US20100147682A1 - Probe for measuring electric potential of cell - Google Patents
Probe for measuring electric potential of cell Download PDFInfo
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- US20100147682A1 US20100147682A1 US12/712,370 US71237010A US2010147682A1 US 20100147682 A1 US20100147682 A1 US 20100147682A1 US 71237010 A US71237010 A US 71237010A US 2010147682 A1 US2010147682 A1 US 2010147682A1
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- probe
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
- G01N33/48728—Investigating individual cells, e.g. by patch clamp, voltage clamp
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- Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
Abstract
A probe for measuring an electric potential of a cell includes a plate having a surface having a first cavity provided therein, and a sensor element provided in the first cavity. A second cavity is provided in the bottom surface of the first cavity. The first flow passage having first and second openings is provided in the plate. The first and second openings of the first flow passage open to the second cavity and outside the plate, respectively. The sensor element includes a thin plate, and a supporting substrate provided around the thin plate and in the first cavity of the plate. The thin plate has a through-hole therein having a first opening and a second opening communicating with the second cavity of the plate. The first flow passage allows fluid to flow therein. A sucking device is coupled with the second opening of the first flow passage as to suck the fluid flowing in the first flow passage. This probe can measure an electric potential of a cell floating in solution as it is in this environment.
Description
- The present invention relates to a probe for measuring an electric potential of a cell, such as an intracellular potential or an extracellular potential, used for measuring physicochemical change produced by activity of the cell.
- A patch clamping method is known as a conventional method of screening candidate pharmaceuticals by monitoring electrical activity of a cell in order to select effective pharmaceutical. In the patch clamping method, a hollow glass tube having a microscopic tip is inserted directly into a cell, thereby measuring a difference between an inside and outside of the cell. (For instance, “Single Channel Currents Recorded From Membrane of Denervated Frog Muscle Fibers”, Nature 260: 799-802, Neher E & Sakmann B, 1976) This method provides accurate measurement of the status of activities of an ion channel existing in a cell membrane.
- International Publication No. WO02/055653 discloses a device and a method for measuring an extracellular electric potential. This device includes a substrate having a holding section and electrodes to measure an extracellular electric potential. This device provides data as accurate as data provided by the patch clamping method, and measures a large amount of samples easily and quickly.
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FIG. 24 is a sectional view of the above-mentioned device for measuring an extracellular electric potential.Culture solution 51 is put incontainer 50.Target cell 52 is caught and held with the holding section provided atsubstrate 53. This holding section is formed withcavity 54, opening 55, and through-hole 56 which are all formed insubstrate 53, andhole 56 communicating withcavity 54.Reference electrode 58 is provided incontainer 50.Measuring electrode 57 is provided near through-hole 56.Electrode 57, a sensing section, is coupled to an external signal detector via wiring. -
Target cell 52 is sucked via through-hole 56 by a suction pump from the outside,contacts cavity 54, thus being held atcavity 54. Electrical signals produced by activity oftarget cell 52 is detected as an electric potential difference between measuringelectrode 57 disposed near through-hole 56 andreference electrode 58 without leakage intoculture solution 51. - This conventional device includes
substrate 53 havingcavity 54 and through-hole 56 formed therein andcontainer 50 provided onsubstrate 53.Container 50 is used for receiving and storing culture solution and chemicals. This structure, therefore, cannot measure electric potentials of cells floating in the solution in a large space as it is in this environmental condition. - The conventional device has two areas partitioned with
substrate 53, namely, one area havingtarget cell 52 therein and the other area having measuringelectrode 57, and cannot introduce respective culture solutions or chemicals different from each other into the areas. - A probe for measuring an electric potential of a cell includes a plate having a surface having a first cavity provided therein, and a sensor element provided in the first cavity. A second cavity is provided in the bottom surface of the first cavity. The first flow passage having first and second openings is provided in the plate. The first and second openings of the first flow passage open to the second cavity and outside the plate, respectively. The sensor element includes a thin plate, and a supporting substrate provided around the thin plate and in the first cavity of the plate. The thin plate has a through-hole therein having a first opening and a second opening communicating with the second cavity of the plate. The first flow passage allows fluid to flow therein. A sucking device is coupled with the second opening of the first flow passage as to suck the fluid flowing in the first flow passage.
- This probe can measure an electric potential of a cell floating in solution as it is in a current environment.
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FIG. 1 is a perspective view of a probe for measuring an electric potential of a cell in accordance withExemplary Embodiment 1 of the present invention. -
FIG. 2 is an exploded perspective view of the probe in accordance withEmbodiment 1. -
FIG. 3 is a sectional perspective view of the probe in accordance withEmbodiment 1. -
FIG. 4 is an enlarged sectional perspective view of the probe in accordance withEmbodiment 1. -
FIG. 5 is a sectional view of the probe in accordance withEmbodiment 1. -
FIG. 6 is an enlarged sectional view of the probe in accordance withEmbodiment 1. -
FIG. 7 is a perspective view of the probe in accordance withEmbodiment 1. -
FIG. 8 is a perspective view of the probe for illustrating its usage in accordance withEmbodiment 1. -
FIG. 9 is a schematic diagram of the probe in accordance withEmbodiment 1. -
FIG. 10 is a sectional view of the probe in accordance withEmbodiment 1. -
FIG. 11 is a sectional view of the probe in accordance withEmbodiment 1. -
FIG. 12 is a sectional view of the probe in accordance withEmbodiment 1. -
FIG. 13 is a sectional view of the probe in accordance withEmbodiment 1. -
FIG. 14 is a sectional view of the probe in accordance withEmbodiment 1. -
FIG. 15 is a plan view of another probe for measuring an electric potential of a cell in accordance withEmbodiment 1. -
FIG. 16A is an enlarged sectional view of the probe shown inFIG. 15 . -
FIG. 16B is an enlarged sectional view of still another probe for measuring an electric potential of a cell in accordance withEmbodiment 1. -
FIG. 17 is a sectional view of a probe for measuring an electric potential of a cell in accordance withExemplary Embodiment 2 of the invention. -
FIG. 18 is an enlarged sectional view of the probe in accordance withEmbodiment 2. -
FIG. 19A is a sectional view of the probe for illustrating its usage in accordance withEmbodiment 2. -
FIG. 19B is an enlarged sectional view of the probe shown inFIG. 19A . -
FIG. 20 is an exploded perspective view of a probe for measuring an electric potential of a cell in accordance withExemplary Embodiment 3 of the invention. -
FIG. 21 is a sectional perspective view of the probe in accordance withEmbodiment 3. -
FIG. 22 is an enlarged sectional view of the probe in accordance withEmbodiment 3. -
FIG. 23 is a perspective view of a probe array for measuring an electric potential of a cell in accordance withEmbodiment 3. -
FIG. 24 is a sectional view of a conventional probe for measuring an electric potential of a cell. -
- 1 Probe for Measuring Electric Potential of Cell
- 2 Plate
- 2A Molded Plate
- 2B Molded Plate
- 3 Cavity (First Cavity)
- 4 Sensor Element
- 5 Cavity (Third Cavity)
- 6 Cavity (Second Cavity)
- 7 Supporting Substrate
- 8 Thin Plate
- 9 Through-Hole
- 10 Flow Passage (Second Flow Passage)
- 10A Opening (First Opening)
- 11 Flow Passage (First Flow Passage)
- 11A Opening (First Opening)
- 12 Opening (Second Opening)
- 13 Sucking Device
- 15 Container (Pouring Device)
- 16 Measurement Solution
- 17 Bump
- 18 Reference Electrode (First Electrode)
- 19 Measuring Electrode (Second Electrode)
- 20 Target Cell
- 21 Culture Solution
- 22 Opening (Second Opening)
- 23 Valve
- 26 Supporting Substrate
- 27 Probe for Measuring Electric Potential of Cell
- 28 Plate
- 29 Sensor Element
- 30 Thin Plate
- 31 Through-Hole
- 32 Cavity
- 33 Microscope
- 34 Patch Probe
- 35 Target Cell
- 36 Culture Solution
- 37A, 37B Recess
- 117 Bump
- 501 Probe for Measuring Electric Potential of Cell
- 502 Plate
- 503 Cavity (First Cavity)
- 504 Sensor Element
- 505 Cavity (Third Cavity)
- 506 Cavity (Second Cavity)
- 507 Thin Plate
- 508 Through-Hole
- 509 Flow Passage (Second Flow Passage)
- 510 Flow Passage (First Flow Passage)
- 511 Opening (Second Opening)
- 512 Supporting Substrate
- 514 Reference Electrode (First Electrode)
- 515 Measuring Electrode (Second Electrode)
- 518 Opening (Second Opening)
- 519 Probe Array for Measuring Electric Potential of Cell
- 520 Well Array
- 521A Through-Hole
- 521B Through-Hole
- 521C Through-Hole
- 522 Well
- 523 Well
- 524 Well
-
Exemplary Embodiment 1 -
FIG. 1 is a perspective view ofprobe 1 for measuring an electric potential of a cell in accordance withExemplary Embodiment 1 of the present invention.FIG. 2 is an exploded perspective view ofprobe 1.FIG. 3 is a sectional perspective view ofprobe 1.FIG. 4 is an enlarged sectional perspective view ofprobe 1.FIG. 5 is a sectional view ofprobe 1.FIG. 6 is an enlarged sectional view of an essential part ofprobe 1.Probe 1 includessensor element 4 andplate 2 made of insulating material, such as resin or glass.Plate 2 hascavity 3 provided inupper surface 2C thereof.Sensor element 4 is fit intocavity 3.Cavity 6 is provided underbottom surface 3A ofcavity 3.Cavity 6 is positioned undersensor element 4. -
Plate 2 includes moldedplate 2A and moldedplate 2B attached ontoplate 2A, and can be shaped in a complicated shape easily.Plate 2B hasflow passages Plate 2A hasopenings Cavity 3 shaped like a through-hole andcavity 6 communicate with each other. -
Cavity 6 communicates withopenings flow passages plate 2, respectively.Other openings flow passages upper surface 2C ofplate 2, respectively. The sectional area of each offlow passages flow passages Lower surface 6A ofcavity 6 hasbump 17 thereon projecting towardsensor element 4, i.e. projecting upward towardscavity 6. This structure enables the adjusting of the sectional areas offlow passages openings cavity 6, so that solution to be used for measuring can move smoothly throughflow passage 10,cavity 6, and flowpassage 11. -
Sensor element 4 includes supportingsubstrate 7 made of a silicon substrate or a laminated body including a silicon substrate and a silicon-dioxide film on the silicon substrate.Upper surface 7A of supportingsubstrate 7 faces towards a direction identical to a direction towards whichupper surface 2C ofplate 2 faces, and hascavity 5 provided therein.Thin plate 8 providesbottom surface 5A ofcavity 5.Thin plate 8 has through-holes 9 having small diameters allowingupper surface 8A (bottom surface 5A of cavity 5) to communicate withlower surface 8B ofthin plate 8. Oneopening 9A of each of through-holes 9 opens tocavity 5, and anotheropening 9B of each of through-holes 9 communicates withcavity 6 provided inplate 2. - Measuring
electrode 19 made of platinum, gold, silver, or silver chloride is provided onlower surface 8B ofthin plate 8, i.e., onlower surface 7B of supportingsubstrate 7 ofsensor element 4. Measuringelectrode 19 is connected with a lead electrode made of a wire or a thin-film electrode for which connecting the measuring electrode with a measuring instrument outsideprobe 1 for detecting a signal. -
Sensor element 4 is bonded so securely intocavity 3 with an adhesive so that the solution (measurement solution) to be used formeasurement filling passages cavity 6 can be prevented completely from leakage.Sensor element 4 may be bonded intocavity 3 by fusion bonding or ultrasonic bonding. -
FIG. 7 is a perspective view ofprobe 1 for measuring an electric potential of a cell.Tube 24A is connected with opening 12 offlow passage 10.Tube 24B is connected withflow passage 11.Tube 24B is connected with suckingdevice 13, andtube 24A is connected withcontainer 15.Valve 23 is provided betweencontainer 15 andopening 12 to stop the flow of fluid, such as the measurement solution, upon necessary. Suckingdevice 13 providescavity 6 with decompressed atmosphere therein having a pressure lower than that incavity 5. Suckingdevice 13 may be an ordinary pump, such as a diaphragm pump, a syringe pump, or sucking with a human mouth, and is not limited to these. - A method of measuring an electric potential of a cell with
probe 1 will be described below. -
FIG. 8 is a perspective view ofprobe 1 for illustrating its usage.Probe 1 is mounted to measuringstick 25.Probe 1 is fixed to end 25A of measuringstick 25.Tube 24A coupled withflow passage 10,tube 24B coupled withflow passage 11, andelectrode wire 19A electrically coupled with measuringelectrode 19 are arranged insidestick 25, and are drawn out from anotherend 25B ofstick 25.Electrode wire 19A is connected with an external measuring instrument for supplying measured signals to the instrument. -
FIG. 9 is a schematic diagram ofprobe 1 which being used. Measuringstick 25 havingprobe 1 mounted thereto is dipped intoculture solution 21 stored incontainer 14.Target cells 20 float insolution 21.Reference electrode 18contacts solution 21 incontainer 14, thus sensing an electric potential ofsolution 21 incontainer 14.Probe 1 is positioned so thatsensor element 4 can be dipped insolution 21. -
FIGS. 10 to 14 are sectional views ofprobe 1 for illustrating a method for measuring an electric potential of a cell with the probe. - As shown in
FIG. 10 ,target cells 20 float abovesensor element 4 insolution 21. - Next, as shown in
FIG. 11 ,valve 23 is closed so thatflow passages cavity 6 are shut off fromcontainer 15. Then,cavity 6 is decompressed by suckingdevice 13 to have a pressure therein lower than that incavity 5. This operation causessolution 21 andcells 20 fillingcavity 5 to be sucked towards through-holes 9, and then, causessolution 21 to flow intocavity 6. Each ofcells 20 has a size larger than the sectional area of through-hole 9, and hence, does not pass through through-holes 9, thus being held atopenings 9A ofholes 9.Solution 21 flowing intocavity 6contacts measuring electrode 19, thereby allowing an electric potential incavity 6 to be detected. In this situation, a difference between respective electric potential ofreference electrode 18 and measuringelectrode 19, an electrical resistance between the electrodes, and a capacitance between the electrodes can be measured. - When
target cells 20 are held atopenings 9A of through-holes 9,sensor element 4 separatesculture solution 21 intoportion 21A incavity 5 andportion 21B incavity 6, thereby increases the resistance betweenreference electrode 18 and measuringelectrode 19. - Then,
cavity 6 is further decompressed by suckingdevice 13, and accordingly, as shown inFIG. 12 , the surface oftarget cell 20 is urged more strongly ontoopening 9A ofhole 9, accordingly providing the resistance betweenelectrodes cell 20 is merely held atopening 9A. At this moment, the resistance exceeds 100MΩ and may exceed 1GSZ, which is called “Giga-Seal”. In the Giga-Seal, an ion-channel activity ofcells 20 causes ion exchange betweenculture solution 21 andcells 20, thereby changing an inner electric potential of each ofcells 20. This change can be detected as the difference between respective electric potentials ofreference electrode 18 and measuringelectrode 19. - The ion channel activity changes according to pharmaceutical contained in
culture solution 21, and is detected as the difference of respective electrical potentials ofelectrodes target cells 20, thus allowing a pharmaceutical chemically effect tocells 20 to be determined. -
Reference electrode 18 and measuringelectrode 19 are arranged nearopenings holes 9, respectively, to measure the electric potential difference aroundcell 20 accurately.Probe 1 can catchcells 20 floating insolution 21 easily to provide the Giga-Seal. -
Upper surface 2A ofplate 2 is flush withupper surface 7A of supportingsubstrate 7, and hence,solution 21 includingcells 20 can be directly supplied ontoupper surface 7A of supportingsubstrate 7 or intocavity 5 with a plate pipette, as shown inFIG. 13 . This arrangement allowscells 20 to be observed easily with a microscope from aboveupper surface 2C ofplate 2. Further, this arrangement allows bubbles produced aroundcells 20 to be removed easily, accordingly enabling the pharmaceutical to be applied tocells 20 without fail. - When
valve 23 is opened in the Giga-Seal shown inFIG. 12 ,measurement solution 16 incontainer 15 is sucked intoflow passage 10 andcavity 6, as shown inFIG. 14 . Thus,container 15 functions as a pouring device for introducingmeasurement solution 16 intoflow passage 10.Flow passage 11 is decompressed by suckingdevice 13, and accordingly,portion 21B ofsolution 21 incavity 6 is replaced bymeasurement solution 16.Measurement solution 16, including a large concentration of K+, allows the change in the electrical potential ofcells 20 to be measured more accurately. -
Reference electrode 18 and measuringelectrode 19 may be formed nearopenings holes 9 by a thin-film technique to detect the change in the electric potential oftarget cell 20. -
FIG. 15 is a plan view of anotherprobe 1A for measuring an electric potential of a cell in accordance withEmbodiment 1. Each offlow passages passages culture solution 21 andmeasurement solution 16 flowing intocavity 6 from leaking to outside, and from having bubbles in the solutions from outside. -
FIG. 16A is an enlarged sectional view ofprobe 1A at line 16-16 shown inFIG. 15 .Pocket 37A having a diameter larger than that of through-hole 9 is provided atopening 9A of through-hole 9 facingcavity 5 as to catch the target cell more securely. -
FIG. 16B is an enlarged sectional view of still anotherprobe 1B in accordance withEmbodiment 1. Inprobe 1B,pocket 37B having a diameter larger than that of through-hole 9 is provided atopenings 9B of through-holes 9 facingcavity 6. This structure stabilizes the fluidity ofculture solution 21 incavity 6 and the fluidity ofmeasurement solution 16 nearopenings 9B of through-holes 9. - As shown in
FIGS. 16A and 16B ,edge 117A ofbump 117 andedge 6B ofcavity 6 are chamfered to have rounded shapes, thereby allowingmeasurement solution 16 to flow smoothly. - The insulating material, resin or glass, of
plate 2 may be transparent to transmit visible light through the material. This structure allows the user to observeopenings 9A of through-holes 9 easily fromcavity 6 with a microscope. Hence, monitoringculture solution 21 andmeasurement solution 16 flowing intocavity 6 as well as presence of bubbles, a user can measure the electric potential oftarget cell 20. -
Thin plate 8 ofsensor element 4 may be made of transparent material, such as resin or glass, transmitting visible light therein. This structure allows a user to observetarget cell 20 from below the lower surface ofplate 2 with a microscope. -
FIG. 17 is a sectional view ofprobe 27 for measuring an electric potential of a cell in accordance withExemplary Embodiment 2 of the present invention.FIG. 18 is an enlarged sectional view ofsensor element 29 ofprobe 27. Components identical to those ofEmbodiment 1 are denoted by the same reference numerals, and their descriptions will be omitted. -
Probe 27 includesplate 28 andsensor element 29.Upper surface 28C ofplate 28 hascavity 83 provided therein.Cavity 6 is provided inbottom surface 83A ofcavity 83.Sensor element 29 is fit intocavity 83.Sensor element 29 includes supportingsubstrate 26. Supportingsubstrate 26 haslower surface 26 B having cavity 32 provided therein.Thin plate 30 is provided atbottom surface 32A ofcavity 32.Thin plate 30 has through-holes 31 allowingupper surface 30A ofplate 30 to communicate withlower surface 30B (bottom surface 32A of cavity 32) ofplate 30. Opening 31A of each of through-holes 31 opens atupper surface 30A of thin plate 30 (upper surface 26A of supporting substrate 26) and communicates with the outside. Opening 31B of each of through-holes 31 opens atlower surface 30B ofthin plate 30 and communicates withcavity 32 andcavity 6. Thus, through-holes 31 communicate withflow passages cavity 6 provided inplate 28. Measuringelectrode 19 is provided onlower surface 30B ofthin plate 30 upon necessary. -
FIG. 19A is a sectional view ofprobe 27 for illustrating its usage.FIG. 19B is an enlarged sectional view ofprobe 27 shown inFIG. 19A . Similarly to probe 1 ofEmbodiment 1,upper surface 26A of supportingsubstrate 26 ofsensor element 29 is flush withupper surface 28C ofplate 28, so that no bump or dip is provided thereon. This structure allowstarget cell 35 to be observed more closely to the cell withmicroscope 33. Observingcells 35 withmicroscope 33, a user can attachpatch probe 34 tocell 35. This operation allows the user to measure ion-channel activity at plural portions ofcell 35. For instance, when pharmaceutical is put intoculture solution 36, the probe can detect simultaneously two electric potentials: an electric potential ofpatch probe 34 attached toportion 35A near an applying position wherecell 35 is supplied; and an electric potential of measuringelectrode 19 nearportion 35B ofcell 35 caught at through-holes 31.Portion 35A is farther from the applying position thanportion 35A. This simultaneous detection of those two electric potentials allows a transferring state fromportion 35A toportion 35B of ion-channel activity incell 35 to be detected. - As well as
probe 1,plate 2, and supportingsubstrate 7 ofEmbodiment 1,plate 28 andthin plate 30 ofprobe 27 may be made of transparent material transmitting visible light therethrough, providing effects similar to those ofEmbodiment 1. -
FIG. 20 is an exploded perspective view ofprobe 501 for measuring an electric potential of a cell in accordance withExemplary Embodiment 3 of the present invention.FIG. 21 is a sectional perspective view ofprobe 501.FIG. 22 is an enlarged sectional view of an essential part ofprobe 501.Probe 501 includesplate 502,sensor element 504, andwell array 520.Plate 502 is made of insulating material, such as resin or glass.Upper surface 502C ofplate 502 hascavity 503 provided therein.Bottom surface 503A ofcavity 503 hascavity 506 provided therein.Sensor element 504 is fit intocavity 503.Cavity 506 is positioned belowsensor element 504. -
Cavity 506 is connected withflow passages Flow passage 509 has opening 511 thereof provided inupper surface 502C ofplate 502.Flow passage 510 has opening 518 thereof provided atupper surface 502C.Flow passages plate 502. Moldedplate 502A previously molded is stuck on moldedplate 502B previously molded, thus providingplate 502.Flow passages plate 502B.Openings plate 502A.Cavities plate 502A are shaped like a through-hole and communicate with each other.Sensor element 504 includes supportingsubstrate 512 andthin plate 507. As shown inFIG. 22 ,cavity 505 is provided below thin plate 507 (at the side oflower surface 512B ofplate 502 opposite toupper surface 502C about plate 502). In other words,thin plate 507 providesbottom surface 505A ofcavity 505.Thin plate 507 has small through-holes 508 allowingupper surface 507A (upper surface 512A of supporting substrate 512) to communicate withlower surface 507B.Openings 508A of through-holes 507 provided atupper surface 507A (upper surface 512A of supporting substrate 512) hold target cells, respectively. Through-holes 508 necessarily have diameters smaller than the sizes of the target cells. Similarly to the probe shown inFIG. 16A , a pocket having a diameter larger than that of through-hole 508 may be provided at each ofopenings 508A to hold the target cell securely and stably. Each of through-hole 508 hasopening 508B which opens tocavity 505 atlower surface 507B (lower surface 505A of cavity 505) ofthin plate 507. Opening 508A of through-hole 508 communicates withupper surface 512A ofsubstrate 512 ofsensor element 504. Opening 508B of through-hole 508 communicates withcavity 506 viacavity 505. This structure allows liquid, such as culture solution and chemicals, to flow in through-holes 508 andcavities - In
sensor element 504,thin pate 507 is placed at the upper part, that is,upper surface 512A of supportingsubstrate 512 andupper surface 502C ofplate 502 are positioned in a single, common plane. However, similarly to the probe shown inFIG. 6 in accordance withEmbodiment 1,cavity 505 may be provided inupper surface 512A of supportingsubstrate 512. - Well
array 520 is placed onupper surface 502A ofplate 502. Wellarray 520 has a predetermined capacity for receiving, storing, or circulating liquid, such as culture solution and chemicals, therein. Wellarray 520 haswells Lower surface 522A of well 522 has through-hole 521A provided therein and communicates with opening 511 offlow passage 509.Lower surface 523A of well 523 has through-hole 521B provided therein and communicates with through-hole 508 provided inthin plate 507 ofsensor element 504.Lower surface 524A of well 524 has through-hole 521C provided therein and communicates with opening 518 offlow passage 510.Wells openings Reference electrode 514 is provided inwell 523. Measuringelectrode 515 is provided inflow passage 510 and is drawn out to the outside ofplate 502. - Culture solution containing the target cells is introduced into well 523 from opening 523B, and is sucked from opening 524B of well 524 with a sucking device, such as a suction pump. The culture solution accordingly flows in through-
holes 508 and is sucked into well 524 viacavities flow passage 510, andopening 518. Alternately, measurement solution or culture solution is introduced into well 522, and is sucked from well 524. Then, the solution sufficiently fillsflow passages cavities flow passages well 522 is closed, and after that, the cells are input into well 523 while the measurement solution is sucked from well 524. - Since through-
holes 508 ofsensor element 504 have the diameters small enough to preventing the target cells from passing through the holes, the cells can be held atopenings 508A ofholes 508, thereby having electric potentials measured while held at through-holes 508. According toEmbodiment 3,thin plate 507 has plural through-holes 508 provided therein, thus measuring the electric potentials of the cells at once. After the target cells clogs all of through-holes 508, the other cells remain inwell 523. Then, the amount of the culture solution flowing intocavity 505 accordingly decreases, and it is accordingly detected that the cells are held atopenings 508A of through-holes 508. This operation can be performed by controlling a suctioning force at well 524 while measuring a flow rate of the culture solution. The suctioning may be performed from well 522, providing the same effects. - Opening 523B of
well 523 is closed. Then, chemicals is introduced into well 522 and is sucked from well 524 with the sucking device, accordingly flowing in through-hole 521A, throughopening 511,flow passage 509,cavities flow passage 510, andopening 518, and then being sucked intowell 524. At this moment, the chemicals contact, throughopenings 508B ofholes 508, the target cells trapped atopenings 508A of through-holes 508, causing the cells to react with the chemicals. The electric potentials of the cells produced due to the reaction can be measured throughreference electrode 514 contacting the culture solution in well 523 and through measuringelectrode 515 contacting the chemicals inflow passage 510. -
Probe 501 allows liquids, such as culture solution and chemicals, different from each other to be introduced into well 523 having the target cells therein and flowpassage 510 having measuringelectrode 515 therein, respectively. Sucking the solution between well 522 and well 524 allows one solution to be replaced easily by the other solution. - Well
array 520 having threewells holes 508. In this case, the well array may have only two wells (for example,wells 523 and 524) therein as to perform the measurement. -
Upper surface 502C ofplate 502 is attached securely ontobottom surface 520A ofwell array 520 to enable wellarray 520 to sealplate 502 securely, thereby preventing the solution securely from leakage. - Well
array 520 may be made of material identical to that ofplate 502, hence preventing their deformation due to a difference between respective expansion coefficients of the materials, and thereby sealingplate 502 securely. - Well
array 520 andplate 502 may be made of thermoplastic resin, such as polystyrene, cycloolefin polymer, or cycloolefin copolymer, hence providing a secure sealing by ultrasonic fusion or laser welding, and allowingprobe 501 to be manufactured at a high productivity. - Well
array 520 andplate 502 may be made of glass material or quartz material. These materials can have surfaces directly bonded onto each other without an adhesive if the surfaces are polished to be finished in mirror-like. Each of these materials has a large resistance to heat, thus being bonded to each other with non-organic adhesive, such as glass adhesive or ceramic adhesive. Wellarray 520 andplate 502 made of these materials have large heat resistance, hence providingprobe 501 re-usable by heat-washing. - As shown in
FIG. 21 , at least through-hole 521B out of through-holes lower surfaces wells opening 523B of well 523, that is, may taper towards through-hole 508 ofsensor element 504. This structure introduces the culture solution or chemicals, which are put into well 523, into through-holes 508 ofsensor element 504 quickly. - As shown in
FIG. 21 , through-hole 521B has a size larger than that ofthin plate 507 having through-holes 508 provided therein, allowing the target cells to be introduced efficiently into through-holes 508. Wellarray 520 has well 523 having the culture solution containing the target cells input thereinto, well 522 having the chemicals input thereinto, and well 524 coupled with the sucking device. This structure allowsupper surface 502C ofplate 502 to hold the target cells easily, and allows operations, such as the inputting of the chemicals, to be performed independently from above wellarray 520, thus allowingprobe 501 to be manipulated easily for measuring the electric potential. - Through-
hole 521A of well 522 has a size larger that of opening 511 offlow passage 509, and through-hole 521C ofwell 524 has a size larger than that of opening 518 offlow passage 510. This structure can introduce liquid, such as the chemicals, quickly into the flow passages, allowingprobe 501 to measure the electric potential of the cells accurately with little variation. -
Reference electrode 514 is provided in well 523 at a predetermined position contacting the culture solution. Measuringelectrode 515 is provided inflow passage 510 and contacts the liquid, such as the culture solution or the chemicals, inflow passage 510. This structure can measure an electric potential of the target cell in the culture solution and an electric potential of the cell after the liquid, such as the chemicals is input from well 522 or well 523, thus measuring the change between the above potentials. Measuringelectrode 515 may be provided nearcavity 505 orcavity 506. -
Reference electrode 514 and measuringelectrode 515 are made of wires or thin-film electrodes, and are coupled to a measuring instrument outsideprobe 501 for detecting signals from those electrodes. - A method of measuring an electric potential of the cells with
probe 501 will be described below. - First, the culture solution containing the target cells is introduced into well 523, and is sucked with by the sucking device from well 522 or well 524 for holding the cells at through-
holes 508 ofsensor element 504. An electric resistance betweenreference electrode 514 which contacts the culture solution and is provided in well 523, and measuringelectrode 515 provided inflow passage 510 is measured. A suctioning pressure of the suction device is controlled so that the resistance betweenelectrodes flow passage 510 exceeds 100 MΩ.Reference electrode 514 and measuringelectrode 515 are made of conductive material, such as Au, Ag, or AgCl, and contact the culture solution to be connected electrically with the solution. Therefore, the positions ofelectrodes - Next, the measurement solution, such as chemicals, are stored in well 522 and is sucked from well 524, thereby causing the culture solution in
flow passage 509,cavities passage 510 to be replaced by the measurement solution. Thus, solutions, such as the culture solution and the measurement solution, different from each other can be introduced easily into well 523 having the cells therein andcavity 506 having measuringelectrode 515 therein, respectively. This operation allows the electric potential of the cells to be measured quickly. - Even if respective functions of well 522 and well 524 are replaced by each other, the electric potential of the cells can be measured.
-
Wells probe 5 to be controlled easily. - Another
probe 519,probe array 519, includingplural probes 501 in accordance withEmbodiment 3 will be described below.FIG. 23 is an exploded perspective view of probe 519 (probe array 519) for measuring an electric potential of a cell.Probes 501 are arranged in a matrix having four rows and eight columns. Pluralwell arrays 520 each havingwells array unit 520A. -
Probe array 519 includingplural probes 501 arranged in a predetermined arrangement allows a robot to pour the chemicals, to input cells, and to suck the cells. Thus, probe 519 can measure respective electric potentials of a lot of cells in a short time for determining pharmacological effect, thus screening candidate pharmaceuticals quickly. - A probe for measuring an electric potential of a cell according to the present invention can measure electric potentials of cells floating in solution as they are in environment, hence being used for determining pharmacological effects to the cells and for screening pharmaceuticals.
Claims (29)
1-33. (canceled)
34. A probe for measuring an electric potential of a cell, said probe being arranged to be used with a sucking device, said probe comprising:
a plate made of resin and having a surface, the plate having a first cavity provided in the surface of the plate, a second cavity, and a first flow passage provided in the plate, the first cavity having a bottom surface, the second cavity being provided in the bottom surface of the first cavity, the first flow passage having a first opening and a second opening, the first opening of the first flow passage opening to the second cavity, the second opening of the first flow passage opening outside the plate; and
a sensor element made of silicon and provided in the first cavity, the sensor element including
a thin plate having a first surface and a second surface opposite to the first surface of the thin plate, the thin plate having a through-hole provided therein, the through-hole having a first opening and a second opening, the first opening of the through-hole opening to the first surface of the thin plate, the second opening of the through-hole opening to the second surface of the thin plate and connected with the second cavity of the plate, and a supporting substrate provided around the thin plate and in the first cavity of the plate,
wherein the first flow passage allows fluid to flow therein, and the sucking device is arranged to be coupled with the second opening of the first flow passage so as to suck the fluid flowing in the first flow passage, and
wherein the second opening of the second flow passage is arranged to be coupled to a pouring device, and the pouring device is operable to put fluid into the second opening of the second flow passage.
35. The probe of claim 34 , wherein the bottom surface of the first cavity and the second surface of the thin plate of the sensor element are flush with each other.
36. The probe of claim 35 , wherein
the supporting substrate of the sensor element have a first surface and a second surface, the first surface of the supporting substrate facing towards a direction identical to a direction towards which the surface of the plate faces, the second surface of the supporting substrate is provided on the bottom surface of the first cavity of the plate, and
a third cavity is provided on the first surface of the thin plate.
37. The probe of claim 34 , wherein the supporting substrate of the sensor element is bonded to the plate.
38. The probe of claim 34 , wherein the plate further have a second flow passage provided therein, the second flow passage having a first opening and a second opening, the first opening of the second flow passage opening to the second cavity, the second opening of the second flow passage opening outside the plate.
39. The probe of claim 38 , wherein the second opening of the second flow passage is arranged to be coupled to a pouring device, and the pouring device is operable to put fluid into the second opening of the second flow passage.
40. The probe of claim 34 , wherein a valve is arranged to be connected between the pouring device and the second flow passage.
41. The probe of claim 38 , wherein at least one of the first flow passage and the second flow passage has a curved portion.
42. The probe of claim 38 , wherein the plate includes a bump which is provided between the first flow passage and the second flow passage and 10 which projects toward the second cavity.
43. The probe of claim 34 , further comprising electrodes provided on the sensor element around the first opening of the through-hole and the second opening of the through-hole, respectively.
44. The probe of claim 34 , wherein the thin plate of the sensor element has a pocket provided therein at at least one of the first opening of the through-hole and the second opening of the through-hole of the thin plate, the pocket having a diameter larger than a diameter of the through-hole of the thin plate.
45. The probe of claim 34 , wherein the surface of the plate and the first surface of the thin-plate of the sensor element are flush with each other.
46. The probe of claim 45 , wherein
the supporting substrate of the sensor element have a first surface and a second surface, the first surface of the supporting substrate facing towards a direction identical to a direction towards which the surface of the plate faces, the second surface of the supporting substrate is provided on the bottom surface of the first cavity of the plate, and
a third cavity is provided on the first surface of the thin plate.
47. The probe of claim 34 , further comprising a well array having a first well, a second well, and a third well provided therein, the first well, the second well, and the third well having openings and bottom surfaces, respectively, wherein
the bottom surface of the first well has a through-hole which is provided therein and which communicates with the second opening of the first flow passage,
the bottom surface of the second well has a through-hole which is provided therein and which communicates with the through-hole of the thin plate of the sensor element, and
the bottom surface of the third well has a through-hole which is provided therein and which communicates with the second opening of the second flow passage.
48. The probe of claim 47 , wherein the through-hole of the second well tapers toward the through-hole of the thin-plate of the sensor element.
49. The probe of claim 47 , further comprising:
a first electrode provided in the second well; and
a second electrode provided in one of the third well and the first flow passage.
50. The probe of claim 47 , wherein
fluid including a target cell is input in the second well,
fluid for detecting reaction with the target cell is input into the third well, and
the first well is coupled to the sucking device.
51. The probe of claim 47 , wherein the second well is provided above the first surface of the thin plate of the sensor element.
52. The probe of claim 51 , wherein the through-hole of the second well has a size larger than a size of the thin plate.
53. The probe of claim 47 , wherein the through-hole of the first well is larger than the second opening of the first flow passage.
54. The probe of claim 47 , wherein the through-hole of the third well is larger than the second opening of the second flow passage.
55. The probe of claim 47 , wherein the well array has a bottom surface, the bottom surface of the well array having the through-hole of the first well, the through-hole of the second well, and the through-hole of the third well open thereto, the bottom surface of the well array and the surface of the plate is positioned in a plane.
56. The probe of claim 47 , wherein the well array comprises material identical to material of the plate.
57. The probe of claim 47 , wherein the plate and the well array comprise thermoplastic resin.
58. The probe of claim 47 , further comprising:
another plate having a plurality of openings provided therein; and another sensor element including another thin plate, the another thin plate having a plurality of through-holes opening in a direction identical to a direction in which the plurality of openings of the another plate open,
wherein the well array further has a plurality of other wells, each of the other wells having bottom surfaces, the bottom surfaces of the other wells having a plurality of through-holes provided therein, respectively, and the plurality of through-holes of the other wells communicate with the plural openings of the another plate and the plurality of through-holes of the another sensor element, respectively.
59. The probe of claim 34 , the resin is exposed to the first flow passage entirely from the first opening of the first flow passage to the second opening of the first flow passage.
60. The probe of claim 38 , the resin is exposed to the second flow passage entirely from the first opening of the second flow passage to the second opening of the second flow passage.
61. The probe of claim 34 , further comprising:
a first tube connected to the second opening of the first flow passage to suck the fluid through the first tube; and
a second tube connected to the second opening of the second flow passage to put the fluid into the second flow passage through the second tube.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/712,370 US20100147682A1 (en) | 2004-08-25 | 2010-02-25 | Probe for measuring electric potential of cell |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004245574 | 2004-08-25 | ||
JP2004-245574 | 2004-08-25 | ||
JP2004-323358 | 2004-11-08 | ||
JP2004323358 | 2004-11-08 | ||
PCT/JP2005/013029 WO2006022092A1 (en) | 2004-08-25 | 2005-07-14 | Probe for measuring cell potential |
US10/595,275 US7736477B2 (en) | 2004-08-25 | 2005-07-14 | Probe for measuring electric potential of cell |
US12/712,370 US20100147682A1 (en) | 2004-08-25 | 2010-02-25 | Probe for measuring electric potential of cell |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/013029 Continuation WO2006022092A1 (en) | 2002-06-05 | 2005-07-14 | Probe for measuring cell potential |
US11/595,275 Continuation US7566564B2 (en) | 2003-09-02 | 2006-11-09 | Signal amplification using a synthetic zymogen |
Publications (1)
Publication Number | Publication Date |
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US20100147682A1 true US20100147682A1 (en) | 2010-06-17 |
Family
ID=35967312
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Application Number | Title | Priority Date | Filing Date |
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US10/595,275 Expired - Fee Related US7736477B2 (en) | 2004-08-25 | 2005-07-14 | Probe for measuring electric potential of cell |
US12/712,370 Abandoned US20100147682A1 (en) | 2004-08-25 | 2010-02-25 | Probe for measuring electric potential of cell |
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US10/595,275 Expired - Fee Related US7736477B2 (en) | 2004-08-25 | 2005-07-14 | Probe for measuring electric potential of cell |
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US (2) | US7736477B2 (en) |
EP (1) | EP1783202B1 (en) |
JP (1) | JPWO2006022092A1 (en) |
WO (1) | WO2006022092A1 (en) |
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CN109473614A (en) * | 2017-09-08 | 2019-03-15 | 莫仕连接器(成都)有限公司 | Battery connection module |
Also Published As
Publication number | Publication date |
---|---|
EP1783202B1 (en) | 2013-10-02 |
US7736477B2 (en) | 2010-06-15 |
US20070105183A1 (en) | 2007-05-10 |
WO2006022092A1 (en) | 2006-03-02 |
JPWO2006022092A1 (en) | 2008-05-08 |
EP1783202A4 (en) | 2012-02-29 |
EP1783202A1 (en) | 2007-05-09 |
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