Pore ​​chip housing and microparticipant measurement system

Abstract

A pore chip package 700 houses a pore chip 110. A main body 710 includes a chip receiving space 720, a first chamber 722, and a second chamber 724. The pore chip 110 is housed in the chip receiving space 720 and held in a vertical plane. The first chamber 722 and the second chamber 724 are adjacent to each other in the horizontal direction and are divided by the pore chip 110.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to measurement using a pore device. STATE OF THE ART

[0002] A method for measuring particle size distribution, the so-called electrical sensor area method (based on the Coulter principle), is already known. In this measurement method, an electrolyte solution containing particles is passed through a pore called a nanopore. As each particle passes through the pore, the electrolyte solution in the pore decreases in volume by an amount equal to the volume of the particle, thereby increasing the electrical resistance of the pore. The volume (or particle size) of the particle can therefore be determined by measuring the electrical resistance of the pore.

[0003] Fig. Figure 1 is a block diagram showing a microparticle measurement system 1R that uses the electrical sensor area method. The microparticle measurement system 1R consists of a pore device 100, a measuring device 200R, and a data processor 300.

[0004] The interior of the pore device 100 is filled with an electrolyte solution 2 containing particles 4 to be detected. The interior of the pore device 100 is divided by a pore chip 102 into two chambers, each containing an electrode 106 and an electrode 108. Under the potential difference generated between the electrode 106 and the electrode 108, an ion current flows between the electrodes, causing the particles 4 to migrate from one chamber through the pore 104 into the other chamber while driven by electrophoresis.

[0005] The measuring device 200R generates a potential difference between the electrode pair 106, 108 and acquires information correlated with the resistivity Rp between the electrode pair. The measuring device 200R includes a transimpedance amplifier 210, a voltage source 220, and a digitizer 230. The voltage source 220 is configured to generate a potential difference Vb between the electrode pair 106, 108. The potential difference Vb provides a driving force for electrophoresis as well as a bias signal for measuring the resistivity Rp.

[0006] The microcurrent Is flows between the electrode pair 106, 108, which is inversely proportional to the specific resistance of the pore 104. Is=Vb / Rp

[0007] The transimpedance amplifier 210 is designed to convert the microcurrent Is into a voltage signal Vs. With a conversion gain of r, the following equation applies. Vs=−r×Is

[0008] Substituting equation (1) into equation (2), we obtain the following equation (3). Vs=−Vb×r / Rp

[0009] The digitizer 230 is configured to convert the voltage signal Vs into digital data Ds. In this way, the voltage signal Vs, which is inversely proportional to the resistivity Rp of the pore 104, can be measured with the measuring device 200R.

[0010] Fig. 2 is an example waveform diagram of the microcurrent Is measured by the measuring device 200R. Note that the ordinates and abscissas of a waveform diagram and a timing chart referred to herein are enlarged or reduced accordingly for ease of understanding, and the waveforms shown here are also simplified, exaggerated, or emphasized for ease of understanding.

[0011] During the brief period of time each particle passes through, the resistivity Rp of pore 104 increases. Therefore, the current Is decreases in a pulsating manner each time a particle passes. The amplitude of each current pulse correlates with the particle size. The data processor 300 is configured to process the digital data Ds and analyze the number, particle size, or the like of the particles 4 contained in the electrolyte solution 2. STATE OF THE ART LITERATURE PATENT LITERATURE Patent Document 1: JP 2017-016881 A Patent Document 2: JP 2014-219235 A Patent Document 3: JP 2018-054594 A Patent 4: WO 2002 / 084306 SUMMARY OF THE INVENTION TECHNICAL PROBLEM

[0012] Fig. Figure 3 is a cross-sectional view of a pore device studied by the present inventors. A pore device 100R includes a pore chip 110 and a pore chip package 800R. The pore chip 110 includes a pore 112.

[0013] The pore chip package 800R is configured to support the pore chip 110 in a horizontal plane. The pore chip package 800R has a first chamber 802 and a second chamber 804 within it, separated by the pore chip 110. The first chamber 802 communicates with the outside world via a flow path 806, while the second chamber 804 communicates with the outside world via a flow path 808.

[0014] Before measurement, a solution is injected into the first chamber 802 through the flow path 806, while the solution is injected into the second chamber 804 through the flow path 808.

[0015] In a package in which the pore chip 110 is arranged horizontally, as in Fig. As shown in Figure 3, an opening axis of the pore is oriented vertically. Therefore, upon introduction of the solution into the chambers 802, 804, an air pocket 8 will tend to form in the pore 112, as the pore 112 will eventually be enclosed by the solution from above and below.

[0016] The formation of an air pocket 8 in pore 112 prevents the solution from entering pore 112, preventing the current from flowing through pore 112. Particles also cannot pass through the pore. Once formed, it is not easy to remove the air pocket 8. One possible method for removing the air pocket would be ultrasonic cleaning. However, this method is considered less reliable, and the ultrasonic vibrations would damage the membrane in which the pore is formed.

[0017] One possible method to suppress the formation of air pockets would be to plasma-treat the pore chip to impart hydrophilicity. However, this treatment is time-consuming and would increase costs.

[0018] The present disclosure has been prepared in consideration of such circumstances, and an exemplary embodiment thereof is the provision of a pore chip package capable of preventing the formation of air pockets. SOLUTION TO THE PROBLEM

[0019] One embodiment of the present disclosure relates to a pore chip package structured to accommodate a pore chip. A main body of the pore chip package is configured to support the pore chip in a vertical plane. The main body has a first chamber and a second chamber that are adjacent to each other in the horizontal direction and divided by the pore chip.

[0020] It should be noted that free combinations of these components as well as all components and expressions exchanged between the method, the apparatus and the system are also considered modes of this invention. ADVANTAGEOUS EFFECTS OF THE INVENTION

[0021] An embodiment of the present disclosure can prevent the formation of air pockets. BRIEF DESCRIPTION OF THE DRAWINGS Fig. Figure 1 is a block diagram illustrating a microparticle measurement system using the electrical sensor zone method. Fig. Figure 2 is an example curve diagram of the microcurrent Is measured with a measuring device. Fig. Figure 3 is a cross-sectional view of a pore device studied by the inventors. Fig. 4 is a perspective view showing a pore chip package according to an embodiment. Fig. Figure 5 is a cross-sectional view showing the pore chip package. Fig. Figure 6 is a cross-sectional view showing how the pore chip package accommodates the pore chip. Fig. Figure 7 is a cross-sectional view showing the pore chip package specifically around the pore chip. Fig. Figure 8 is a diagram illustrating the relationship between water pressure p and the number of particles passed through. DESCRIPTION OF THE EMBODIMENTSOverview of the embodiments

[0022] Some example embodiments of the present disclosure are outlined. This outline is intended to briefly illustrate some concepts of one or more embodiments to provide a basic understanding of the embodiments, as an introduction before the detailed description below, without limiting the scope of the invention or the disclosure. This overview is not a comprehensive overview of all possible embodiments and is therefore not intended to indicate key elements of all embodiments, nor to delimit the scope of some or all embodiments. For convenience, the term "one embodiment" may be used to refer to a single embodiment (example or modified example) or a plurality of embodiments (examples or modified examples) disclosed in the present description.

[0023] A pore chip package according to one embodiment is configured to accommodate a pore chip. The pore chip package has a main body configured to support the pore chip in a vertical plane. The main body has a first chamber and a second chamber that are adjacent to each other in the horizontal direction and divided by the pore chip.

[0024] In this structure, a solution filled into the first and second chambers raises the liquid level from bottom to top. This successfully prevents the formation of an air inlet in the pore.

[0025] In an embodiment where the pore chip package is filled with a liquid, the height level of a liquid surface of the liquid may be 10 mm or more higher than a height level of the pore.

[0026] This structure can enable an increase in the water pressure in the pore compared to the state of the art, thus improving the permeability of the particle and the efficiency of the measurement.

[0027] In one embodiment, the main body may include: a first flow path extending from a level lower than a pore level of the pore chips in the first chamber toward a top surface of the main body; a second flow path extending from a level higher than the pore level in the first chamber toward the top surface of the main body; a third flow path extending from a level lower than the pore level in the second chamber toward the top surface of the main body; and a fourth flow path extending from a level higher than the pore level in the second chamber toward the top surface of the main body.

[0028] In one embodiment, the height level of the top surface of the main body may be higher than the height level of the pore of the pore chip by 10 mm or more.

[0029] In one embodiment, the main body may further include a protrusion formed on the top of the main body to separate the first and second flow paths from the third and fourth flow paths. This successfully prevents a short circuit between the solution in the first chamber and the solution in the second chamber.

[0030] In one embodiment, the pore housing may further comprise a first electrode provided on a wall surface of the first flow path and a second electrode provided on a wall surface of the third flow path.

[0031] In one embodiment, the porous housing may further include an electrode plate connected to a bottom surface of the main body. The first electrode and the second electrode may be formed on the electrode plate.

[0032] In one embodiment, the main body may be divided into a first section and a second section, with the vertical plane serving as a boundary.

[0033] In one embodiment, a pore device including the pore chip and the pore chip housing configured to receive the pore chip, and a measuring device including an interface socket to which the pore device is attached may be included. Embodiment

[0034] A preferred embodiment will be explained below with reference to the accompanying drawings. All similar or equivalent components, parts, and methods shown in the individual drawings are provided with the same reference numerals to avoid redundant explanations. The embodiment is for illustrative purposes only and is not limiting the invention. All features and combinations thereof described in the embodiment are not always necessarily essential to the present invention.

[0035] In the present specification, the term “state in which an element A is coupled to an element B” includes a case in which the element A and the element B are physically and directly coupled, and a case in which the element A and the element B are indirectly coupled by placing another element therebetween that does not substantially affect the electrically coupled state or deteriorate the function or effect demonstrated by the coupling.

[0036] Similarly, a "state in which element C is provided between elements A and B" includes the case in which element A and element C or element B and element C are directly connected, and the case in which they are indirectly connected by placing another element therebetween which does not substantially impair the electrical connection state between the elements or deteriorate the function or effect exhibited by the elements.

[0037] The dimensions (thickness, length, width, etc.) of the individual elements shown in the drawings may be enlarged or reduced accordingly for clarity. Furthermore, the dimensions of the multiple elements do not necessarily indicate the size relationship between them, so that a particular element A shown thicker than another element B in a drawing may actually be thinner than that element.

[0038] Fig. Figure 4 is a perspective view showing a pore chip package 700 according to one embodiment. The pore chip package 700 includes a main body 710 and an electrode plate 760. The main body 710 is configured to receive and support a pore chip in a chip receiving space 720 provided therein.

[0039] Fig. 5 is a cross-sectional view of the pore chip package 700. The main body 710 has a first chamber 722, the chip accommodation space 720, and a second chamber 724, which are adjacent to each other in the horizontal direction. When the pore chip is accommodated in the chip accommodation space 720, the first chamber 722 and the second chamber 724 are divided by the pore chip. A first flow path 741 and a second flow path 742 are formed inside the main body 710, extending from the first chamber 722 to a top surface S1 of the main body 710. Specifically, the first flow path 741 extends from a level lower than a pore level 721 of the pore chip in the first chamber 722 toward a first opening 431 of the top surface S1. The second flow path 742 extends from a level higher than the pore level 721 in the first chamber 722 toward a second opening 732 of the top side S1.The first flow path 741 is L-shaped and has a horizontal section 741a and a vertical section 741b. The second flow path 742 is also L-shaped.

[0040] Similarly, a third flow path 743 and a fourth flow path 744 are formed inside the main body 710, extending from the second chamber 724 toward the top surface S1 of the main body 710. More specifically, the third flow path 743 extends from a level lower than the pore level 721 of the pore chip in the second chamber 724 toward a third opening 433 of the top surface S1. The fourth flow path 744 extends from a level higher than the pore level 721 in the second chamber 724 toward a fourth opening 734 of the top surface S1. The third flow path 743 is also L-shaped and has a horizontal section 743a and a vertical section 743b. The fourth flow path 744 is also L-shaped.

[0041] The main body 710 has a first electrode E1 and a second electrode E2. The first electrode E1 is located in the first chamber 722 or in the first flow path 741. The second electrode E2 is located in the second chamber 724 or in the second flow path 742. The first electrode E1 and the second electrode E2 correspond to the electrodes 106, 108 in Fig. 1.

[0042] Now referring back to Fig. 4. The electrode plate 760 is fixed to a bottom surface of the main body 710. The electrode plate 760 also serves as the inner wall of a horizontally laid portion 741a of the first flow path 741 and a horizontally laid portion 743a of the third flow path 743. On the electrode plate 760, the first electrode E1 is formed in a portion corresponding to the inner wall of the first flow path 741, and the second electrode E2 is formed in a portion corresponding to the inner wall of the third flow path 743.

[0043] The electrode plate 760 has a contact electrode Ec1 electrically connected to the first electrode E1 and a contact electrode Ec2 electrically connected to the second electrode E2. At the time of measurement, a voltage signal is applied to the contact electrodes Ec1 and Ec2.

[0044] The main body 710 is divisible into a first section 712 and a second section 714. The chip receiving space 720 is formed in the first section 712.

[0045] On the upper surface S1 of the main body 710 and at a boundary between the first portion 712 and the second portion 714, a protrusion 750 is formed, separating the first flow path 741 and the second flow path 742 from the third flow path 743 and the fourth flow path 744. The protrusion 750 can prevent a short circuit between the solution in the first chamber 722 and the solution in the second chamber 724.

[0046] When the pore chip package is filled with the liquid, the height level of the liquid surface may preferably be 10 mm or more higher than the pore level 721. The height level of the liquid surface may be regarded as the height level of the top surface S1.

[0047] Fig. 6 is a cross-sectional view showing how the pore chip package 700 accommodates the pore chip 110. The pore chip 110 has a pore 112. The pore chip 110 is housed in the chip accommodation space 720 of the pore chip package 700 while being held upright in the vertical direction.

[0048] The structure of the pore chip package 700 has been described. The advantages are then described.

[0049] Fig. 7 is a cross-sectional view showing the pore chip package 700, specifically around the pore chip 110. In a preparatory phase of the measurement, an electrolyte solution 2 is injected through the first opening 731. The electrolyte solution 2a flows through the first flow path 741 and enters the first chamber 722. Similarly, an electrolyte solution 2b is injected through the third opening 733. The electrolyte solution 2b flows through the third flow path 743 and enters the second chamber 724. In the first chamber 722 and the second chamber 724, a liquid surface 6 of the electrolyte solutions 2a, 2b rises from bottom to top. Air 7 that was in the pore 112 of the pore chip 110 can escape upward as the liquid surface 6 rises. This successfully suppresses the formation of air pockets.

[0050] The pore chip package 700 also has the following advantages. The pore chip package 700 has a height difference of 10 mm or more between the pore 112 and the height level of the top surface S1. This means that the water pressure in the pore 112 increases. The water pressure p is determined by the height h measured from the pore to the water surface, which is given by the following equation: p=ρ⋅gh, where ρ is the density of water and g is the acceleration due to gravity.

[0051] The electrolyte solution commonly used in microparticle measurement systems, for example, is a chloride solution (NaCl, KCl, PBS, etc.) with a concentration of less than 1 mol. The density of the solution can therefore be assumed to be almost equal to that of water without any significant influence. ρ = 997 kg / m 3 and g = 9.81 m / s 2 , The water pressure p is 9781 × h [kPa]. For h = 10 mm = 0.01 m, this results in p = 0.09781 kPa.

[0052] Fig. Figure 8 is a graph illustrating the relationship between water pressure p and the number of particles passed through. The abscissa represents time, and the ordinate represents the number of particles passed through. The result shows that the number of particles passed through per unit time (1 minute) increases with increasing water pressure p. Assuming h = 10 mm and p ≈ 0.1 kPa, it turns out that 6.6 or more particles can be detected per minute. Considering that a total of about 200 particles are required for sufficient measurement accuracy, this embodiment can complete the measurement within 30 minutes.

[0053] The previous pore chip could achieve a particle count of about 3 particles per minute. This means the measurement takes one hour. By using the pore chip package 700 of this embodiment, the measurement time can be almost halved.

[0054] The embodiment has been described. Those skilled in the art will understand that the embodiment is merely illustrative, that the individual components or combinations of various methods may be modified in various ways, and that such modifications are within the scope of the present disclosure. Such modified examples are explained below.

[0055] The electrodes E1 and E2 formed on the electrode plate 760 in this embodiment are not limited in their location and shape. For example, the electrode E1 can be formed in the first chamber 722 or the second flow path 742. Similarly, the electrode E2 can be formed in the second chamber 724 or the fourth flow path 744.

[0056] Electrodes E1 and E2 can alternatively be designed as rod-shaped probe electrodes. In this mode, electrode E1 can be inserted through the first opening 731 or the second opening 732, or through another opening on the side surface of the first section 712, so that at least a portion of the probe electrode is exposed to the first flow path 741, the first chamber 722, or the second flow path 742. The same applies to electrode E2.

[0057] The present invention is not limited to the device for measuring microparticles described here, but finds broad application to measuring devices responsible for measuring microcurrents using the pore device, such as DNA sequencers.

[0058] Having described the present invention with reference to the embodiment, the embodiment merely illustrates the principle and applications of the present invention, and various modifications and changes in design are possible without departing from the spirit of the present invention as set forth in the claims. INDUSTRIAL APPLICABILITY

[0059] The present invention relates to measurement using a pore device. REFERENCE SYMBOL LIST 1 microparticle measuring system, 2 electrolyte solution, 4 particles, 8 Air inclusion, 100 pore device, 200R measuring device, 210 transimpedance amplifiers, 220 voltage source, 230 digitizers, 300 data processor, 100 pore device, 110 pore chips, 112 pores, 700 pore chip housing, 710 main body, 712 first section, 714 second section, 720 chip receiving room, 722 first chamber, 724 second chamber, S1 top, 731 first opening, 732 second opening, 733 third opening, 734 fourth opening, 741 first flow path, 742 second flow path, 743 third flow path, 744 fourth flow path, 750 lead, 760 electrode plate, E1 first electrode, E2 second electrode. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] JP 2017-016881 A

[0011] JP 2014-219235 A

[0011] JP 2018-054594 A

[0011] WO 2002 / 084306

[0011]

Claims

[1] A pore chip package (700) for accommodating a pore chip (110), comprising: - a main body (710) structured to support the pore chip (110) in a vertical plane, and having a first chamber (722) and a second chamber (724) adjacent to each other in the horizontal direction and divided by the pore chip (110). [2] The pore chip package (700) according to claim 1, wherein after filling with a liquid inside the pore chip package (700), a height level of a liquid surface (6) of the liquid is 10 mm or more higher than a height level of a pore (112) of the pore chip (110). [3] The pore chip package (700) according to claim 1, wherein the main body (710) comprises: - a first flow path (741) extending from a level below the pore level (721) of the pore chip (110) in the first chamber (722) to a top surface (S1) of the main body (710); - a second flow path (742) extending from a higher level than the pore level (721) in the first chamber (722) towards the top (S1) of the main body (710); - a third flow path (743) extending from a level below the pore level (721) in the second chamber (724) towards the top of the main body (710); and - a fourth flow path (744) extending from a higher level than the pore level (721) in the second chamber (724) towards the top (S1) of the main body (710). [4] The pore chip package (700) according to claim 3, wherein a height level of the top surface (S1) of the main body (710) is 10 mm or more higher than the height level of the pore (112) of the pore chip (110). [5] The pore chip package (700) according to claim 3 or 4, wherein the main body (710) further comprises a protrusion (750) structured to separate the first flow path (741) and the second flow path (742) from the third flow path (743) and the fourth flow path (744) on the top surface (S1) of the main body (710). [6] The pore chip package (700) according to claim 3 or 4, further comprising: - a first electrode (E1) provided on a wall surface of the first flow path (741); and - a second electrode (E2) attached to a wall surface of the third flow path (743). [7] The pore chip package (700) according to claim 6, further an electrode plate (760) connected to a bottom of the main body (710), and the first electrode (E1) and the second electrode (E2) are formed on the electrode plate (760). [8] The pore chip package (700) according to claim 1 or 2, wherein the main body (710) can be divided into a first section (712) and a second section (714), the vertical plane being a boundary. [9] A microparticle measuring system (1) comprising: - a pore device (100) having a pore chip (110), wherein the pore chip housing (700) according to claim 1 or 2 is constructed to accommodate the pore chip (110); and - a measuring system (200R) with an interface socket to which the pore device (100) is attached.

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