WO2009081521A1 - 細胞電気生理センサの製造方法およびその製造装置 - Google Patents
細胞電気生理センサの製造方法およびその製造装置 Download PDFInfo
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- WO2009081521A1 WO2009081521A1 PCT/JP2008/003510 JP2008003510W WO2009081521A1 WO 2009081521 A1 WO2009081521 A1 WO 2009081521A1 JP 2008003510 W JP2008003510 W JP 2008003510W WO 2009081521 A1 WO2009081521 A1 WO 2009081521A1
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- glass tube
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- holding
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- cell electrophysiological
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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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- the present invention relates to a method for manufacturing a cell electrophysiological sensor that can be used for analysis of pharmacological reactions of cells and the like, and a manufacturing apparatus therefor.
- the patch clamp method in electrophysiology is known as a method for measuring ion channels existing in cell membranes, and various functions of ion channels have been elucidated by this patch clamp method. And the action of ion channels is an important concern in cytology, which has also been applied to drug development.
- the patch clamp method requires extremely high ability to insert a fine micropipette into a single cell with high accuracy in the measurement technique. Therefore, it is not an appropriate method when a skilled worker is required and measurement is required with high throughput.
- the conventional cellular electrophysiological sensor includes a mounting substrate 1 made of resin, a sensor chip 3 made of silicon inserted into a through hole 2 of the mounting substrate 1, and above and below the mounting substrate 1. Electrodes 4 and 5 are provided, respectively.
- the sensor chip 3 includes a conduction hole 6.
- the electrolytic cell 7 disposed in the through hole 2 of the mounting substrate 1 and on the mounting substrate 1 and the electrolytic cell 8 disposed on the lower side are both filled with the electrolytic solution. These electrolytic cells 7 and 8 are partitioned by the mounting substrate 1 and the sensor chip 3.
- this cell electrophysiological sensor can inject
- a drug is administered from above the cell 9 and the potential difference between the electrolytic cells 7 and 8 is measured with the electrodes 4 and 5, the pharmacological reaction of the cell 9 can be determined (for example, see Patent Document 1). ).
- the conventional sensor chip 3 has a problem that the measurement accuracy of the cell electrophysiological sensor is low. This is because the bubbles 10 are likely to adhere to the vicinity of the conduction hole 6 of the sensor chip 3.
- the conventional cell electrophysiological sensor is manufactured by directly inserting the sensor chip 3 into the mounting substrate 1 and fixing it with an adhesive or the like.
- the outer periphery of the sensor chip 3 is surrounded by the inner wall of the through hole 2 of the mounting substrate 1. Since the mounting substrate 1 is hydrophobic, bubbles are easily generated in the through holes 2.
- the adhesion between the cell 9 and the opening of the conduction hole 6 is weakened, or conduction between the upper and lower sides of the conduction hole 6 is inhibited, and the suction of the cell 9 is hindered. It is done. As a result, the measurement accuracy of the cell electrophysiological sensor decreases.
- An object of the present invention is to produce a cell electrophysiological sensor with high measurement accuracy.
- the present invention includes a step of holding a sensor chip, a step of holding a glass tube surrounding the outer periphery of the side surface of the sensor chip, and applying wind pressure from the outside of the glass tube toward the side of the glass tube, and melting the glass tube.
- a side surface of the sensor chip and a step of glass welding are provided.
- the present invention can manufacture a cell electrophysiological sensor with high measurement accuracy. That is, according to the present invention, the outer periphery of the sensor chip can be surrounded by a highly hydrophilic glass tube. Therefore, it is possible to manufacture a cell electrophysiological sensor in which bubbles are not easily generated around the sensor chip. As a result, it is possible to manufacture a cell electrophysiological sensor with high measurement accuracy because bubbles are unlikely to adhere to the vicinity of the conduction hole.
- FIG. 1 is a cross-sectional view of a cell electrophysiological sensor according to an embodiment of the present invention.
- FIG. 2 is an enlarged cross-sectional view of a main part of the cell electrophysiological sensor.
- FIG. 3 is a schematic cross-sectional view of the same cell electrophysiological sensor manufacturing apparatus.
- FIG. 4A is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4B is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4C is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4D is a diagram showing a method of manufacturing the same cell electrophysiological sensor.
- FIG. 4E is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4A is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4B is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4C
- FIG. 4F is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4G is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 4H is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 5A is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 5B is a diagram showing a method for producing the same cell electrophysiological sensor.
- FIG. 6A is a process cross-sectional view for explaining another adsorption method in the manufacturing method.
- FIG. 6B is a process cross-sectional view for explaining another adsorption method in the manufacturing method.
- FIG. 6C is a process cross-sectional view for explaining another adsorption method in the same manufacturing method.
- FIG. 6A is a process cross-sectional view for explaining another adsorption method in the manufacturing method.
- FIG. 6B is a process cross-sectional view for explaining another adsorption method
- FIG. 7 is a cross-sectional view of another cell electrophysiological sensor according to one embodiment of the present invention.
- FIG. 8 is a cross-sectional view of still another cell electrophysiological sensor in the same embodiment.
- FIG. 9 is a cross-sectional view of a conventional cell electrophysiological sensor.
- FIG. 1 is a cross-sectional view of a cell electrophysiological sensor according to an embodiment of the present invention.
- FIG. 2 is an enlarged cross-sectional view of a main part of the cell electrophysiological sensor.
- the cell electrophysiological sensor in the present embodiment is inserted into a mounting substrate 11, a glass tube 13 inserted into the through hole 12 of the mounting substrate 11, and a lower end portion of the glass tube 13.
- the sensor chip 14 is provided.
- the inside of the glass tube 13 and the inside of the through hole 12 of the mounting substrate 11 are used as an electrolytic cell 15.
- a flow path substrate 16 abuts below the mounting substrate 11, and a space between the flow path substrate 16 and the mounting substrate 11 is used as an electrolytic cell 17.
- electrodes 18 and 19 that are electrically connected to the electrolytic solution injected into the electrolytic cells 15 and 17 are disposed in the electrolytic cells 15 and 17, respectively.
- the sensor chip 14 includes a disk-shaped thin plate 20 and a cylindrical frame body 21 arranged on the thin plate 20.
- the sensor chip 14 is formed by dry etching a so-called SOI (Silicon On Insulator) substrate in which both sides of a silicon dioxide layer are sandwiched between silicon layers.
- SOI Silicon On Insulator
- the thin plate 20 is a laminated body of a silicon layer and a silicon dioxide layer, and the frame body 21 is made of a silicon layer. That is, in the present embodiment, the cell trapping surface 22 of the thin plate 20 is composed of a silicon dioxide layer. Conductive holes 23 are formed in the thin plate 20 by dry etching, and the electrolytic holes 15 and 17 in FIG.
- the thin plate 20 has a thickness of 10 ⁇ m to 100 ⁇ m, and the conduction hole 23 has an opening diameter of 1 ⁇ m to 3 ⁇ m ⁇ .
- the opening diameter of the conduction hole 23 is 5 ⁇ m or less, which is suitable for holding cells.
- the glass tube 13 is preferably formed of highly hydrophilic glass having a contact angle with water of 0 ° to 10 °. Accordingly, the material of the glass tube 13 is preferably glass containing silicon dioxide. Examples thereof include borosilicate glass (Corning; # 7052, # 7056), aluminosilicate glass or lead borosilicate glass (Corning; # 8161).
- the contact angle with water refers to an angle formed between the droplet surface and the solid surface in a state where a droplet such as pure water is placed on the solid surface and is in equilibrium.
- the measuring method can generally use the ⁇ / 2 method.
- the contact angle can be obtained from the angle of the straight line connecting the left and right end points and the vertex of the droplet with respect to the solid surface. It is also possible to measure using a protractor or the like.
- the inner diameter d1 of the glass tube 13 is larger than the outer diameter d2 of the sensor chip 14 and is 1400 ⁇ m.
- the outer diameter d3 of the glass tube 13 was 2000 ⁇ m.
- the distance d4 between the inner surface of the glass tube 13 and the outer surface of the sensor chip 14 is about 0.05 mm to 0.4 mm.
- the length d5 of the glass tube 13 is longer than the length d6 of the sensor chip 14 and is 2000 ⁇ m.
- the softening point of glass is an important factor from the viewpoint of workability.
- a temperature convenient for welding the glass tube 13 to the side surface of the sensor chip 14 is not less than the softening point of the glass, and more preferably in the range of 500 to 900 ° C. This is because the strength is insufficient if glass capable of being welded is lower than 500 ° C., and the workability deteriorates if it exceeds 900 ° C.
- the mounting substrate 11 and the flow path substrate 16 as shown in FIG. 1 are made of resin, they can be easily molded and assembled.
- the material is more preferably a thermoplastic resin.
- these materials can obtain a highly homogeneous molded body with good productivity by using means such as injection molding.
- these thermoplastic resins are polycarbonate (PC), polyethylene (PE), olefin polymer, polymethyl methacrylate acetate (PMMA), or a combination of two or more thereof.
- the mounting substrate 11 made of these materials can be easily joined to the glass tube 13 having excellent hydrophilicity by using the ultraviolet curable adhesive 24 (FIG. 1).
- the thermoplastic resin is a cyclic olefin polymer, a linear olefin polymer, a cyclic olefin copolymer obtained by polymerizing them, or polyethylene (PE), from the viewpoint of workability, production cost, and material availability.
- PE polyethylene
- the cyclic olefin copolymer is excellent in transparency and has high resistance to inorganic chemicals such as alkalis and acids, and is suitable for the production method or use environment of the present invention.
- these materials can transmit ultraviolet rays, they are effective when the ultraviolet curable adhesive 24 is used.
- the method of mounting the sensor chip 14 on the mounting substrate 11 is the case where the entire mounting substrate 11 is formed of a silicon substrate and the conduction hole 23 (FIG. 2) is directly formed in the mounting substrate 11. Compared with the cost, the cost is reduced and the yield is improved. Along with this, there is repairability when a defective conduction hole 23 exists in part.
- the extracellular fluid is stored in the electrolytic bath 15 in the through hole 12 (including the inside of the glass tube 13) of the mounting substrate 11, and the intracellular fluid is filled in the lower electrolytic bath 17.
- the extracellular fluid is typically an electrolyte solution to which about 4 mM of K + ions, about 145 mM of Na + ions, and about 123 mM of Cl ⁇ ions are added.
- the intracellular solution is an electrolytic solution to which K + ions are added at about 155 mM, Na + ions at about 12 mM, and Cl ⁇ ions at about 4.2 mM.
- a conduction resistance value of about 100 k ⁇ to 10 M ⁇ can be observed between the electrode 18 electrically connected to the extracellular fluid and the electrode 19 electrically connected to the intracellular fluid. This is because the intracellular fluid or extracellular fluid permeates through the conduction hole 23 (FIG. 2), and an electric circuit is formed between the two electrodes 18 and 19.
- the cells are put into the upper electrolytic cell 15. Thereafter, when the pressure of the lower electrolytic cell 17 is reduced, the cells are attracted to the opening of the conduction hole 23 and block the opening of the conduction hole 23. As a result, the electrical resistance between the extracellular fluid and the intracellular fluid becomes sufficiently high at 1 G ⁇ or more (hereinafter, this state is referred to as “giga-seal”). In this giga-seal state, even if the potential inside or outside the cell changes due to the electrophysiological activity of the cell, even a slight potential difference or current can be measured with high accuracy.
- FIG. 3 is a schematic cross-sectional view of a cell electrophysiological sensor manufacturing apparatus according to the present embodiment.
- the manufacturing apparatus includes a holding head 25 that holds the sensor chip 14, and a glass tube holding mechanism 26 that is disposed on the outer periphery of the holding head 25.
- the manufacturing apparatus includes a single combustion device (burner 27) that locally applies wind pressure from the outside of the glass tube 13 toward the side surface of the glass tube 13 and melts the glass tube 13.
- the holding head 25 and the glass tube holding mechanism 26 have a function of rotating the sensor chip 14 and the glass tube 13 about their vertical axes 25c and 26c.
- the holding head 25 may be a mechanism that holds the side surface of the sensor chip 14 by holding, but in the present embodiment, a mechanism that holds by suction is used. With this adsorption mechanism, the stress load on the fine sensor chip can be reduced. That is, the holding head 25 of the present embodiment is formed of a columnar base portion 25a and a distal end portion 25b following the base portion 25a. The outer diameter d7 of the distal end portion 25b is smaller than the outer diameter of the base portion 25a. At the center of the columnar shape, a suction hole 25d with a columnar vertical shaft 25c as an axis is formed. By sucking upward from the suction hole 25d, the sensor chip 14 is sucked. The lower surface of the distal end portion 25b is a surface that adsorbs the sensor chip 14.
- the glass tube holding mechanism 26 may also be an adsorbing mechanism similar to the holding head 25. However, since the glass tube 13 has a larger outer shape and higher mechanical strength than the sensor chip 14, in this embodiment, a chuck mechanism that sandwiches the side surface of the glass tube 13 is used. That is, the glass tube holding mechanism 26 includes a left holding portion 26a and a right holding portion 26b. The left holding part 26 a and the right holding part 26 b are arranged on the outer periphery of the holding head 25. A space formed by the left holding portion 26 a and the right holding portion 26 b, that is, a space surrounding the holding head 25 forms a cylindrical space having a vertical axis 26 c that coincides with the vertical axis 25 c that is the center of the holding head 25.
- the left holding part 26a and the right holding part 26b are respectively movable left and right. Therefore, the glass tube 13 is held by the left holding portion 26a and the right holding portion 26b moving in the direction approaching the vertical shaft 26c. When the left holding part 26a and the right holding part 26b move in directions away from the vertical shaft 26c, the holding of the glass tube 13 is released.
- a burner 27 that can simultaneously apply wind pressure and a combustion flame is used as a combustion device.
- wind pressure generating means such as a motor that locally applies wind pressure from the outside of the glass tube 13 toward the side of the glass tube 13, and heating means such as IH (Induction Heating), a heater, or a laser that melts the glass tube; May be used in combination.
- IH Induction Heating
- the glass tube 13 can be thermally deformed inward as will be described later by heating the wind pressure application region while applying wind pressure to the side surface of the glass tube 13.
- the combustion flame is used in the glass welding step, but hot air may be used. That is, instead of the burner 27, the manufacturing apparatus may be provided with hot air generating means that can melt the glass tube 13 while applying wind pressure with hot air from the outside of the glass tube 13 toward the side surface of the glass tube 13.
- the glass tube 13 can be deformed while being curved toward the inner sensor chip 14 by wind pressure and heat, and there is a gap between the glass tube 13 and the sensor chip 14. Can be easily welded.
- this manufacturing apparatus is designed such that the tip of the small diameter portion of the holding head 25, that is, the diameter d7 of the cross section of the surface that adsorbs the sensor chip 14 is smaller than the outer diameter d8 of the sensor chip 14. Thereby, it can suppress that the fuse
- FIG. 1 the tip of the small diameter portion of the holding head 25, that is, the diameter d7 of the cross section of the surface that adsorbs the sensor chip 14 is smaller than the outer diameter d8 of the sensor chip 14.
- both the holding head 25 and the glass tube holding mechanism 26 are made of a material having high heat resistance so that the heat can be extinguished in the glass welding process described later.
- the holding head 25 is made of a superalloy having a higher thermal conductivity than the glass tube holding mechanism 26, and suppresses occurrence of temperature unevenness in the sensor chip 14 during the glass welding process.
- the glass tube holding mechanism 26 is made of a ceramic having higher heat insulation than the holding head 25, thereby suppressing the ambient temperature from being lowered inside the apparatus during the glass welding process.
- FIGS. 4A to 4H, FIGS. 5A, and 5B are diagrams showing a method for manufacturing the cell electrophysiological sensor of the present embodiment.
- the sensor chip 14 is sucked and held by the holding head 25 while being sucked in the direction of the arrow from the suction hole 25d.
- centering is performed so that the sensor chip 14 is positioned at the center of the holding head 25 with the sensor chip 14 being sucked and held.
- the side view and top view of the glass tube holding mechanism 26 were shown up and down.
- FIG. 4C a side view and a plan view of the glass tube holding mechanism 26 are shown up and down. That is, in the centering step, as shown in FIG. 4B, the holding head 25 and the glass tube holding mechanism 26 are attracted and held by the holding head 25 as indicated by the arrows by the centering mechanism 31 arranged so that the vertical axes coincide with each other.
- the sensor chip 14 is sandwiched from the left and right.
- the sensor chip 14 is centered and held so that the vertical axis coincides with the holding head 25 and the glass tube holding mechanism 26. Thereafter, as shown by the arrow in FIG. 4C, the centering mechanism 31 is moved left and right to be removed. This corresponds to the step of holding the sensor chip 14.
- the holding head 25 holding the sensor chip 14 is inserted into the aligned glass tubes 13.
- the glass tube 13 is held by the glass tube holding mechanism 26. This corresponds to the step of holding the glass tube 13.
- the process of holding the glass tube 13 may be performed before the sensor chip 14 is held, the glass tube 13 is held after the process of holding the sensor chip 14 in the present embodiment. This is because the sensor chip 14 is less likely to be damaged and the positional relationship between the glass tube and the sensor chip can be held in the center.
- the burner 27 is directed from the outside of the glass tube 13 to the side surface of the lower end portion of the glass tube 13, and substantially parallel to the horizontal cross section of the glass tube 13 (that is, in FIG. 2).
- the combustion flame is ejected vigorously (in parallel with the thin plate 20).
- the rotation function of the holding head 25 and the glass tube holding mechanism 26 is used to rotate the sensor chip 14 and the glass tube 13 around the vertical axis of the sensor chip 14 in the arrow direction.
- the sensor chip 14 can be easily and uniformly welded at 360 °. This corresponds to the step of melting the glass tube 13 and welding the side surface of the sensor chip 14 to the glass.
- the frame 21 (FIG. 2) and the glass tube 13 of the sensor chip 14 are both cylindrical, so that the heat uniformity during heating is high and uniform welding is possible.
- the integrated body of the sensor chip 14 and the glass tube 13 is inserted into the through hole 12 of the mounting substrate 11 and bonded with an adhesive 24 or the like as shown in FIG. 5B.
- the cell electrophysiological sensor in the present embodiment can be manufactured.
- the projections 28 are provided on the inner wall of the through hole 12, the glass tube 13 can be easily positioned.
- 6A to 6C are process cross-sectional views for explaining another adsorption method in the manufacturing method of the present embodiment.
- a hollow metal tube 29 having heat resistance such as stainless steel is prepared.
- the hollow 30 of the metal tube 29 is filled with a liquid 30 having a predetermined surface tension such as water, and a droplet 30a is formed at the tip of the metal tube 29 while controlling the pressure. For this reason, it is preferable to fill the hollow metal pipe 29 with the liquid 30 and to provide a valve control device for reducing the pressure inside the hollow.
- the size (in particular, the width dimension) of the droplet 30a is larger than the shape of the sensor chip 14.
- a metal material that can be easily processed into a hollow shape.
- glass welding is performed in the subsequent process, it is possible to use a metal material having heat resistance, a ceramic material stable at high temperature, or heat-resistant glass.
- the sensor chip 14 in contact with the surface of the droplet 30a is attracted to the center of the tip of the droplet 30a having a spherical shape by the surface tension of the droplet 30a.
- the liquid droplet 30a is formed at the tip of the metal tube 29 having a predetermined size having a hollow structure, and the adsorption and centering of the sensor chip 14 is performed by using the adsorption method utilizing the surface tension of the liquid droplet 30a. This can be done easily via the drop 30a. Thereafter, the liquid 30 and the droplets 30a existing inside the hollow of the metal tube 29 are removed by vacuum suction by a valve operation or the like. At the same time, by maintaining the hollow interior in a reduced pressure state, it is possible to realize a state in which the sensor chip 14 is vacuum-adsorbed to the center of the tip of the metal tube 29.
- a cellular electrophysiological sensor arranged at a predetermined position can be manufactured through the manufacturing method after the step of FIG. 4D.
- the manufacturing method and the manufacturing apparatus for adsorbing the sensor chip 14 while performing centering with the droplet it is possible to hold the minute sensor chip 14 without applying mechanical stress to the sensor chip 14. Become. Therefore, it is possible to provide a manufacturing method that can significantly reduce structural defects such as chipping and cracking of the sensor chip 14.
- the method and apparatus for adsorbing while centering with droplets as described above are sensors of various sensors such as a DNA microarray, a protein sensor, and a carbohydrate sensor. It can also be applied to mounting chips and other small devices. In particular, if a minute device is to be handled in a normal air atmosphere, it is very difficult to install and move it to the originally desired location due to a force generated by static electricity, mechanical contact with a jig, or the like. On the other hand, the manufacturing method using droplets can reduce the force received from the external pressure generated during handling. Therefore, in particular, when handling a sensor chip or device to which hydrophilicity is imparted, it is effective because centering and adsorption can be easily performed.
- a cell electrophysiological sensor with a high degree of measurement can be manufactured by using the manufacturing method and manufacturing apparatus in the present embodiment.
- the reason for this is that in the present embodiment, it is possible to form the sensor chip 14 in which bubbles are difficult to adhere in the vicinity of the conduction hole 23 of the sensor chip 14.
- the manufacturing method and manufacturing apparatus of the present embodiment are used, as shown in FIG. 1, the outer periphery of the sensor chip 14, that is, between the through hole 12 of the mounting substrate 11 and the sensor chip 14 in the present embodiment.
- a glass tube 13 having high hydrophilicity can be interposed. Therefore, bubbles generated around the sensor chip 14, that is, in the through hole 12, can be reduced. Therefore, bubbles adhering to the vicinity of the opening of the conduction hole 23 can be reduced, and as a result, a cell electrophysiological sensor with high measurement accuracy can be manufactured.
- the glass tube 13 surrounds the upper part of the sensor chip 14. Thereby, it can suppress that a bubble covers the upper part of the sensor chip 14.
- both the sensor chip 3 and the inner wall of the through hole 2 are made of a hydrophobic material. For this reason, when the electrolyte solution is filled, air bubbles may cover the entire inside of the frame body from above the sensor chip 3, and measurement may not be possible.
- hydrophilic glass tube 13 surrounds the upper part of the sensor chip 14 manufactured in the present embodiment, it is possible to prevent bubbles from covering the upper part of the sensor chip 14.
- the outer periphery of the fine sensor chip 14 can be tightly fixed with the glass tube 13 having a larger outer diameter. Therefore, since the glass tube 13 can be mounted on the mounting substrate 11, mounting is easy. Further, the material cost can be reduced by using an inexpensive glass tube 13 rather than increasing the outer diameter of the sensor chip 14 made of silicon.
- the bonding strength is high and the airtightness is excellent. Therefore, it is possible to suppress the electrolyte from flowing into the gap between the glass tube 13 and the sensor chip 14, which contributes to a reduction in leakage current. That is, by using the manufacturing method and manufacturing apparatus of the present embodiment, a cell electrophysiological sensor with high measurement accuracy can be manufactured.
- the combustion flame is ejected vigorously in parallel to the horizontal cross section of the glass tube 13. For this reason, a combustion flame can concentrate on the lower end part of the glass tube 13, and it can form so that the outer surface 13a (FIG. 2) in this lower end part may curve inside. Thereby, the glass tube 13 can be easily inserted into the through hole 12 of the mounting substrate 11.
- the inner wall 13b (FIG. 2) at the lower end of the glass tube 13 is also curved inward. If curved in this way, bubbles are less likely to be generated than when corners are formed.
- the combustion flame can be ejected vigorously and the combustion flame can be applied locally. Therefore, even when there is a gap between the glass tube 13 and the sensor chip 14, a part of the glass tube 13 can be moved to the sensor chip 14 side by utilizing the momentum of the flame.
- combustion flame may be ejected from multiple directions at once, it is preferable to install the burner 27 only in one region and eject the combustion flame only from one direction as in the present embodiment.
- hot air is generated using the burner 27, but it is also possible to generate wind using, for example, a motor or the like. Also in this case, it is more desirable to generate wind from one direction toward the side surface of the glass tube 13. This is because when wind is generated from multiple directions, the wind pressure may decrease due to interference.
- the gap between the glass tube 13 and the sensor chip 14 is narrow, a large number of burners 27 may be used because the glass tube 13 and the sensor chip 14 can be easily joined even if the wind pressure is low. In this case, uniform welding can be achieved by arranging the burners 27 radially. And when many burners 27 are used, the welding time can be shortened.
- the sensor chip 14 is inserted into the lower end of the glass tube 13, but may be inserted into the upper end as shown in FIG. Or you may insert in the center as shown in FIG. In these cases, the glass tube 13 is present below the sensor chip 14, and the inside of the glass tube 13 can be used as a lower electrolytic cell. Therefore, it is possible to suppress bubbles from adhering to the vicinity of the outlet of the conduction hole 23. Therefore, for example, when the cells are sucked by reducing the pressure in the electrolytic cell 17 (FIG. 1), it is possible to prevent the pressure from being transmitted to the upper electrolytic cell 15 due to bubbles. Moreover, it can suppress that electrical conduction is inhibited between the conduction holes 23 (FIG. 2). As a result, the measurement accuracy of the cell electrophysiological sensor is improved.
- the direction of the sensor chip 14 may be upside down, since the SOI substrate is used in this embodiment, it is preferable to arrange the silicon dioxide layer in the direction that becomes the cell trapping surface 22 (FIG. 2). That is, since the silicon dioxide layer has higher insulation than the silicon layer, the leakage current through the sensor chip 14 can be reduced.
- the present invention can efficiently produce a cell electrophysiological sensor with high measurement accuracy, and is useful for producing a cell electrophysiological sensor.
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Abstract
Description
12 貫通孔
13 ガラス管
14 センサチップ
15 電解槽
16 流路基板
17 電解槽
18 電極
19 電極
20 薄板
21 枠体
22 細胞捕捉面
23 導通孔
24 接着剤
25 保持ヘッド
26 ガラス管保持機構
27 バーナー
28 突起
29 金属管
30 液体
30a 液滴
図1は、本発明の一実施の形態における細胞電気生理センサの断面図である。図2は、同細胞電気生理センサの要部拡大断面図である。図1に示すように、本実施の形態における細胞電気生理センサは、実装基板11と、この実装基板11の貫通孔12内に挿入されたガラス管13と、このガラス管13の下端部に挿入されたセンサチップ14とを備えている。
Claims (16)
- センサチップを保持する工程と、
前記センサチップの側面外周を囲むガラス管を保持する工程と、
前記ガラス管の外方から前記ガラス管側面に向けて風圧を与えるとともに、
前記ガラス管を溶融させて前記センサチップの側面とガラス溶着させる工程とを備えた細胞電気生理センサの製造方法。 - 前記センサチップを保持する工程が、筒状または棒状の保持具の先端に球面状の液滴を形成し、前記液滴の表面に前記センサチップを接触させ、前記液滴の表面張力によって前記センサチップを前記保持具の前記先端の中央部に整列させて保持する請求項1記載の細胞電気生理センサの製造方法。
- 前記ガラス溶着させる工程は、
前記ガラス管の外方から前記ガラス管側面に向けて燃焼炎を噴出することにより、前記ガラス管を前記センサチップの側面とガラス溶着させる請求項1記載の細胞電気生理センサの製造方法。 - 前記ガラス溶着させる工程における前記風圧の方向は一方向である請求項1記載の細胞電気生理センサの製造方法。
- 前記ガラス溶着させる工程は、
燃焼炎を一方向から前記ガラス管の側面に向けて噴出する請求項1記載の細胞電気生理センサの製造方法。 - 前記ガラス溶着させる工程は、
前記ガラス管を内側へ湾曲させる請求項1記載の細胞電気生理センサの製造方法。 - 前記ガラス溶着させる工程は、
前記ガラス管および前記ガラス管の内方の前記センサチップを、前記センサチップの垂直軸を中心に回転させる請求項1記載の細胞電気生理センサの製造方法。 - 前記センサチップを保持する工程の後、
前記ガラス管を保持する請求項1記載の細胞電気生理センサの製造方法。 - センサチップを保持する保持ヘッドと、
前記保持ヘッドの外周に配置され、ガラス管を保持するガラス管保持機構と、
前記ガラス管の外方から前記ガラス管側面に向けて風圧を与えるとともに前記ガラス管を燃焼により溶融する燃焼装置とを備えた細胞電気生理センサの製造装置。 - 前記燃焼装置はバーナーから構成される請求項9記載の細胞電気生理センサの製造装置。
- センサチップを保持する保持ヘッドと、
前記保持ヘッドの外周に配置され、ガラス管を保持するガラス管保持機構と、
前記ガラス管の外方から前記ガラス管側面に向けて風圧を与える風圧発生部と、
前記ガラス管を溶融する加熱部とを備えた細胞電気生理センサの製造装置。 - センサチップを保持する保持ヘッドと、
前記保持ヘッドの外周に配置され、ガラス管を保持するガラス管保持機構と、
前記ガラス管の外方から前記ガラス管側面に向けて風圧を与えるとともに、
前記ガラス管を熱風により溶融する熱風発生部を備えた細胞電気生理センサの製造装置。 - 前記保持ヘッドおよび前記ガラス管保持機構は、
前記ガラス管および前記センサチップを、前記センサチップの垂直軸を中心に回転させる機能を有する請求項9、11、12のいずれか一項に記載の細胞電気生理センサの製造装置。 - 前記保持ヘッドの前記センサチップを保持する先端部の外径は、前記センサチップの外径よりも小さい請求項9、11、12のいずれか一項に記載の細胞電気生理センサの製造装置。
- 前記保持ヘッドは、前記ガラス管保持機構よりも熱伝導性の高い材料からなる請求項9、11、12のいずれか一項に記載の細胞電気生理センサの製造装置。
- 前記ガラス管保持機構は、前記保持ヘッドよりも断熱性の高い材料からなる請求項9、11、12のいずれか一項に記載の細胞電気生理センサの製造装置。
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US20130136673A1 (en) * | 2010-07-09 | 2013-05-30 | Sophion Bioscience A/S | Chip assembly for use in a microfluidic analysis sytem |
JP2014178280A (ja) * | 2013-03-15 | 2014-09-25 | Nikon Corp | 生体分子アレイの処理方法、生体分子アレイのスクリーニング方法、生体分子アレイ用筺体、バイオアッセイ装置及びスクリーニング装置 |
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JP2007174990A (ja) * | 2005-12-28 | 2007-07-12 | Matsushita Electric Ind Co Ltd | 細胞電気生理センサアレイおよびその製造方法 |
WO2007119772A1 (ja) * | 2006-04-14 | 2007-10-25 | Panasonic Corporation | 細胞電気生理センサおよびその製造方法 |
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US20130136673A1 (en) * | 2010-07-09 | 2013-05-30 | Sophion Bioscience A/S | Chip assembly for use in a microfluidic analysis sytem |
JP2014178280A (ja) * | 2013-03-15 | 2014-09-25 | Nikon Corp | 生体分子アレイの処理方法、生体分子アレイのスクリーニング方法、生体分子アレイ用筺体、バイオアッセイ装置及びスクリーニング装置 |
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