That is, the Peltier elements may be disposed in the heat block (110) at a certain distance from each other, and heat transfer may be achieved through direct or indirect thermal contact with a portion of the heat block (110) where the groove (113) and the gap (112) are not formed. In other words, by forming the groove (113), direct contact between the Peltier elements is blocked, and the groove (113) may serve as an insulating spacer between the Peltier elements.

[0110] Referring further to Fig. 12, the gap (112) and groove (113) according to the fourth embodiment of the present invention will be described. Unlike the second embodiment of the present invention, the gap (112) according to the fourth embodiment of the present invention illustrated in Fig. 12 may be formed such that the central recessed portion (112d) has a smaller width than the adjacent peripheral recessed portions (112c, 112e). At this time, the remaining peripheral recessed portions (112a, 112b, 112f, 112g) may be formed such that the widths thereof decrease as they get farther away from the central recessed portion (112d).

[0111] The linear depressions (112a to 112g) according to the fourth embodiment of the present invention, like the various shapes of the gaps (112) in the first to third embodiments, prevent more heat from accumulating in the center of the heat block (110) to improve heat uniformity. In particular, the central region in the fourth embodiment is formed on the lower surface (S B ) may include the center point of each of the Peltier elements thermally connected to the heat block (110).

[0112] More specifically, in the fourth embodiment, the central recessed portion (112d) among the linear recessed portions (112a to 112g) may be formed to pass through the central portion of each of the Peltier elements. Although not illustrated in FIG. 12, the central region in the fourth embodiment of the present invention is formed on the lower surface (S) of the heat block (110), as described above with reference to FIG. 4. B ) can be defined by a dotted rectangle (not shown) including the center point of the rectangle and part of two of the four sides of the edge that are parallel to each other. That is, the inner area of ​​the rectangle can be the central area, and the other area can be the outer area. The central area of ​​this rectangle can be defined by the first distance (not shown) and the second distance (not shown), as in Fig. 4.

[0113] The lower surface (S) of the heat block (110) according to the fourth embodiment of the present invention B) is the maximum distance from the center point of the square to the vertex of the square, the first distance is the bottom (S B ) from the center point (S) B ) is smaller than the second distance, which is the distance to the vertex of the first surface. The ratio of the area occupied by the linear depressions (112a to 112g) formed according to the fourth embodiment of the present invention is larger in the central area than in the outer area. That is, the gap (112) is formed on the lower surface (S B ) are distributed at a higher density in the central region than in the outer region. In this way, since the total area of ​​the voids (112) formed in the central region is larger than the total area of ​​the voids (112) formed in the outer region, uneven heat accumulation of the six bar-type Peltier elements used when the heat block (110) is heated and / or cooled can be alleviated or prevented.

[0114] In addition, as shown in FIG. 12, the groove (113) of the heat block (110) according to the fourth embodiment of the present invention is lower (S B ) may include first side grooves (113a) and second side grooves (113g) formed on both sides of the first side groove (113a), and first to fifth grooves (113b, 113c, 113d, 113e, 113f) formed at regular intervals therebetween.

[0115] The width of the first side groove (113a) and the second side groove (113g) may be equal to or smaller than the width of the first to fifth grooves (113b, 113c, 113d, 113e, 113f). These grooves (113a to 113f) may be formed on the lower surface (S) of the heat block (110). B ), direct contact between the Peltier elements is blocked. The Peltier elements can be arranged so that the grooves (113a to 113f) are located on both sides of the Peltier elements, and the grooves (113a to 113f) can serve as insulating spacers.

[0116] One embodiment of the present disclosure may relate to a detection device for detecting a target analyte in a sample. As used herein, a "sample" may include biological samples (e.g., cells, tissues, and fluids from biological sources) and non-biological samples (e.g., food, water, and soil). The biological samples may be viruses, bacteria, tissues, cells, blood (e.g., whole blood, plasma, and serum), lymph, bone marrow fluid, saliva, sputum, swabs, aspirations, milk, urine, feces, eye fluid, semen, brain extracts, spinal fluid, synovial fluid, thymic fluid, bronchial lavage fluid, ascites, and amniotic fluid. Additionally, the sample may include natural and synthetic nucleic acid molecules isolated from a biological source. According to one embodiment of the present invention, the sample may include additional substances such as water, deionized water, saline solution, pH buffer, acidic solution, or basic solution.

[0117] A thermal cycler according to one embodiment of the present specification may include a nucleic acid amplification device. A nucleic acid amplification device refers to a device capable of performing a nucleic acid amplification reaction to amplify a nucleic acid having a specific nucleotide sequence. Methods for amplifying the nucleic acid include polymerase chain reaction (PCR), ligase chain reaction (LCR), transcription-mediated amplification, nucleic acid sequence-based amplification (NASBA), rolling circle amplification (RCA), and Q-Beta Replicase.

[0118] A thermal cycler according to one embodiment of the present disclosure may be a device that performs a nucleic acid amplification reaction while undergoing temperature changes. For example, to amplify DNA (deoxyribonucleic acid) having a specific base sequence, the nucleic acid amplification device may perform a denaturing step, an annealing step, and an extension (or amplification) step.

[0119] The denaturation step is a step in which a solution containing a sample and reagents containing double-stranded DNA as a template nucleic acid is heated to a specific temperature, for example, about 95°C, to separate the double-stranded DNA into single-stranded DNA. The annealing step is a step in which an oligonucleotide primer having a nucleotide sequence complementary to the nucleotide sequence of the nucleic acid to be amplified is provided, and the primer is cooled to a specific temperature, for example, 60°C, together with the separated single-stranded DNA, to bind the primer to a specific nucleotide sequence of the single-stranded DNA to form a partial DNA-primer complex. The extension step is a step in which, after the annealing step, the solution is maintained at a specific temperature, for example, 72°C, to allow a DNA polymerase to form double-stranded DNA based on the primer of the partial DNA-primer complex.

[0120] By repeating the three steps described above, for example, 10 to 50 times, DNA having the specific nucleotide sequence can be exponentially amplified. In some cases, the nucleic acid amplification device can perform the annealing and extension steps simultaneously. In this case, the nucleic acid amplification device can complete the first cycle by performing two steps: a denaturation step and an annealing / extension step.

[0121] In particular, a thermal cycler according to one embodiment of the present specification may be a device that performs a nucleic acid amplification reaction and a reaction that generates an optical signal dependent on the presence of a nucleic acid while accompanying a change in temperature, and detects the generated optical signal.

[0122] A thermal cycler according to one embodiment of the present disclosure may include a thermal module, an optical module, and a main control unit. The thermal module may include the heat block (110) of the present invention as described above. The thermal module according to one embodiment may perform thermal cycling by applying heat to the heat block (110) and cooling the heat block (110). For example, the thermal module may perform a nucleic acid amplification reaction of a sample while performing thermal cycling. At this time, the thermal module may further include a heat sink, a cooling fan, a control circuit board, etc., and thermal cycling may be performed through the operation of these.

[0123] The optical module may include a luminescence module and a detection module. In one embodiment, the luminescence module supplies an appropriate optical stimulus to a sample accommodated in the heat block (110), and the detection module detects an optical signal generated from the sample in response thereto. The optical signal may be luminescence, phosphorescence, chemiluminescence, fluorescence, polarized fluorescence, or another colored signal. The optical signal may be an optical signal generated in response to an optical stimulus applied to the sample.

[0124] The above description is merely an illustrative illustration of the technical idea of ​​the present invention, and those skilled in the art will appreciate that various modifications and variations can be made without departing from the essential quality of the present invention. Therefore, the embodiments disclosed in the present invention are intended to illustrate, rather than limit, the technical idea of ​​the present invention, and the scope of the technical idea of ​​the present invention is not limited by these embodiments. The scope of protection of the present invention should be interpreted by the following claims, and all technical ideas within a scope equivalent thereto should be interpreted as being included in the scope of the rights of the present invention.

Claims

1. A heat block for performing multiple reactions. The above heat block has an upper surface and a lower surface having a length and a width, A plurality of sample wells open upward are formed on the upper surface. In the above, a gap is formed in a predetermined pattern, A heat block characterized in that the ratio of the area occupied by the above-mentioned gap formation is larger in the central area than in the outer area of ​​the lower surface.

2. In paragraph 1, A heat block characterized in that the above gap is formed in the shape of a trench on the lower surface.

3. In paragraph 2, A heat block characterized in that the above gap includes a plurality of linear depressions arranged parallel to one another.

4. In paragraph 3, The above plurality of linear depressions are: A heat block characterized by including a central depression formed across the central area and peripheral depressions distributed on both sides based on the central depression.

5. In paragraph 4, A heat block characterized in that the peripheral depression has a smaller width the farther away it is from the central depression.

6. In paragraph 4, A heat block characterized in that the peripheral depressions are spaced apart from each other at a wider interval the farther away they are from the central depression.

7. In paragraph 5, A heat block characterized in that the central recessed portion has a smaller width than adjacent peripheral recessed portions among the peripheral recessed portions.

8. In paragraph 7, A heat block characterized in that, among the above peripheral depressions, the remaining peripheral depressions, excluding the adjacent peripheral depressions, have a smaller width the farther away they are from the central depression.

9. In paragraph 8, A heat block characterized in that the remaining peripheral depressions are spaced apart from each other by a wider gap the farther away they are from the adjacent peripheral depressions.

10. In paragraph 2, A heat block characterized in that the above gap comprises a plurality of linear depressions, at least some of which are arranged intersectingly.

11. In paragraph 1, A heat block characterized in that the above predetermined pattern includes a point-symmetric pattern.

12. In paragraph 1, A heat block characterized in that the above predetermined pattern includes a line-symmetric pattern.

13. In paragraph 2, A heat block characterized in that the above gap comprises a plurality of loop-shaped depressions having different circumferences.

14. In paragraph 13, A heat block characterized in that the above gap further includes a linear depression extending across the plurality of loop-shaped depressions and connecting at least a portion of the outer region and the central region.

15. In paragraph 13, A heat block characterized in that the above loop-shaped recessed portions are distributed from the central region to the outer region while sharing the same center point.

16. In paragraph 1, A heat block characterized in that the above gap includes a plurality of recessed portions having a geometric cross-section.

17. In paragraph 16, A heat block characterized in that the plurality of recessed portions include a plurality of circular recessed portions having a predetermined diameter.

18. In paragraph 17, A heat block characterized in that the plurality of circular depressions are distributed radially based on the center point of the lower surface.

19. In paragraph 1, A heat block characterized in that the ratio of the area of ​​the gap to the total area of ​​the above surface is set to improve the heat uniformity of the heat block.

20. In paragraph 1, The above-mentioned lower surface includes a plurality of grooves formed at a depth shallower than the above-mentioned gap, A heat block characterized in that the above grooves are formed vertically across the surface and spaced apart at regular intervals.

21. A thermal cycler comprising a heat block according to paragraph 1, Further comprising a thermoelectric element in thermal contact with at least a portion of the lower surface of the above heat block; A thermal cycler, characterized in that the heat transfer rate between the above-mentioned heat block and the above-mentioned thermoelectric element varies depending on the gap distributed on the lower surface.

22. In paragraph 21, A thermal cycler, wherein the heat transfer rate between the heat block and the thermoelectric element is smaller in the central area than in the outer area of ​​the lower surface.

23. In paragraph 21, A thermal cycler further comprising a thermal transfer member interposed between the heat block and the thermoelectric element.

24. Heat block for performing multiple reactions; A thermoelectric element in thermal contact with at least a portion of the lower surface of the above heat block; and It includes a thermal transfer member interposed between the above heat block and the above thermoelectric element, The above heat block is, It has upper and lower surfaces having length and width, A plurality of sample wells open upward are formed on the upper surface. In the above, a gap is formed in a predetermined pattern, The ratio of the area occupied by the above-mentioned gap is greater in the central area than in the outer area of ​​the above-mentioned surface, A thermal cycler, characterized in that the heat transfer rate between the above-mentioned heat block and the above-mentioned thermoelectric element is smaller in the central area than in the outer area of ​​the lower surface due to the gap distributed on the lower surface.

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