Measurement device

Abstract

Provided is technology whereby a sensor for measuring an object to be inspected can be repeatedly used.　Provided is a measurement device for measuring the characteristics of an object to be inspected through a change in an electric field, the measurement device comprising: a holding means for holding the object to be inspected; a detection means for generating the electric field and detecting a change in the dielectric constant of the object to be inspected based on the electric field; and a detachment means interposed between the detection means and the holding means so that the detection means and the holding means can be physically separated and brought into contact with each other, the detachment means being thinner than the penetration depth of the electric field and being incapable of penetrating the object to be inspected.

Description

Measuring equipment

[0001] SUMMARY OF THE INVENTION Embodiments of the present invention relate to techniques for making measurements related to microorganisms.

[0002] A conventional technique of this type uses a high-frequency CMOS oscillator (semiconductor) sensor to measure the increase or decrease of microorganisms, such as bacteria, as a test object as a change in dielectric constant. The closer the sensor surface is to the microorganisms, the more sensitive the measurement. However, if the distance between the sensor surface and the microorganisms exceeds a predetermined distance, such as 20 μm or more, the change in dielectric constant cannot be detected accurately, making it difficult to measure the increase or decrease of the microorganisms. For this reason, the sensor must be designed so that the microorganisms come into physical contact with the sensor surface. However, if the sensor surface is designed so that the microorganisms come into contact with the sensor surface, the sensor must be replaced after each measurement.

[0003] JP 2022-76939 A Japanese Patent No. 6549256 A Japanese Patent No. 6486740 A

[0004] Takeshi Mitsunaka, Nobuyuki Ashida, Akira Saito, Kunihiko Iizuka, Tetsuhito Suzuki, Yuichi Ogawa, Minoru Fujishima. “28.3 CMOS Biosensor IC Focusing on Dielectric Relaxations of Biological Water with 120GHz and 60GHz Oscillator 2016 IEEE International Solid-State Circuits Conference. Yuichi Ogawa, Shojiro Kikuchi, Keiichiro Shiraga, Takeshi Mitsunaka. Near-field sensor array with 64-GHz CMOS Oscillators for early detection of viable Escherichia coli. Biosensors and Bioelectronics. 2021: 176; 112935.

[0005] The problem to be solved by the embodiments of the present invention is to provide a technique that enables repeated use of a sensor for measuring an object to be inspected.

[0006] In order to solve the above-mentioned problems, an embodiment of the present invention is a measuring device that measures the characteristics of a test object by changes in an electric field, and is characterized by comprising: a holding means for holding the test object; a detection means for generating the electric field and detecting changes in the dielectric constant of the test object based on the electric field; and a peeling means that is interposed between the detection means and the holding means so as to be able to physically separate and connect the detection means and the holding means, is thinner than the penetration depth of the electric field, and is not able to pass through the test object.

[0007] 1 is a block diagram showing a measurement system including a measurement device according to an embodiment. FIG. 2 is a schematic plan view showing the measurement device according to an embodiment. FIG. 3 is a cross-sectional view taken along line AA of FIG. 2. FIG. 4 is a schematic exploded perspective view showing the measurement device according to an embodiment. FIG. 5 is a schematic view showing the configuration of a sensor IC according to an embodiment. FIG. 6 is an exploded perspective view showing a release sheet according to an embodiment. FIG. 7 is a view for explaining a state in which the release sheet according to an embodiment is used. FIG. 8 is a view for explaining a state in which the measurement device according to an embodiment is used. FIG. 9 is a view for explaining removal of a culture well and a release sheet from a detection device according to an embodiment. FIG. 10 is a graph showing results of measurement using a measurement method according to an embodiment and results of measurement using an existing measurement method. FIG. 11 is a view for explaining a sensor IC according to a first application example of an embodiment. FIG. 12 is a view for explaining a sensor IC according to a second application example of an embodiment. FIG. 13 is an exploded perspective view showing a first application example of a release sheet according to an embodiment. FIG. 14 is an exploded perspective view showing a second application example of a release sheet according to an embodiment. FIG. 15 is an exploded perspective view showing a second application example of a release sheet according to an embodiment.

[0008] Hereinafter, embodiments of the present invention will be described with reference to the drawings. In this specification and the drawings, components having substantially the same functional configurations are designated by the same reference numerals, and redundant description will be omitted.

[0009] (Overall Configuration) Fig. 1 is a block diagram showing a measurement system including a measurement device according to this embodiment. As shown in Fig. 1, the measurement system 1 according to this embodiment includes a measurement device 10 and a control device 12 that controls the measurement device 10. The measurement device 10 has a detection device 60, which will be described later, and uses the detection device 60 to measure changes in the dielectric constant of a test object, which are related to the increase / decrease and activity of microorganisms contained in the test object. In this embodiment, an example will be described in which the measurement device 10 simultaneously evaluates the efficacy of multiple types of antimicrobial agents against microorganisms. Specific details of the measurement device 10 will be described later.

[0010] The control device 12 is connected to the measuring device 10 via a wired or wireless connection so as to be able to transmit signals thereto, and controls the measuring device 10. The control device 12 is an information processing device, such as a PC, that has a CPU (Central Processing Unit), RAM (Random Access Memory), ROM (Random Access Memory), etc. The control device 12 has an input device 122, such as a mouse or keyboard, that accepts input from an operator, and an output device 124, such as a GUI (Graphical User Interface) for operator input and a display that displays output from the measuring device 10. The control device 12 accepts operator input (e.g., instructions related to driving or selecting an oscillator circuit 642 of the sensor IC 64, described below) via the input device 122 and controls the measuring device 10. It also receives output from the measuring device 10 (for example, measurement results from a detection circuit 648 described later) and displays them on the output device 124 as appropriate.

[0011] (Measuring Device 10) The configuration and operation of the measuring device 10 according to this embodiment will be described in detail below. Fig. 2 is a schematic plan view showing the measuring device according to this embodiment, and Fig. 3 is a cross-sectional view taken along line A-A thereof. Fig. 4 is a schematic exploded perspective view showing the measuring device according to this embodiment. In the following description, the lower side in Fig. 2 is the front side, the upper side is the back side, the direction perpendicular to these surfaces is referred to as the front-rear direction, and the direction perpendicular to the front-rear direction and the up-down direction is referred to as the left-right direction.

[0012] As shown in Figures 2 to 4, the measurement device 10 of this embodiment includes a culture well 20 that holds a test object R1, which is a liquid such as a bacterial liquid containing microorganisms, a detection device 60 that detects the dielectric constant of the test object R1, a release sheet 80 that is interposed between the culture well 20 and the detection device 60, and a grid 40 that supports the release sheet 80.

[0013] (Culture Well 20) The culture well 20 is formed in the shape of a hollow, upside-down truncated cone whose circumferential surface gradually tapers downward, and its top surface is open. The culture well 20 holds the test specimen R1 on its bottom surface. For example, the test specimen R1 can be held in the culture well 20 by immersing the bottom surface of the culture well 20 in a container containing the test specimen R1. Alternatively, a bacterial solution may be applied. Examples of microorganisms contained in the test specimen R1 include bacteria, cells (with or without viral infection), fungi, yeast, and the like. In other words, the measurement device 10 according to this embodiment can evaluate the growth potential of various microorganisms, such as bacteria, cells (with or without viral infection), fungi, and yeast, based on changes in dielectric constant detected by the detection device 60.

[0014] The culture well 20 is provided with a liquid-permeable membrane filter 22 at least on its bottom wall. The culture well 20 stores a liquid medium R2 for the microorganisms, and the liquid medium R2 that permeates through the membrane filter 22 is supplied to the test object R1. Such a membrane filter 22 is preferably a hydrophilic thin film. This is because if a hydrophobic thin film were used for the membrane filter 22, when the microorganisms generate gases such as air, the gases may become trapped between the sensor IC 64 and the filter, reducing detection accuracy; specifically, the detected dielectric constant may include the gas. By providing such a membrane filter 22, the test object R1 can be held in a good condition.

[0015] The membrane filter 22 may be made of a resin material, such as a thin film of a fluorine-based resin such as PTFE (Polytetrafluoroethylene). The portions of the culture well 20 other than the bottom wall, such as the peripheral wall, may be made of an inexpensive resin material to which microorganisms easily adhere, such as polycarbonate.

[0016] In this embodiment, an electric field is generated by a sensor IC (Integrated Circuit) 64 of the detection device 60 for the test specimen R1 held in the culture well 20, and a change in the dielectric constant of the test specimen R1 based on this electric field is detected. In this embodiment, as described above, in order to simultaneously evaluate the efficacy of multiple types of antimicrobial agents (four types in this example) against microorganisms, five culture wells 20 are prepared, each holding a test specimen R1 containing a certain amount of the same type of microorganism, and one culture well 20 is prepared that does not hold a test specimen R1. In other words, the measurement device 10 is configured to be able to simultaneously measure a total of six culture wells 20. Specifically, different antimicrobial agents are added to the liquid medium R2 of each of the four culture wells 20 holding the test specimen R1, while no antimicrobial agent is added to the liquid medium R2 of the one culture well 20 holding the test specimen R1. Meanwhile, one culture well 20 that does not hold the test specimen R1 stores liquid medium R2 to which no antibiotic has been added. The reason for preparing a culture well 20 that stores only liquid medium R2 without holding the test specimen R1 is to calculate the difference between the measurement results of the culture well 20 containing only liquid medium R2 and that of the other culture wells 20 when the measurement results of each of the other culture wells 20 are abnormal values, and to verify whether any environmental changes have occurred.

[0017] As described above, the membrane filter 22 is hydrophilic, and therefore the liquid medium R2 permeates and leaks downward. Because the sensor IC 64 is positioned below the culture well 20, if the underside of the culture well 20 and the sensor IC 64 were in direct contact, the sensor IC 64 would be contaminated by the leaked liquid. However, in this embodiment, the release sheet 80, described in detail below, specifically the water-repellent thin film 82 included in the release sheet 80, prevents contamination of the sensor IC 64.

[0018] The size of the culture well 20 is preferably determined according to the size of the sensor IC 64, particularly the size of its sensor surface (measurement site), and it is particularly preferable that the lower surface including the membrane filter 22 is smaller than the sensor surface of the sensor IC 64. For example, if the sensor surface of the sensor IC 64 is 8 mm x 8 mm, the lower end of the culture well 20 may have an outer diameter of 6 mm and an inner diameter of 4 mm, and the upper end may have an outer diameter of 14 mm and an inner diameter of 12 mm. The membrane filter 22 has a diameter of, for example, 6 mm and a thickness of, for example, approximately 60 μm. However, the diameter and thickness are not limited to these values.

[0019] (Detection Device 60) The detection device 60 has a rectangular, flat substrate 62, on which multiple sensor ICs 64 are provided. In this embodiment, six culture wells 20 are treated as one unit to simultaneously measure multiple test subjects R1. To do this, six sensor ICs 64 are provided to individually correspond to each of the six culture wells 20. For infection control, the sensor ICs 64 are spaced apart so as to be independent of one another. Preferably, the six sensor ICs 64 are spaced apart at a distance such that the six culture wells 20 do not physically interfere with one another and the electric fields of the sensor ICs 64 do not interfere with one another, allowing measurements to be made for each culture well 20.

[0020] The sensor IC 64 will be described in detail below. Fig. 5 is a schematic diagram showing the configuration of the sensor IC according to this embodiment. Fig. 5 shows the internal structure of the sensor IC 64 in a plan view.

[0021] In this embodiment, the sensor IC 64 is a so-called high-frequency CMOS (Complementary Metal Oxide Semiconductor) oscillator (semiconductor) sensor.

[0022] The sensor IC 64 according to this embodiment is designed to measure changes in the dielectric constant of a test object composed of microorganisms and microbial-derived substances. It evaluates the state of the water contained in the test object, specifically, by measuring the dielectric constant of water in real time, it can quantitatively evaluate the growth of the water-containing test object, i.e., the increase or decrease of microorganisms. In particular, by operating in the 65 GHz band (millimeter wave band), the sensor IC 64 can be made particularly sensitive to bulk water without being affected by hydrated water or ions. For detailed information on the principles of such a sensor, please refer to the aforementioned non-patent document 1.

[0023] 5, the sensor IC 64 is configured such that a plurality of oscillator circuits 642 for detecting the dielectric constant of a nearby test object R1 are arranged on a semiconductor substrate 641. The oscillator circuit 642 has a differential circuit 643 composed of two cross-coupled transistors, an inductor 644 made of a metal layer connected between the differential terminals of the two cross-coupled transistors, a frequency divider circuit 645, and a terminal 646.

[0024] Specifically, a differential circuit 643 is formed on a semiconductor substrate 641, and an inductor 644 is formed above the differential circuit 643 via an interlayer insulating film made of silicon dioxide or the like. The inductor 644 is also covered from above with a protective film made of silicon dioxide or the like.

[0025] Of the two cross-coupled transistors that make up the differential circuit 643, one cross-coupled transistor has its drain connected to one end of the inductor 644, its source connected to ground, and its gate connected to the other end of the inductor 644. The other cross-coupled transistor has its drain connected to the other end of the inductor 644, its source connected to ground, and its gate connected to one end of the inductor 644. The differential circuit 643 outputs a differential signal using the output signal from the drain of one cross-coupled transistor and the output signal from the drain of the other cross-coupled transistor.

[0026] The oscillation signal output from each drain of the two cross-coupled transistors is input to the frequency divider circuit 645. The frequency divider circuit 645 performs a frequency division operation to divide the oscillation signal into a low-frequency signal and outputs it to a terminal 646.

[0027] The oscillation frequency of the oscillation circuit 642 is preferably set to a frequency band in which the dielectric constant of the test object R1 changes optimally, for example, a frequency between 20 GHz and 180 GHz. However, this is not limited to this, and the oscillation frequency may be changed appropriately depending on the film thickness of the water-repellent thin film 82 of the release sheet 80, which will be described later.

[0028] The oscillator circuit 642 detects changes in the oscillation frequency of the oscillation signal output by the differential circuit 643 by utilizing the inductance value of the inductor 644, which changes with changes in the dielectric constant, which is a physical constant (physical property), of the test object R1 that is in contact with the surface of the release sheet 80 via the water-repellent thin film 82. A plurality of such oscillator circuits 642, for example, several hundred, are densely arranged to form a sensor surface. Note that the oscillator circuits 642 may be arranged in a lattice (grid) pattern, but in order to increase resolution by densely arranging them on a single semiconductor substrate 641, it is preferable to arrange them in a staggered pattern, particularly in the case of the inductors 644, which have a larger area than the other elements, in a staggered pattern.

[0029] A drive control circuit 647 is provided at one end of the semiconductor substrate 641, and a detection circuit 648 is provided at the other end. These circuits are connected to the control device 12 via an interface (not shown) so as to be able to communicate with and control the control device 12. The drive control circuit 647 selects and controls which of the multiple oscillation circuits 642 to drive. The detection circuit 648 receives a concentrated input of output signals from each oscillation circuit 642 and detects frequency changes at each time in each oscillation circuit 642. As a result, in this embodiment, it is possible to detect frequency changes at each time at the position of each oscillation circuit 642, detect frequency changes at each time at each position on the test subject R1, and detect changes in dielectric constant based on the frequency changes.

[0030] The operation of the sensor IC 64 will be briefly described. When the device under test R1 comes into contact with the sensor IC 64 via the release sheet 80, the drive control circuit 647 drives, for example, a unit cell (not shown) corresponding to a certain oscillator circuit (referred to as oscillator circuit 642A for the sake of explanation). In this unit cell, a change in the inductance value of the inductor 644 of the oscillator circuit 642A occurs due to electromagnetic induction caused by a change in the dielectric constant of the device under test R1. The change in inductance value changes the oscillation frequency of the oscillator circuit 642A.

[0031] The unit cell outputs the changed oscillation frequency signal to a frequency divider circuit 645, which divides the oscillation frequency signal into a low-frequency signal. The low-frequency signal output from the frequency divider circuit 645 is output via a terminal 646 to a detection circuit 648, which detects the dielectric constant.

[0032] For more detailed information on the configuration, preferred forms, application forms, and operation details of the sensor IC 64, please refer to the above-mentioned Patent Documents 2 and 3.

[0033] (Release sheet 80) As shown in Figures 2 to 4, the release sheet 80 is a rectangular sheet-like object that extends to cover the top of the detection device 60, and a portion of it is interposed between the culture well 20 and the sensor IC 64, and is configured to be removable from the detection device 60.

[0034] The configuration of the release sheet 80 will be described in detail below. Fig. 6 is an exploded perspective view schematically showing the release sheet according to this embodiment. Fig. 7 is a diagram illustrating the release sheet according to this embodiment in use. Fig. 8 is a diagram illustrating the measurement device according to this embodiment in use. Note that Figs. 7 and 8 show details of the release sheet 80 in the vicinity of one culture well 20 and the sensor IC 64 in the cross section taken along line A-A in Fig. 2.

[0035] As shown in Figures 6 and 7, the release sheet 80 is a so-called laminated sheet that is composed of a water-repellent thin film 82, an upper reinforcing sheet 84 that overlaps the upper surface of the water-repellent thin film 82, and a lower reinforcing sheet 86 that overlaps the lower surface of the water-repellent thin film 82.

[0036] The water-repellent thin film 82 is a water- and oil-repellent thin film that is configured to be impermeable to the test object R1, particularly microorganisms, and the liquid culture medium R2 that has passed through the membrane filter 22, and is therefore able to retain these on its upper surface. The water-repellent thin film 82 is preferably made of a resin material, particularly a fluorine-based resin material, and more preferably has a low refractive index, electrical insulation, and chemical resistance. An example of such a material is CYTOP (registered trademark) manufactured by AGC Corporation.

[0037] High-frequency CMOS oscillator sensors such as the sensor IC 64 can achieve higher sensitivity measurements when the distance between the sensor surface and the test object is shorter. However, experiments conducted by the present inventors have shown that if the sensor surface and the test object are separated by a distance exceeding the detection limit, such as 20 μm or more, detection accuracy drops significantly, making it difficult to detect changes in dielectric constant. For this reason, it is important to keep the distance between the sensor surface and the test object below the detection limit and minimize the fluidity of the liquid medium.

[0038] In relation to this detection limit distance, in this embodiment, a water-repellent thin film 82 is interposed between the sensor IC 64 and the test object R1, and the sensor IC 64 and the test object R1 are separated by the thickness of the water-repellent thin film 82. The inventors of the present invention have confirmed that the thickness of the water-repellent thin film 82 is an important factor in detecting the dielectric constant, ensuring that the electric field generated by the sensor IC 64 penetrates the water-repellent thin film 82 and reaches the test object R1. In other words, by making the water-repellent thin film 82 thinner than the penetration depth of the electric field generated by the sensor IC 64, the separation distance between the sensor surface and the test object R1 can be kept below the detection limit distance. Note that if a strong electric field can be generated from the sensor IC 64, the water-repellent thin film 82 can be made thicker. Therefore, it can be said that the detection limit distance changes appropriately depending on the magnetic field strength of the sensor IC 64.

[0039] For example, when the sensor IC 64 operates in the 65 GHz band, the thickness of the water-repellent thin film 82 should be 2 μm or less, and particularly in the range of 500 nm to 1 μm. The water-repellent thin film 82 having such a thickness can be manufactured by, for example, sputtering, vapor deposition, spin coating, electrospray, or the like, and of course, may also be manufactured by other physical vapor deposition or chemical vapor deposition methods. Note that it is preferable that the water-repellent thin film 82 has a low dielectric constant, but even if the dielectric constant is high, the sensor IC 64 can be designed taking this into consideration.

[0040] However, since the thinner the water-repellent thin film 82, the more physically fragile it becomes, it is important to achieve both detection sensitivity and physical strength. Therefore, the inventors have decided to sandwich the water-repellent thin film 82 between an upper reinforcing sheet 84 and a lower reinforcing sheet 86, thereby laminating the water-repellent thin film 82 so as to reinforce it from above and below.

[0041] The upper and lower reinforcing sheets 84, 86 are each hydrophobic sheet-like material and have the same size as the water-repellent thin film 82. The upper and lower reinforcing sheets 84, 86 may be thinner than the water-repellent thin film 82, but are preferably thicker than the water-repellent thin film 82 in order to reinforce the water-repellent thin film 82. The upper and lower reinforcing sheets 84, 86 may each be formed to a thickness of, for example, approximately 10 μm. The lower reinforcing sheet 86 also serves to prevent the water-repellent thin film 82 from coming into contact with the mold resin used in the substrate 62 or the sensor IC 64, resulting in unintended adhesion, etc. The upper and lower reinforcing sheets 84, 86 may be made of a resin material, such as a fluororesin such as PTFE.

[0042] In order to prevent a decrease in the measurement accuracy of the sensor IC 64 due to the provision of the upper and lower reinforcing sheets 84, 86, holes are provided in the portions adjacent to the culture wells 20 and the sensor IC 64. In this embodiment, six holes 842 corresponding to the six culture wells 20 respectively are provided in the upper reinforcing sheet 84, and six holes 862 corresponding to the six sensor ICs 64 respectively are provided in the lower reinforcing sheet 86. These holes are provided spaced apart from one another so that the center positions of the holes individually coincide with the center positions of the sensor surfaces of the sensor ICs 64.

[0043] The diameter of the hole 842 in the upper reinforcement sheet 84 is preferably larger than that of the sensor surface of the sensor IC 64 so that the sensor surface of the sensor IC 64 can uniformly contact the membrane filter 22 of the culture well 20 via the water-repellent thin film 82. For example, if the sensor surface of the sensor IC 64 is 8 mm × 8 mm, the diameter of the hole 842 may be approximately 12 mm. On the other hand, the diameter of the hole 862 in the lower reinforcement sheet 86 is smaller than that of the hole 842 in the upper reinforcement sheet 84. For example, if the diameter of the hole 842 is 12 mm, the diameter of the hole 862 may be approximately 10 mm. This results in a structure in which the difference in diameter between the holes 842 and 862 squeezes the test subject R1 and the liquid medium R2 downward.

[0044] 8, the release sheet 80 is slightly bent in the space between the sensor IC 64 and the lower frame 44 of the grid 40 (described later), forming a ring-shaped reservoir 88 (see FIG. 2). This reservoir 88 is able to receive the test specimen R1 and liquid medium R2 that have leaked through the culture well 20, thanks to the function of the release sheet 80, particularly the hydrophobic upper reinforcing sheet 84. This prevents the test specimen R1 and liquid medium R2 from reaching the detection device 60 and contaminating the sensor IC 64, and from leaking out of the measurement device 10.

[0045] In this embodiment, the thickness of the water-repellent thin film 82 is 1 μm, and the thickness of the upper and lower reinforcing sheets 84, 86 is each 10 μm, resulting in a thickness of 21 μm for the release sheet 80. Even with this thickness, the electric field from the sensor IC 64 can reach the test object R1, and thus the dielectric constant of the test object R1 can be detected.

[0046] The release sheet 80 having the above-described structure is provided to the detection device 60 so as to be mounted on the grid 40, as shown in FIGS.

[0047] (Grid 40) The grid 40 is a support member that supports the release sheet 80 so that it can be maintained in a state interposed between the culture well 20 and the sensor IC 64, and that functions to accurately position the culture well 20, the detection device 60, and the release sheet 80 relative to each other. The grid 40 is preferably made of a heat-resistant material. The grid 40 is formed into a box shape by an upper frame 42, a lower frame 44, and multiple vertical frames 46, and in this embodiment, can accommodate a total of six culture wells 20, with three rows in the left-right direction and two columns in the front-back direction. The upper frame 42 extends horizontally to form a hollow rectangular frame, and the culture wells 20 and the release sheet 80 can be placed inside the grid 40 from above by inserting them into the hollow portion.

[0048] The lower frame 44 includes a frame body 442 extending horizontally to form a hollow rectangular frame body, a central sash member disposed in the hollow portion of the frame body 442 and extending laterally to divide the hollow portion in the front-rear direction, and a central sash member 444 consisting of two central sash members equally spaced in the front-rear direction. The central sash member extending laterally is positioned to divide the hollow portion of the lower frame 44 into two portions in the left-right direction, while the two central sash members extending in the front-rear direction are positioned to divide the hollow portion into three portions in the left-right direction. Therefore, the central sash member 444 divides the hollow portion of the frame body 442 into six equal sections. Each of these divided hollow sections will be referred to as a "divided region" hereinafter. A release sheet 80 is detachably mounted on the lower frame 44 configured in this manner. In other words, the release sheet 80 is preferably sized to cover the entire top surface of the lower frame 44. The number of divided regions is six, but this is to accommodate the number of culture wells 20 and sensor ICs 64, and the grid 40 may be designed to increase or decrease the number as appropriate depending on the number of culture wells 20 and sensor ICs 64.

[0049] Each of the multiple vertical frames 46 has an upper end connected to the upper frame 42 and a lower end connected to the lower frame 44, thereby fixing the upper frame 42 so that it cannot move relative to the lower frame 44. Specifically, ten vertical frames 46 are provided on the upper and lower frames 42, 44: one at each of the four corners, two equally spaced at the front and rear sides, and one each on the left and right sides located approximately in the center in the fore-and-aft direction. Because a release sheet 80 is installed on the upper surface of the lower frame 44, it is preferable that the vertical frames 46 be connected to the outer periphery of the lower frame 44. Note that instead of the vertical frames 46, walls may be provided on the front, rear, left, and right sides.

[0050] The sensor IC 64 of the detection device 60 is positioned from below in the approximate center of each of the six divided regions of the grid 40, and the culture well 20 is positioned from above so as to be located directly above the sensor IC 64. In this case, it is preferable that the grid 40 is configured so that the sensor IC 64 can be accurately positioned with respect to the culture well 20. Here, "accurately" means, for example, that the approximate center of the sensor surface of the sensor IC 64 is positioned at the approximate center of the membrane filter 22 of the culture well 20. By accurately aligning the culture well 20 with the sensor IC 64 using the grid 40, it is possible to perform testing on the test subject R1 with high precision.

[0051] Possible positioning means for such culture well 20 include, for example, providing a holder capable of surface or point contact with the circumferential surface of culture well 20 on the upper frame 42 or the vertical frame 46. Meanwhile, possible positioning means for sensor IC 64 include, for example, providing engaging means for engaging with each other on the substrate 62 and the lower frame 44 of the detection device 60. Possible engaging means include, for example, providing a hole on the upper surface of substrate 62 and providing a protrusion on the lower surface of the lower frame 44 that fits into the hole, or providing a groove on substrate 62 into which the lower surface of the lower frame 44 fits uniformly. Alternatively, the lower surface of middle crosspiece 444 may be positioned above the lower surface of frame 442 to form an upwardly recessed recess between the lower surface of middle crosspiece 444 and the inner circumferential surface of frame 442 positioned below the lower surface, and substrate 62 may be detachably fitted into the recess. Furthermore, markers for aligning the culture well 20, the substrate 62 of the detection device 60, and / or the sensor IC 64 may be attached to the lower frame 44. Accurate alignment can be achieved by having the operator align each with the marker.

[0052] Meanwhile, as described above, the release sheet 80 is used by being placed on the lower frame 44 of the grid 40. In this case, it is preferable that the centers of the hole 842 in the upper reinforcing sheet 84 and the hole 862 in the lower reinforcing sheet 86 coincide with approximately the center of the sensor surface of the sensor IC 64 and the center of the membrane filter 22. Therefore, it is preferable that the lower frame 44 be provided with a means for accurately installing the release sheet 80 on the lower frame 44 of the grid 40. One possible means for this is to provide markers on the upper surface of the lower frame 44 for aligning the corners and sides of the release sheet 80. Alternatively, the space surrounded by the multiple vertical frames 46 may be the same size as the release sheet 80, thereby enabling alignment.

[0053] As described above, the grid 40 is detachable from the detection device 60, and therefore, as shown in Fig. 9, after measurement of the test object R1, the grid 40 can be detached from the detection device 60 together with the culture well 20 and the release sheet 80. The detection device 60 separated from the grid 40 is not contaminated by the liquid medium R2 or the like due to the function of the release sheet 80, and can therefore be reused for the next measurement.

[0054] The thickness of the lower frame 44 in the vertical direction is preferably equal to or greater than the height from the top surface of the substrate 62 to the top surface of the sensor IC 64. By having such a thickness, the above-described storage section 88 can be reliably formed on the release sheet 80 placed on the lower frame 44.

[0055] (Method of Use) When performing measurements using the measurement device 10 according to this embodiment, first, as a preparation step, the detection device 60 is installed below the grid 40. At this time, any positioning means is used to position the six sensor ICs 64 so that the centers of the six sensor ICs 64 individually coincide with the centers of the six divided regions of the lower frame 44. Next, the release sheet 80 is installed on the grid 40, that is, the release sheet 80 is placed on the lower frame 44. At this time, any positioning means is used to position the six sensor ICs 64 individually so that the centers of the six holes 842, 862 individually coincide with the centers of the six divided regions of the lower frame 44 and the six sensor ICs 64. Note that the installation order of the detection device 60 and the release sheet 80 on the grid 40 may be reversed. Thereafter, the culture wells 20 are positioned using any positioning means so that the centers of the bottom surfaces of the six culture wells 20 individually coincide with the centers of the six holes 842 on the top surface of the release sheet 80. After placement, the above-mentioned dielectric constant detection is performed using each sensor IC 64, thereby measuring the change in dielectric constant of the test object R1 in each of the six culture wells 20, and evaluating the growth potential of each microorganism.

[0056] FIG. 10 is a graph showing the results of measurements performed using the measurement method according to the embodiment and the results of measurements performed using an existing measurement method. The vertical axis in FIG. 10 represents the frequency change Fe, and the horizontal axis represents the elapsed time t. The microorganism being evaluated here is Escherichia coli. Mean, Max, Min, and Std in FIG. 10 represent the time-dependent changes in the mean, maximum, minimum, and standard deviation of the frequency change measured using the measurement method of the measurement device 10 according to the embodiment. The existing measurement method uses the same sensor IC 64 as used in the measurement method of the measurement device 10 according to the embodiment. As shown in FIG. 10, the frequency change measured using the measurement method of the measurement device 10 according to the embodiment is significantly greater than the result of measuring the same Escherichia coli strain as the Escherichia coli strain being evaluated using the measurement method using the existing measurement method (Non-Patent Document 2, Figure 3(a)). For example, in a 60-minute measurement, the amount of frequency change is 16.5 MHz with the existing measurement method, whereas it is 26.5 MHz with the measurement method of the measuring device 10, and the measurement sensitivity is improved by 1.61 times.

[0057] According to the embodiment described above, the measuring device 10, which measures the characteristics of a test object by changing the electric field, is provided with a peeling means that physically peels off the detection means and the test object R1 while maintaining a connection from the perspective of the electric field. This allows the detection means to be reused by replacing the test object R1. For example, using a peeling sheet 80 as the peeling means allows the sensor IC 64 as the detection means to be used repeatedly. This allows for faster measurement of microbial increase or decrease.

[0058] More specifically, a release sheet 80 having a barrier structure that is thinner than the seepage depth of the electric field generated by the sensor IC 64 and impermeable to microorganisms is interposed between the culture well 20 and the sensor IC 64. This prevents contamination of the sensor IC 64 during measurement. This allows the detection device 60 and its sensor IC 64 to be reused. For example, single-use (disposable) contact sensors are typically required for measurement of clinical specimens and infectious specimens such as drug-resistant bacteria and acid-fast bacteria. Sensors are expensive, and single-use leads to increased costs, which in turn increases medical expenses, environmental impact, and delays in practical application. However, the measurement device 10 according to this embodiment, which allows the sensor IC 64 to be reused, solves these problems and is extremely useful.

[0059] Furthermore, the release sheet 80 according to this embodiment, particularly the water-repellent thin film 82, can retain the test subject R1 attached to the membrane filter 22 and the liquid medium R2 that has passed through the membrane filter 22 on its surface, thereby minimizing the fluidity of the test subject R1 and the liquid medium R2.

[0060] Furthermore, according to this embodiment, the detection device 60 has multiple independent sensor ICs 64, so it can simultaneously detect changes in the dielectric constant of multiple test specimens R1. This also allows for faster detection. For example, as described above, different antibiotics can be added to the liquid medium R2 in each of the four culture wells 20, and no antibiotic can be added to the liquid medium R2 in one culture well 20, while the remaining culture well 20 contains only the liquid medium R2 without any test specimens R1 attached to it. This allows for the efficacy of four antibiotics against microorganisms to be evaluated simultaneously.

[0061] In addition, in this embodiment, the bottom surface of the culture well 20, in other words the membrane filter 22, is formed smaller than the sensor IC 64, which has the effect of preventing adhesion to the sensor IC 64 via the release sheet 80.

[0062] In this embodiment, the release sheet 80 is described as being placed on the lower frame 44, but this is not limiting. The grid 40, specifically the lower frame 44, may be integrally incorporated with the release sheet 80. For example, the grid 40 and the release sheet 80 can be integrated by positioning the middle crosspiece 444 between the water-repellent thin film 82 and the lower reinforcing sheet 86 of the release sheet 80. Such integration eliminates the need to place the release sheet 80 on the grid 40, thereby speeding up measurements.

[0063] In this embodiment, each of the multiple culture wells 20, i.e., the multiple test specimens R1, is individually associated with a sensor IC 64. However, multiple culture wells 20 may be positioned on one sensor IC 64, and multiple test specimens R1 may be simultaneously measured.

[0064] In this embodiment, the liquid medium R2 is stored in the culture well 20 as the medium, but a solid medium such as a gel may be stored instead. In this case, the antibacterial agent or other agent may be applied to the membrane filter 22. In this case, the membrane filter 22 may be eliminated and the agent may be applied to the release sheet 80.

[0065] Although the present embodiment has been described with the sensor IC 64 mounted on the substrate 62, this is not limiting. For example, as shown in FIG. 11 , the sensor IC 64 may be embedded in the substrate 62 so that the upper surface of the sensor IC 64 is substantially flush with the upper surface of the substrate 62. In this case, unnecessary tension on the water-repellent thin film 82 can be avoided. On the other hand, as shown in FIG. 12 , the sensor IC 64 may be embedded in the substrate 62 so that the upper surface of the sensor IC 64 is positioned lower than the upper surface of the substrate 62. In this case, unnecessary tension is applied to the water-repellent thin film 82 compared to the application example shown in FIG. 11 . However, the test specimen R1 and liquid culture medium R2 that have permeated the membrane filter 22 can be retained near the sensor IC 64, further enhancing the function of preventing leakage of these liquids. By using the release sheet 80 according to this embodiment, even in the detection device shown in FIGS. 11 and 12 , the culture well 20 and release sheet 80 can be collected and discarded after measurement, allowing the sensor IC 64 to be reused.

[0066] Although the release sheet 80 in this embodiment is described as a three-layer laminated sheet, it may be laminated to four or more layers by further adding, for example, another reinforcing sheet or a water-repellent thin film. Furthermore, as shown in FIG. 13 , instead of the upper and lower reinforcing sheets 84, 86, a release sheet 80A may be formed by laminating only a plurality of water-repellent thin films 82. In this case, the upper water-repellent thin film 82 may be provided with a hole 822 corresponding to the hole 842 in the reinforcing sheet 84, and similarly, the lower water-repellent thin film 82 may be provided with a hole 824 corresponding to the hole 862 in the reinforcing sheet 86. Furthermore, as shown in FIG. 14 , the upper reinforcing sheet 84 may be removed from the release sheet 80 to form a release sheet 80B. This is because the strength of the release sheet 80, including only the lower reinforcing sheet 86, is improved compared to the water-repellent thin film 82 alone. On the other hand, if contact between the molded resin and the water-repellent thin film 82 can be avoided by performing surface treatment on the substrate 62 or the sensor IC 64, the lower reinforcing sheet 86 may be removed from the release sheet 80 to form a release sheet 80C, as shown in Figure 15.

[0067] The present invention can be embodied in various other forms without departing from the spirit or main characteristics thereof. Therefore, the above-described embodiments are merely illustrative in all respects and should not be interpreted as limiting. The scope of the present invention is defined by the claims and is not limited to the text of the specification. Furthermore, all modifications, improvements, substitutions, and alterations within the scope of the claims are within the scope of the present invention.

[0068] REFERENCE SIGNS LIST 1 Measurement system 10 Measurement device 20 Culture well (holding means) 22 Membrane filter 40 Grid (support frame) 44 Lower frame (support frame) 444 Middle crosspiece 60 Detection device (detection means) 62 Substrate 64 Sensor IC (detection means) 80 Release sheet (release means) 82 Water-repellent thin film 84 Upper reinforcing sheet 86 Lower reinforcing sheet

Claims

1. A measuring device that measures the characteristics of an object under test by changes in an electric field, comprising: a holding means for holding the object under test; a detecting means for generating the electric field and detecting changes in the dielectric constant of the object under test based on the electric field; and a peeling means that is interposed between the detecting means and the holding means so as to be able to physically separate the detecting means and the holding means, is thinner than the penetration depth of the electric field, and is not able to pass through the object under test.

2. The measuring device according to claim 1, wherein the test object contains water, and the peeling means has a water-repellent thin film.

3. The measuring device according to claim 1, characterized in that the water-repellent thin film is 1 μm or less.

4. The measuring device according to claim 2, wherein said peeling means has a reinforcing sheet that contacts said water-repellent thin film so as to reinforce said water-repellent thin film.

5. The measuring device according to claim 4, characterized in that the peeling means has at least two of the reinforcing sheets, and the water-repellent thin film is sandwiched between the two reinforcing sheets.

6. A measuring device according to claim 4 or 5, characterized in that the reinforcing sheet has holes formed in the area adjacent to the detecting means.

7. A measuring device as described in claim 5, characterized in that the two reinforcing sheets have holes formed in portions close to the detection means, and the hole in the reinforcing sheet located below the water-repellent thin film is smaller than the hole in the reinforcing sheet located above the water-repellent thin film.

8. A measuring device as described in claim 1, characterized in that the test object contains a microorganism, the test object is attached to the underside, and the holding means has: a well that contains a culture medium for the microorganism; and a filter that is provided on the bottom of the well, is permeable to the culture medium, and holds the test object by the test object being attached to the underside, and is sandwiched between the well and the peeling means.

9. The measuring device according to claim 8, wherein the bottom surface of the well is smaller than the detecting means.

10. The measuring device according to claim 1, wherein the detecting means is provided on a substrate, and a support frame is disposed between the substrate and the peeling means, the support frame supporting the peeling means and being separable from the substrate.

11. The measuring device according to claim 10, wherein the peeling means is detachably attached to the support frame.

12. The measuring device according to claim 10, wherein the peeling means is provided integrally with the support frame.

13. The measuring device described in claim 10, characterized in that the support frame is arranged to surround the detection means and has a vertical height equal to or greater than that of the detection means, the peeling means is formed in a sheet shape and extends to cover the support frame and the detection means, and a storage section capable of storing liquid leaking from the holding means is formed between the portion of the peeling means on the detection means and the portion of the peeling means on the support frame.

14. The measuring device according to claim 1, wherein the detecting means is embedded in the substrate, and the upper surface of the detecting means is substantially flush with the upper surface of the substrate.

15. The measuring device according to claim 1, wherein the detecting means is embedded in the substrate, and the upper surface of the detecting means is located below the upper surface of the substrate.

Images