In vitro diagnostic chip with multiple hydrophilic properties

Abstract

An in vitro diagnostic chip having multiple hydrophilic properties is disclosed that can differentially control the flow speed of a liquid sample to distribute the liquid sample evenly to the corners and edge regions of a reaction space. The in vitro diagnostic chip having multiple hydrophilic properties includes a well array including a plurality of wells; and a multiple hydrophilic coating layer that is coated on the well array and controls the flow speed of the sample differently from each other. The hydrophilic coating layer is formed on the well array so that the central region of the well array has high hydrophilicity and the peripheral region of the well array has low hydrophilicity, thereby preventing the generation of air pockets in the reaction space. This makes it possible to prevent errors caused by air pockets in PCR test results.

Description

[Technical Field]

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2021-0081935, filed on June 23, 2021, and all contents disclosed in the documents of this Korean Patent Application are incorporated herein by reference.

[0002] The present invention relates to an in vitro diagnostic chip having multiple hydrophilic properties, and more particularly, to an in vitro diagnostic chip having multiple hydrophilic properties that can differentially control the flow rate of a liquid sample to uniformly distribute the liquid sample even to corners and edge regions of a reaction space. [Background technology]

[0003] Gene amplification is an essential process in molecular diagnostics, and is a technique for repeatedly replicating and amplifying specific base sequences in trace amounts of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in a sample. Among these, polymerase chain reaction (PCR) is a representative gene amplification technique and consists of three steps: DNA denaturation, primer annealing, and DNA extension. Each step is dependent on the temperature of the sample, so DNA can be amplified by repeatedly changing the temperature of the sample.

[0004] Traditionally, PCR has typically been performed in 96- or 384-microwell plates. When higher throughput is required, traditional microplate PCR methods require increased reagent usage, making them less cost-effective or efficient. On the other hand, reducing the PCR reaction volume can reduce reagent consumption and, with the reduced thermal mass of the reaction volume, shorten amplification times. This strategy can also be implemented in an array format (mxn), resulting in multiple, smaller reaction volumes. Additionally, the use of arrays allows for scalable, high-throughput assays with increased quantitative sensitivity, dynamic range, and specificity.

[0005] Using a very large number of sequences in a very small reaction volume, digital polymerase chain reaction (dPCR) can be performed. Results from dPCR can be used to detect and quantify the concentration of rare alleles, provide absolute quantification of nucleic acid samples, and sensitively measure low nucleic acid concentrations.

[0006] While most quantitative polymerase chain reaction (qPCR) platforms are designed for sample-specific analysis, where PCR results must be addressable for post-hoc analysis, dPCR does not analyze the specific location of each PCR result, but simply the number of positive and negative target copies per sample. Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem of the present invention is to address this issue, and an object of the present invention is to provide an in vitro diagnostic chip having multiple hydrophilic properties that can differentially control the flow rate of a liquid sample to uniformly distribute the liquid sample even to corners and edge regions of a reaction space. [Means for solving the problem]

[0008] To achieve the object of the present invention, an in vitro diagnostic chip having multiple hydrophilicities according to one embodiment includes a well array including a plurality of wells; and multiple hydrophilic coating layers coated on the well array to control sample flow rates different from each other. [Effects of the Invention]

[0009] In such an in vitro diagnostic chip having multiple hydrophilic properties, a hydrophilic coating layer is formed on the well array so that the central region of the well array has high hydrophilicity and the peripheral region of the well array has low hydrophilicity, thereby preventing the formation of air pockets in the reaction space, thereby preventing errors in PCR test results due to air pockets. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a perspective view illustrating an in vitro diagnostic chip having multiple hydrophilic properties according to an embodiment of the present invention. [Figure 2] 2 is a perspective view of the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 1 with a guide member and a well cover removed. FIG. [Figure 3] FIG. 2 is an exploded perspective view illustrating the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 1. [Figure 4] 4 is a cross-sectional view illustrating the bonding relationship of the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 3. FIG. [Figure 5] FIG. 4 is an exploded perspective view illustrating multiple films of the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 3. [Figure 6] FIG. 4 is an exploded perspective view illustrating the tip housing and the inserting member shown in FIG. 3. [Figure 7] 4 is a perspective view for schematically explaining the introduction of a sample into the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 3 and the release of air. FIG. [Figure 8]4 is a diagram illustrating the sequential introduction of a sample through multiple hydrophilic coating layers coated on the well array shown in FIG. 3. DETAILED DESCRIPTION OF THE INVENTION

[0011] To achieve the object of the present invention, an in vitro diagnostic chip having multiple hydrophilicities according to one embodiment includes a well array including a plurality of wells; and multiple hydrophilic coating layers coated on the well array to control sample flow rates different from each other.

[0012] In one embodiment, the multiple hydrophilic coating layers may have high hydrophilicity corresponding to a central region of the well array and low hydrophilicity corresponding to a peripheral region of the well array.

[0013] In one embodiment, the in vitro diagnostic chip having multiple hydrophilic properties may further include a chip housing; and an inserting member that is inserted into the chip housing and accommodates the well array.

[0014] In one embodiment, the inserting member may include silicone.

[0015] In one embodiment, the chip housing may include a side portion having one or more mating holes or mating grooves formed therein, and the inserting member may include a side portion having one or more mating protrusions formed therein that are inserted into the mating holes.

[0016] In one embodiment, the inserting member may be coupled to the upper surface of the chip housing through a bottom surface thereof, and a receiving groove may be formed on the upper surface of the inserting member to receive the well array.

[0017] In one embodiment, the upper surface of the inserting member may be formed with a sample injection port through which a sample is injected, a sample injection section having a width that narrows as it goes from the sample injection port to the well array, and an air vent connecting the outer surface of the well array to the maximum expansion portion of the sample injection section.

[0018] In one embodiment, the chip housing is formed with a chip inlet corresponding to the sample inlet, and the sample inlet and the chip inlet can be in communication with each other.

[0019] In one embodiment, the in vitro diagnostic chip having multiple hydrophilic properties may further include a guide cap having a plug protrusion formed thereon, the guide cap being inserted into the sample inlet through the chip inlet.

[0020] In one embodiment, the air vent may include a first air passage connecting one side of the well array to one side of the sample injection section, and a second air passage connecting the other side of the well array to the other side of the sample injection section.

[0021] In one embodiment, the in vitro diagnostic chip having multiple hydrophilic properties may further include an EEPROM housed in the chip housing and storing data for chip history management.

[0022] In one embodiment, the in vitro diagnostic chip having multiple hydrophilic properties further includes films covering the well array, and the films may include an emission film.

[0023] In one embodiment, the in vitro diagnostic chip having multiple hydrophilicities may further include a well cover that covers the well array; and a guide member that covers the well cover and exposes a portion of the well cover through a hollow hole formed therein.

[0024] The present invention will now be described in more detail with reference to the accompanying drawings. Because the present invention can be modified in various ways and take on various forms, specific embodiments are shown by way of example in the drawings and will be described in detail herein. However, it should be understood that this is not intended to limit the present invention to the specific disclosed form, and that the present invention encompasses all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention.

[0025] In the drawings, like reference numerals have been used to refer to like elements throughout the description, and the dimensions of structures in the drawings have been exaggerated to make the invention clearer.

[0026] Terms such as "first," "second," etc. are used to describe various components, but the components are not limited by these terms. These terms are used only to distinguish one component from another. For example, a first component may be referred to as a "second component," and similarly, a second component may be referred to as a "first component," without departing from the scope of the present invention. A singular term includes a plural term unless the context clearly dictates otherwise.

[0027] In this specification, the terms "comprise" or "have" and the like are intended to specify the presence of a stated feature, number, step, operation, component, part, or combination thereof, but should be understood as not precluding the presence or possible addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0028] Furthermore, unless otherwise defined, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by those skilled in the art. Terms defined in commonly used dictionaries should be interpreted to have a meaning consistent with the contextual meaning of the relevant art, and should not be interpreted as idealized or overly formal unless expressly defined herein.

[0029] FIG. 1 is a perspective view illustrating an in vitro diagnostic chip having multiple hydrophilic properties according to an embodiment of the present invention. FIG. 2 is a perspective view of the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 1 with a guide member and a well cover removed. FIG. 3 is an exploded perspective view illustrating the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 1. FIG. 4 is a cross-sectional view illustrating the coupling relationship of the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 3. FIG. 5 is an exploded perspective view illustrating multiple films of the in vitro diagnostic chip having multiple hydrophilic properties shown in FIG. 3.

[0030] 1, 2, 3, 4 and 5, an in vitro diagnostic chip having multiple hydrophilic properties according to one embodiment of the present invention includes a base member 110, a chip housing 120, an inserting member 130, a well array 140, an EEPROM 150, films 160, a well cover 170, a chip cover 180, and a guide cap 190.

[0031] The base member 110 is disposed on the lower surface of the chip housing 120 .

[0032] A hole for inserting the inserting member 130 and a groove for inserting the EEPROM 150 are formed in the top of the chip housing 120. The hole for inserting the inserting member 130 is covered by the base member 110. A chip inlet corresponding to the sample inlet is formed in the side of the chip housing 120, and the sample inlet and the chip inlet are in communication with each other.

[0033] The inserting member 130 is inserted into a hole formed in the upper part of the chip housing 120 and houses the well array 140 and the EEPROM 150. The inserting member 130 may be made of a silicon material. The upper surface of the inserting member 130 is formed with a sample injection port through which a sample is injected, a sample injection portion having a width that narrows from the sample injection port toward the well array 140, and an air vent that connects the outer surface of the well array 140 and the maximum expansion portion of the sample injection portion.

[0034] The well array 140 includes a plurality of wells and is housed in the inserting member 130. In this embodiment, the number of wells is illustrated as nine, but is not limited to this. The well array 140 has an overall rectangular shape.

[0035] The EEPROM 150 is accommodated in a groove formed in the inserting member 130 and stores data for chip history management. The EEPROM 150 allows for patient information to be written immediately to the ROM while taking a sample, eliminating the need to manually write patient information or attach barcode tape. Furthermore, storing a security key in the EEPROM prevents the in vitro diagnostic chip from being illegally copied and used, and facilitates chip history management.

[0036] The films 160 cover the inserting member 130 that houses the well array 140. The films 160 include a tape 161 disposed underneath, an elastic buffer layer 162, an OCA film 163, an emission film 164, a moisture-proof protective film 165, and a carrier 166 for protecting the moisture-proof protective film. In this embodiment, the emission film 164 blocks excitation light generated from a light source (not shown) and transmits emission light generated from the sample in the reaction space 240.

[0037] The emission film 164 may include a base medium, a semi-hardened photoresist, and a pigment. The base medium may be a transparent synthetic resin, glass, metal oxide, or the like. In this embodiment, the base medium may include an epoxy resin, a silicone resin, or the like that does not emit fluorescence or phosphorescence and has biocompatible properties. The semi-hardened photoresist includes a photoresist that is dispersed in the base medium and solidified by thermal curing, drying, photocuring, or the like. For example, the semi-hardened photoresist may include a negative photoresist. In another embodiment, the semi-hardened photoresist may include a positive photoresist.

[0038] Without intending to limit the scope of the present invention by theory, in order to explain the present invention in more detail, the reason why the emission film 164 of the present invention has unique and excellent optical properties will be explained as follows.

[0039] A typical color filter selectively transmits light by immobilizing a pigment in a transparent medium and allowing the pigment to absorb light of a certain wavelength and transmit light of other wavelengths. Photoresists have the characteristic of changing their chemical and optical properties in response to short-wavelength light such as ultraviolet light, blue light, and green light. Therefore, when semi-hardened photoresists are used in color filters, there is a problem that their optical properties change over time. Therefore, conventional color filters use thermosetting materials that are either completely saturated with short-wavelength light such as ultraviolet light, blue light, and green light, or that do not change even when exposed to short-wavelength light.

[0040] However, since the emission film 164 of the present invention is used in disposable experimental equipment that is not used for long periods of time, it does not need to maintain the same optical properties for a long period of time, but only needs to maintain the optical properties temporarily for a relatively short period of time during the experiment. Specifically, when irradiated with short-wavelength light such as ultraviolet light, blue light, or green light, the semi-hardened photoresist absorbs the short-wavelength light for a certain period of time, temporarily functioning as an optical filter with excellent properties. However, over time, it becomes saturated with short-wavelength light and loses most of its optical filtering function. Therefore, semi-hardened photoresists could not be used in conventional color filters due to their long-term stability.

[0041] Conversely, the present invention utilizes the property of the semi-cured photoresist to absorb short wavelength light as it is saturated and stabilized by short wavelength light such as ultraviolet light, blue light, and green light, thereby realizing an emission film 164 with excellent optical properties that can be used in disposable experimental equipment. That is, the present invention succeeds in producing an emission film 164 with excellent properties regardless of the direction of incident light, which was not possible with existing color filters or interference filters, by primarily blocking excitation light with the pigment and secondarily blocking excitation light with the semi-cured photoresist.

[0042] The pigment is a material that absorbs light of a certain wavelength, and examples thereof include yellow pigments, red pigments, blue pigments, and green pigments. In this embodiment, the pigment includes a yellow pigment. Examples of the yellow pigment include inorganic dyes such as lead chromate, calcium yellow, yellow oxides, complex inorganic color pigments, and bismuth vanadate, and organic dyes such as arylamide, diarylide, benzimidazolone, disazo condensation, organic metal complexes, isoindoline, quinophthalone, anthrapyrimidine, and flavanthrone.

[0043] The well cover 170 has a size that can cover the well array 140 and is placed on the film 160 that is placed on the inserting member 130 that accommodates the well array 140. The well cover 170 presses the film 160 by a pressing action by the user, thereby pressurizing the well array 140 placed underneath the film 160.

[0044] The chip cover 180 is fastened to the chip housing 120 so that the inserting member 130, the well array 140, the EEPROM 150, the films 160, and the well cover 170 are fixed. A circular hole is formed in the center of the chip cover 180 to expose the well cover 170 so that the user can press the well cover 170.

[0045] The guide cap 190 is formed with a plug protrusion that is inserted into the sample inlet through the chip inlet.

[0046] FIG. 6 is an exploded perspective view illustrating the tip housing and inserting member shown in FIG.

[0047] 6, chip housing 120 has a rectangular shape. First, second, and third mating holes 121, 122, and 123 are formed on the sides of chip housing 120. Although not shown, fourth, fifth, and sixth mating holes are also formed on the sides of chip housing 120, facing first, second, and third mating holes 121, 122, and 123, respectively.

[0048] The inserting member 130 is provided on its side with a first mating protrusion 131 that is inserted into the first mating hole 121 of the chip housing 120, a second mating protrusion 132 that is inserted into the second mating hole 122 of the chip housing 120, and a third mating protrusion 133 that is inserted into the third mating hole 123 of the chip housing 120. Although not shown, fourth, fifth, and sixth mating protrusions are formed opposite the first mating protrusion 131, the second mating protrusion 132, and the third mating protrusion 133, respectively. The fourth, fifth, and sixth mating protrusions formed on the inserting member 130 are inserted into the fourth, fifth, and sixth mating holes formed in the chip housing, respectively.

[0049] The upper surface of the inserting member 130 is formed with a sample injection port 135 through which a liquid sample is injected, a sample injection section 136 having a width that narrows as it goes from the sample injection port 135 to the well array 140, and an air vent 137 that connects the outer surface of the well array 140 to the maximum expansion section of the sample injection section 136.

[0050] Figure 7 is a perspective view that schematically illustrates the introduction of a sample into the in vitro diagnostic chip having multiple hydrophilic layers shown in Figure 3 and the release of air. Figure 8 is a diagram that sequentially illustrates the introduction of a sample through the multiple hydrophilic coating layers coated on the well array shown in Figure 3.

[0051] 7 and 8, a liquid sample introduced into a sample inlet gradually spreads downward due to gravity. A first hydrophilic coating layer (HYD-H) is coated on the central region of the well array, and a second hydrophilic coating layer (HYD-L) having a lower hydrophilicity than the first hydrophilic coating layer (HYD-H) is coated on the first and second peripheral regions of the well array. Therefore, the flow rate of the liquid sample in the central region of the well array is faster than the flow rate of the liquid sample in the first and second peripheral regions of the well array.

[0052] Specifically, the liquid sample introduced into the sample inlet reaches the center well of the top row first, and the air present in the center well of the top row moves to the left and right wells and the bottom wells of the top row.

[0053] The liquid sample then reaches the left and right wells in the top row and the center well in the middle row, and the air in the left and right wells in the top row and the center well in the middle row moves to the lower wells.

[0054] The liquid sample then reaches the left and right wells in the middle row and the center well in the bottom row, and the air in those wells moves to the lower wells.

[0055] The liquid sample then reaches the left and right wells in the bottom row, at which point the air present in the left and right wells in the bottom row is released to the outside through the air vent.

[0056] In this way, the air is released to the end through the air vent, which is a passage through which air can escape due to the difference in hydrophilicity of the well array, thereby preventing bubble trapping.

[0057] As described above, according to the present invention, by forming a hydrophilic coating layer on the well array so that the central region of the well array has high hydrophilicity and the peripheral region of the well array has low hydrophilicity, it is possible to prevent the formation of air pockets in the reaction space, thereby preventing errors in PCR test results due to air pockets.

[0058] Although the present invention has been described with reference to the embodiments, those skilled in the art will understand that the present invention can be modified and changed in various ways without departing from the spirit and scope of the present invention as defined in the claims below. [Industrial Applicability]

[0059] The present invention has industrial applicability in devices for testing biochemical substances, blood testing devices, disease testing devices, etc., for research, medical care, disaster prevention, livestock farming, pet treatment, etc. [Explanation of symbols]

[0060] 110: Base material 120: Chip housing 130: Inserting member 135: Sample injection port 136: Sample injection section 137: Air Vent 121, 122, 123: Mating groove 131, 132, 133: mating protrusions 140: Well array 150:EEPROM 160: Films 170: Well Cover 180: Chip cover 190: Guide cap HYD-H: First hydrophilic coating layer HYD-L: Second hydrophilic coating layer

Claims

1. a well array comprising a plurality of wells; a plurality of hydrophilic coating layers coated on the well array to control different sample flow rates; A chip housing; an inserting member that is inserted into the chip housing and accommodates the well array; the inserting member is coupled to the top surface of the chip housing through a bottom surface thereof; a receiving groove is formed on the upper surface of the inserting member to receive the well array; An in vitro diagnostic chip having multiple hydrophilic properties, characterized in that the upper surface of the inserting member is formed with a sample injection port through which a sample is injected, a sample injection section having a width that narrows as it goes from the sample injection port to the well array, and an air vent connecting the outer surface of the well array and the maximum expansion section of the sample injection section.

2. 2. The in vitro diagnostic chip with multiple hydrophilic properties according to claim 1, wherein the multiple hydrophilic coating layer has high hydrophilicity corresponding to a central region of the well array and low hydrophilicity corresponding to a peripheral region of the well array.

3. The in-vitro diagnostic chip having multiple hydrophilic properties according to claim 1 , wherein the inserting member comprises silicon.

4. the chip housing includes a side portion having one or more mating holes or mating grooves formed therein; The in-vitro diagnostic chip according to claim 1 , wherein the inserting member includes a side portion on which one or more fitting protrusions to be inserted into the fitting hole are formed.

5. 2. The in-vitro diagnostic chip having multiple hydrophilic properties according to claim 1, wherein the chip housing is formed with a chip inlet corresponding to the sample inlet, and the sample inlet and the chip inlet are in communication with each other.

6. The in-vitro diagnostic chip having multiple hydrophilic properties according to claim 5, further comprising a guide cap having a plug protrusion formed thereon, the guide cap being inserted into the sample inlet through the chip inlet.

7. 2. The in vitro diagnostic chip having multiple hydrophilic properties according to claim 1, wherein the air vent includes a first air passage connecting one side of the well array to one side of the sample injection portion, and a second air passage connecting the other side of the well array to the other side of the sample injection portion.

8. 2. The in vitro diagnostic chip having multiple hydrophilic properties according to claim 1, further comprising an EEPROM accommodated in the chip housing and storing data for chip history management.

9. Further comprising a film covering the well array, The in-vitro diagnostic chip according to claim 1 , wherein the films include an emission film.

10. a well cover that covers the well array; The in-vitro diagnostic chip according to claim 1 , further comprising: a guide member covering the well cover and exposing a portion of the well cover through a hollow hole formed therein.

Images