BUBBLE JETTING CHIP, LOCAL ABLATION DEVICE AND LOCAL ABLATION METHOD, AND INJECTION DEVICE AND INJECTION METHOD
20170306284 · 2017-10-26
Assignee
Inventors
- Yoko YAMANISHI (Koto-ku, Tokyo, JP)
- Yohei HAMANO (Koto-ku, Tokyo, JP)
- Takuya KAMBAYASHI (Koto-ku, Tokyo, JP)
Cpc classification
B05B17/0607
PERFORMING OPERATIONS; TRANSPORTING
C12M35/02
CHEMISTRY; METALLURGY
C12M35/04
CHEMISTRY; METALLURGY
C12M35/00
CHEMISTRY; METALLURGY
International classification
C12M1/42
CHEMISTRY; METALLURGY
B05B17/06
PERFORMING OPERATIONS; TRANSPORTING
Abstract
The present invention enables fabrication and mass production of a bubble-jetting chip that includes a desired number of bubble jetting portions of the same size having bubble-jetting outlets of the same size.
Mass production is enabled by fabricating a bubble-jetting chip comprising a substrate and a bubble-jetting portion formed on the substrate, the bubble-jetting portion comprising: an electrode that is formed of a conductive material; an insulating portion that is formed of an insulating photosensitive resin, is provided so as to sandwich the electrode, and includes an extended section that extends beyond the tip of the electrode; and a space that is formed between the extended section of the insulating portion and the tip of the electrode.
Claims
1. A bubble-jetting chip, comprising: a substrate and a bubble jetting portion formed on the substrate; the bubble-jetting portion comprising: an electrode that is formed of a conductive material; an insulating portion that is formed of an insulating photosensitive resin, is provided so as to sandwich the electrode, and includes an extended section that extends beyond the tip of the electrode; and a space that is formed between the extended section of the insulating portion and the tip of the electrode.
2. The bubble-jetting chip according to claim 1, wherein the extended section is tapered.
3. The bubble-jetting chip according to claim 1, wherein the photosensitive resin is a negative photoresist.
4. The bubble jetting chip according to claim 1, wherein two or more of the bubble-jetting portions are formed.
5. The bubble-jetting chip according to claim 1, wherein an assist channel is formed in the insulating portion.
6. The bubble-jetting chip according to claim 1, further comprising an energizing portion that is connected to the electrode.
7. The bubble-jetting chip according to claim 1, wherein a counter electrode that constitutes an electrode pair with the electrode of the bubble-jetting portion is formed on the substrate.
8. The bubble jetting chip according to claim 1, wherein a channel for delivering a solution containing an injection material is formed on the space side of the bubble-jetting portion.
9. A localized ablation device, comprising the bubble-jetting chip according to claim 1.
10. An injection device, comprising the bubble-jetting chip according to claim 1.
11. A localized ablation method, comprising: injecting a solution so that a counter electrode has continuity with the electrode of the localized ablation device according to claim 9; applying high-frequency pulses to an electrode pair configured with the electrode of the localized ablation device and the counter electrode to cause bubbles to be ejected from the tip of the bubble-jetting portion; and processing a process target with the bubbles.
12. An injection method, comprising: injecting a solution so that a counter electrode has continuity with the electrode of the injection device according to claim 10; delivering a solution containing an injection material to the front of the bubble-jetting portion; applying high-frequency pulses to an electrode pair configured with the electrode of the injection device and the counter electrode to cause the ejection of bubbles onto which the solution containing the injection material is adsorbed; and introducing the injection material into a process target while localized ablation is performed on the process target with the bubbles.
13. The bubble-jetting chip according to claim 2, wherein the photosensitive resin is a negative photoresist.
14. The bubble-jetting chip according to claim 3, wherein two or more of the bubble-jetting portions are formed.
15. The bubble-jetting chip according to claim 3, wherein an assist channel is formed in the insulating portion.
16. The bubble-jetting chip according to claim 14, wherein an assist channel is formed in the insulating portion.
17. The bubble-jetting chip according to claim 3, wherein a channel for delivering a solution containing an injection material is formed on the space side of the bubble-jetting portion.
18. The bubble-jetting chip according to claim 14, wherein a channel for delivering a solution containing an injection material is formed on the space side of the bubble-jetting portion.
19. A localized ablation device, comprising the bubble-jetting chip according to claim 3.
20. An injection device, comprising the bubble-jetting chip according to claim 3.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0060] The bubble-jetting chip, localized ablation device and localized ablation method, and injection device and injection method of the present invention are described in detail below with reference to the accompanying drawings.
[0061]
[0062] The material for forming the substrate 2 is not particularly limited provided that the electrode 31 and insulating portion 33 can be deposited thereon. Examples include glass, quartz, PMMA, and silicon.
[0063] The material for forming the electrode 31 is not particularly limited provided that the material can be energized and can be layered on the substrate 2 by electroplating, electroless plating, or other methods. Examples include nickel, gold, platinum, silver, copper, tin, magnesium, chromium, tungsten, and other metals, or alloys thereof.
[0064] In the present invention, the insulating portion 33 including the extended section 32 is made by using photolithography. Accordingly, the material for forming the insulating portion 33 including the extended section 32 is not particularly limited provided that the material is an insulating photosensitive resin. Examples include commercial TSMR V50, PMER, and other positive photoresists, and SU-8, KMPR, and other negative photoresists. In the present invention, because bubbles 36 are jetted by energizing the electrode 31 and the counter electrode 5, a load is easily applied to the bubble-jetting outlet 35, which is a very small portion, particularly when high voltage is applied thereto. Because SU-8, KMPR, and other negative photoresists have higher hardness than positive photoresists, a negative photoresist is preferably used as the photosensitive resin when high voltage is applied to the bubble-jetting portion 3.
[0065] The material of the energizing portion 4 and the counter electrode 5 is not particularly limited provided that electricity can be delivered from an external power supply to the electrode 31, and the same material as that of the abovementioned electrode 31 can be used. When the energizing portion 4 is produced separately from the bubble-jetting chip 1, the end of the electrode 31 should extend from the insulating portion 33, and the energizing portion 4 should be produced so as to be easily connected. Also, when the counter electrode 5 is produced separately, the counter electrode 5 should be capable of being energized with the electrode 31 and therefore is not particularly limited to being in the form of a rod, sheet, or other shape.
[0066] Because bubbles formed in the space 34 are jetted from the bubble-jetting outlet 35 so as to be torn off when electricity is outputted to the electrode 31 and the counter electrode 5, there is no need to supply air from the outside to the bubble-jetting portion 3. Also, the space 34 preferably becomes smaller nearer to the bubble-jetting outlet 35 in order to provide the jetted bubbles 36 with directionality, and in the manufacturing steps to be discussed below, a photomask that is shaped so that the extended section 32 is tapered should be used.
[0067] Also, when bubbles are formed inside the space 34, bubbles having a size near the inner diameter (indicated as “diameter D” or “D” below) of the bubble-jetting outlet 35 are produced. Accordingly, the depth (length from the tip of the electrode 31 to the bubble-jetting outlet 35; indicated as “L” below) of the space 34 must be large enough for bubbles to be produced inside the space 34, and the L/D ratio is preferably at least 1. Meanwhile, the upper limit of the L/D ratio is not particularly limited provided that the size is sufficient for bubbles to be continuously jetted. Because the bubble-jetting member described in Patent Document 1is produced by heating and pulling apart, etc., the tip of the bubble-jetting member is very sharp and easily damaged, but in the case of the present invention, the bubble-jetting outlet is formed of a photosensitive resin on a substrate, which eliminates the risk of damage. The L/D ratio can be adjusted according to the shape of the photomask. The size of the jetted bubbles 36 can be adjusted by changing the diameter D of the bubble-jetting outlet 35, and should be adjusted by the shape of the photomask during production.
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[0069] Although not illustrated in
[0070]
[0071] (1) The substrate 2 is cleaned with acetone, ethanol, ultrapure water, etc.
[0072] (2) The material for forming the energizing portion 4 is layered on the substrate 2 by sputtering.
[0073] (3) A photoresist 8 is applied, and photoexposure and development are performed using a mask so that the photoresist 8 remains in the portion where the energizing portion 4 is ultimately to be formed.
[0074] (4) The material other than the portion where the energizing portion 4 is to be formed is removed by wet etching or another method.
[0075] (5) The photoresist 8 is removed, whereby the energizing portion 4 is formed. As for the manufacturing steps below, the portion where the electrode 31 is formed is illustrated as cross-section A-A′, and the portion where the insulating portion 33 including the extended section 32 (only the reference symbol 33 is indicated on the drawing) is formed is illustrated as cross-section B-B′. The positions of cross-section A-A′ and cross-section B-B′ are illustrated in the drawing for (5) above (left side of
[0076] (6) The material for forming the insulating portion 33 including the extended section 32 is layered by spin coating.
[0077] (7) Photoexposure is performed using a photomask designed to a shape such that the insulating portion 33 including the extended section 32 remains. In order to facilitate connection to an external power supply, it is desirable to use a photomask having a shape such that the insulating portion 33 on the end portion of the substrate 2 is removed and the energizing portion 4 is exposed.
[0078] (8) After development, the material other than the portion where the insulating portion 33 including the extended section 32 is formed is removed.
[0079] (9) An electrode 31 is grown by electroplating on the energizing portion 4. (10) An insulating layer 37 is formed.
[0080] The resists, etchants, sputtering devices, etc., used in the abovementioned steps may be publicly known reagents and devices used in the field of micromachining technology.
[0081] In the abovementioned manufacturing steps, the electrode 31 was grown by electroplating on the energizing portion 4, but an energizing portion 4 need not be provided. Specifically, an insulating portion 33 should be formed on a substrate 2 by omitting steps (2) to (4), and next a material for forming a thin-plate-form electrode 31 should be cut to the shape of the electrode 31 and be sandwiched inside the insulating portion 33. In that case, the electrode 31 is preferably formed so as to be exposed on the end of the substrate 2, and is preferably arranged to be capable of being energized directly by an external power supply. Also, in the abovementioned manufacturing steps, an example was illustrated in which the bubble-jetting portion 3 was arranged two-dimensionally on the substrate 2, but the bubble-jetting portion 3 can be formed three-dimensionally on the substrate 2 by repeating steps (2) to (10) after completing step (10).
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[0083] The assist channel 38 is not particularly limited provided that an assist flow to push the bubbles 36 out forward can be formed as mentioned above. For example, the assist flow should be formed so as to flow along the bubble-jetting portion 3. In the example illustrated in
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[0085] The current, voltage, and frequency of output to the electrode 31 and the counter electrode 5 are not particularly limited provided that the ranges are such that bubbles can be jetted and the bubble-jetting portion 3 is not damaged. For example, the current is preferably 10 mA to 80 mA, and more preferably 25 mA to 75 mA. It is undesirable for the current to be less than 10 mA, since it may not be possible to properly produce bubbles 36, or for the current to be greater than 80 mA, since wear of the electrode may occur. The voltage is preferably 100 V to 800 V, and more preferably 200 V to 600 V. It is undesirable for the voltage to be smaller than 100 V, since generation of bubbles 36 may be difficult, or for the voltage to be greater than 800 V, since wear of the electrode 31 or damage to the extended section 32 might occur. The frequency is preferably 1 kHz to 1 GHz, more preferably 5 kHz to 1 MHz, and particularly preferably 10 kHz to 60 kHz. It is undesirable for the frequency to be less than 1 kHz, since the extended section 32 might be damaged, or for the frequency to be greater than 1 GHz, since it might not be possible to produce bubbles 36.
[0086] In the localized ablation method of the present invention, first, the bubble-jetting chip 1 of the localized ablation device 6 of the present invention and the counter electrode 5 are immersed in a conductive solution, or the solution is poured on the substrate 2 so that the counter electrode 5 conducts with the electrode 31. A process target is arranged between the bubble-jetting portion 3 of the bubble-jetting chip 1 and the counter electrode 5, bubbles 36 jetted from the bubble-jetting portion 3 are cause to collide with the process target, whereby localized ablation of the process target can be performed.
[0087] The process target is not particularly limited provided that ablation can be performed thereon using bubbles. Examples include cells and proteins. Examples of cells include stem cells isolated from human or non-human animal tissues, skin cells, mucous cells, liver cells, islet cells, nerve cells, cartilage cells, endothelial cells, epithelial cells, bone cells, muscle cells, egg cells, and other animal cells, and plant cells, insect cells, E. coli, yeast, molds, and other microbial cells, and other cells. “Processing” in the present invention signifies jetting bubbles on a process target to open holes in the target or cut a portion of the target.
[0088] In Patent Document 1, the present inventors demonstrated that bubbles jetted from the bubble-jetting member could adsorb an injection material. Presumably, the bubbles produced by energizing the core are charged with electricity, and the injection material is adsorbed onto the bubbles due to the electricity. Accordingly, when performing localized ablation using the bubble-jetting chip 1 illustrated in
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[0091] Although not illustrated in
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[0093] Also, in the embodiment illustrated in
[0094] Although not illustrated in
[0095] An injection device can be produced by using the bubble-jetting chip 1 for injection instead of the bubble-jetting chip 1 of the localized ablation device 6 mentioned above. Except for delivering a solution containing an injection material in the channel 7, the same procedure as the localized ablation method can be used to introduce the injection material while performing localized ablation on a process target. As shall be apparent, if a conductive solution not containing an injection material is used, then use as a localized ablation device also is possible.
[0096] The injection material is not particularly limited, whether gas, solid, or liquid, provided that the material can be dissolved and/or dispersed in a liquid. Examples of gases include air, nitrogen, helium, carbon dioxide, carbon monoxide, argon, and oxygen; examples of solids include DNA, RNA, proteins, amino acids, and inorganic substances; and examples of liquids include chemical solutions and amino acid solutions. Examples of solutions for dissolving and/or dispersing the injection materials include physiological saline and culture media.
[0097] The present invention is described specifically below with examples, but these examples are provided simply for reference to specific embodiments for description of the present invention. Although these illustrations are for describing specific embodiments of the present invention, they do not represent restrictions or limitations on the scope of the present invention disclosed in the present application.
EXAMPLES
Example 1
[0098] [Production of Bubble-Jetting Chip 1]
[0099] (1) A glass substrate was organically cleaned with an ultrasonic cleaner at 100 kHz for 5 minutes each with acetone, ethanol, and ultrapure water in the stated order, and was baked at 120° C. for 30 minutes.
[0100] (2) The glass substrate was cooled to normal temperature, and Au was then formed into a film on the glass substrate using a sputtering device (Vacuum Device MSP-30T) with plasma current value (80 mA) for one minute.
[0101] (3) OFPR-800LB (200 CP) was spun-coated on the glass substrate at 2000 rpm for 30 seconds and 4000 rpm for 2 seconds, and the coated substrate was pre-baked in an oven at 90° C. for 30 minutes. Next, photoexposure was performed using an emulsion mask, and development was performed using NMD-3. After development, the resulting product was rinsed with ultrapure water and dried upon the water being cast off in a spin dryer, etc.
[0102] (4) The areas other than the patterned OFPR were soaked with an Au etchant (AURUM-302, Kanto Chemical) to etch the Au, and the resulting product was rinsed with ultrapure water.
[0103] (5) The glass substrate was immersed in acetone and the remaining OFPR film was removed, with which patterning of the Au electrode portion concluded.
[0104] (6) SU-8 was spun-coated on the glass substrate, and the coated substrate was pre-baked on a hot plate at 95° C. for 50 minutes.
[0105] (7) Photoexposure was performed using an emulsion mask, and then the resulting product was post-exposure baked on a hot plate at 95° C. for 5 minutes.
[0106] (8) Development was performed using PGMEA (2-Methoxy-1-methylethyl acetate; CAS Number: 142300-82-1). After development, the resulting product was rinsed with ultrapure water and dried, with the water being cast off in a spin dryer, etc., with which the SU-8 patterning operation concluded.
[0107] (9) An electrode was connected to the Au patterned part, and Ni plating was grown to the height (100 μm) of the SU-8 pattern along the SU-8 patterning, resulting in a bubble-jetting chip 1.
[0108] (10) Polydimethylsiloxane (PDMS) was spun-coated on an OHP film at 1000 rpm for 20 seconds, and the resulting product was baked at 90° C. for 15 minutes to prepare a sheet having a thickness of about 100 μm. The PDMS sheet was placed covering the top surface of the produced bubble-jetting chip 1, and bonded thereto using an adhesive agent (Super X, Cemedine).
[0109]
Example 2
[0110] [Production of Bubble-Jetting Chip 1]
[0111] The shape of the emulsion mask in step (7) of the abovementioned example 1 was changed, and a bubble-jetting chip 1 having a plurality of bubble jetting portions formed was fabricated.
Example 3
[0112] [Production of Localized Ablation Device and Injection Device and Bubble Jetting Experiment]
[0113] The bubble-jetting chip 1 produced in example 1 was incorporated in place of the scalpel of an electric scalpel for medical use (product of ConMed Corp., Hyfrecator 2000), a non-dielectric resistor and a DIO port were furthermore incorporated in the electricity output device, and a localized ablation device and injection device were thus produced.
[0114] Next, the bubble-jetting chip 1 was immersed in a 5M NaCl solution, and electricity was outputted to the electrode 31 and the counter electrode 5 with a voltage of 27.7 mA, a current of 309 V, an output frequency of 450 kHz, a sampling frequency for impedance matching of 450 kHz, and feedback at 3.5 kHz. The formation of bubbles was captured using a high-speed camera (VW-9000, product of Keyence Corp.). The counter electrode 5 was produced with a copper plate, and was away from the bubble-jetting chip 1.
[0115]
Example 4
[0116] A bubble-jetting chip 1 including a channel 7 was produced by changing the shape of the emulsion mask in step (7) of the abovementioned example 1.
[0117] [Production of Localized Ablation Device and Injection Device and Bubble Jetting Experiment]
Example 5
[0118] A localized ablation device and an injection device were produced using the same device as in example 3, except that the bubble-jetting chip 1 produced in example 4 was used instead of the bubble-jetting chip 1 produced in example 1, and a bubble jetting experiment was performed.
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[0120] [Key]
[0121] 1: Bubble-jetting chip 1, 2: Substrate, 3: Bubble-jetting portion, 4: Energizing portion, 5: Counter electrode, 6: Localized ablation device, 7: Injection solution channel, 8: First injection solution channel, 9: Second injection solution channel, 31: Electrode, 32: Extended section, 33: Insulating portion, 34: Space, 35: Bubble-jetting outlet, 36: Bubble, 37: Insulating layer, 38: Assist channel, 39: Pump connection part, 61: General commercial AC power supply device, 62: Electric wire, 63: Non-dielectric resistor, 64: High-voltage amplification circuit, 71: Insulating wall, 72: Process-target-placement channel, 81: Hole