BUBBLE-JETTING CHIP, LOCAL ABLATION DEVICE AND LOCAL ABLATION METHOD, AND INJECTION DEVICE AND INJECTION METHOD
20180305654 ยท 2018-10-25
Inventors
Cpc classification
C12M35/02
CHEMISTRY; METALLURGY
C12M35/04
CHEMISTRY; METALLURGY
G03F7/2002
PHYSICS
G03F7/162
PHYSICS
G03F7/038
PHYSICS
International classification
C12M1/42
CHEMISTRY; METALLURGY
G03F7/038
PHYSICS
Abstract
A bubble-jetting chip capable of jetting bubbles upward from a substrate is provided.
Bubbles can be jetted upward from a substrate by a bubble-jetting chip comprising: at least a substrate, an energizing portion, and a bubble-jetting portion; the energizing portion being formed on the substrate; the bubble-jetting portion comprising an electrode that is formed of a conductive material, a shell part formed of an insulating photosensitive resin, and an extended section that extends from the shell part, the shell part covering a periphery of the electrode, the extended section extending beyond a tip of the electrode, and the bubble-jetting portion further comprising a space formed between the extended section and the electrode; and the electrode of the bubble-jetting portion being formed on the energizing portion.
Claims
1-13. (canceled)
14. A bubble-jetting chip, comprising: at least a substrate, an energizing portion, and a bubble-jetting portion; the energizing portion being formed on the substrate; the bubble-jetting portion comprising an electrode that is formed of a conductive material, a shell part that is formed of an insulating photosensitive resin, and an extended section that extends from the shell part, the shell part covering a periphery of the electrode, the extended section extending beyond a tip of the electrode, and the bubble-jetting portion further comprising a space formed between the extended section and the electrode; and the electrode of the bubble-jetting portion being formed on the energizing portion.
15. The bubble-jetting chip according to claim 14, wherein the space of the bubble-jetting portion comprises a bubble-jetting outlet where is on the side opposite from the electrode, the bubble-jetting outlet is formed in a direction in which the energizing portion is layered as seen from the substrate.
16. The bubble-jetting chip according to claim 14, wherein two or more of the bubble-jetting portions are formed.
17. The bubble-jetting chip according to claim 15, wherein two or more of the bubble-jetting portions are formed.
18. The bubble-jetting chip according to claim 16, wherein the heights of the bubble-jetting portions are different.
19. The bubble-jetting chip according to claim 17, wherein the heights of the bubble-jetting portions are different.
20. The bubble-jetting chip according to claim 14, wherein the photosensitive resin is a negative photoresist.
21. The bubble-jetting chip according to claim 15, wherein the photosensitive resin is a negative photoresist.
22. The bubble-jetting chip according to claim 14, wherein a counter electrode that constitutes an electrode pair with the electrode of the bubble-jetting portion is formed on the substrate.
23. The bubble-jetting chip according to claim 14, further comprising an outer shell part formed around the bubble-jetting portion, and a space between the bubble-jetting portion and the outer shell part being capable of storing a solution containing an injection material.
24. The bubble-jetting chip according to claim 15, further comprising an outer shell part formed around the bubble-jetting portion, and a space between the bubble-jetting portion and the outer shell part being capable of storing a solution containing an injection material.
25. The bubble-jetting chip according to claim 23, wherein a channel for delivering a solution containing the injection material and/or a solution for forming an assisting flow is formed in the space.
26. A local ablation device, comprising the bubble-jetting chip according to claim 14.
27. A local ablation device, comprising the bubble-jetting chip according to claim 15.
28. An injection device, comprising the bubble-jetting chip according to claim 14.
29. An injection device, comprising the bubble-jetting chip according to claim 15.
30. A local ablation method, wherein: at least the space of the bubble-jetting chip of the local ablation device according to claim 26 is filled with a solution; high-frequency pulses are applied to an electrode pair configured with the electrode of the local ablation device and the counter electrode to cause bubbles to be released from the tip of the bubble-jetting portion; and a processed object is processed with the bubbles.
31. The local ablation method according to claim 30, wherein electricity is discharged from the electrode when the high-frequency pulses are applied.
32. An injection method, wherein: at least the space of the bubble-jetting chip of the injection device according to claim 28 is filled with a solution containing an injection material; high-frequency pulses are applied to an electrode pair configured with the electrode of the injection device and the counter electrode to cause the release of bubbles onto which the solution containing the injection material is adsorbed; and the injection material is introduced into the processed object while local ablation is performed on the processed object with the bubbles.
33. The injection method according to claim 32, wherein electricity is discharged from the electrode when the high-frequency pulses are applied.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0058] The bubble-jetting chip, local ablation device and local ablation method, and injection device and injection method are described in detail below with reference to the accompanying drawings.
[0059]
[0060] The material for forming the substrate 2 is not particularly limited provided that the energizing portion 4 can be layered thereon. Examples include glass, quartz, PMMA, and silicon.
[0061] The material for forming the electrode 31 is not particularly limited provided that the material can be energized and can be deposited on the energizing portion 4 by electroplating, electroless plating, or other methods. Examples include nickel, gold, platinum, silver, copper, tin, magnesium, chromium, tungsten, and other metals, or alloys thereof.
[0062] In the bubble-jetting chip 1, the shell part 32 and the extended section 33 are made by using photolithography. Accordingly, the material for forming the shell part 32 and the extended section 33 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. 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.
[0063] 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 counter electrode 5 is produced separately, the counter electrode 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. When the counter electrode 5 is formed on the substrate 2, the counter electrode should be layered on the substrate 2 in the same manner as the energizing portion 4.
[0064] Because bubbles formed in the space 34 are jetted from the bubble-jetting outlet 35 so as to be dispersed violently 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.
[0065] Also, when bubbles 36 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 the bubbles 36 to be continuously jetted. The L/D ratio can be adjusted according to the thickness of the layered photosensitive resin and the height of the deposited electrode 31. 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.
[0066] In the embodiment of the bubble-jetting chip 1 illustrated in
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[0069] (1) The material for forming the energizing portion 4 is layered on the substrate 2 by sputtering.
[0070] (2) 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.
[0071] (3) The material other than the portion where the energizing portion 4 is to be formed is removed by wet etching or another method.
[0072] (4) The photoresist 8 is removed, whereby the energizing portion 4 is formed. Though not illustrated, when the counter electrode 5 is formed on the substrate 2, the counter electrode 5 should be formed simultaneously with the energizing portion 4 by changing the shape of the photomask.
[0073] (5) A photoresist is applied, and photoexposure and development are performed using a mask so that the photoresist remains on an unnecessary portion of the energizing portion 4 (the portion where the bubble-jetting portion 3 is not formed). Because the photoresist is cured by photoexposure and development, an insulating layer 37 is formed in the following steps without removing the photoresist.
[0074] (6) A photoresist is applied, and photoexposure and development are performed using a photomask designed in a configuration such that the shell part 32 and the extended section 33 remain. The photoresist cured by photoexposure and development becomes the shell part 32 and the extended section 33. The size of the electrode 31 of the bubble-jetting portion 3 should adjust the size of the photomask.
[0075] (7) The bubble-jetting chip 1 shown in this embodiment can be made by growing the electrode 31 via electroplating on the energizing portion 4. The bubble-jetting chip 1 differs from the multi-bubble-jetting portion chip 1 shown in
[0076] The bubble-jetting chip 1 may be made in various forms by repeating photoresist application, exposure, and development. For example:
[0077] (7-1) Instead of the procedure of (7) described above, the electrode 31 is grown to the same height as the shell part 32.
[0078] (8) A photoresist is applied, and photoexposure and development are performed using a photomask designed to a shape such that the extended section 33 remains. In (8), there is a risk of electricity leakage when the electrode 31 is exposed. Therefore, the extended section 33 should be formed so as to span over the shell part 32 and the electrode 31. When the outside diameter of the extended section 33 is less than the outside diameter of the electrode 31, the exposed electrode 31 should be masked by a photoresist, PDMS, etc., after the extended section 33 is formed. Also, while the extended section 33 is made by photolithography in the procedure described above, the extended section 33 may be formed separately by three-dimensional molding or a processing technique and may be adhered with an adhesive, etc. A tapered shape depicted in (8-1) and (8-2) is given as an example for a separately made extended section 33, but other shapes may also be used. As described above, the size, speed, invasiveness, directionality, and other attributes of the bubbles can be adjusted by making the extended section 33 smaller than the shell part 32.
[0079] (9) After the procedure of (8) described above, an upper electrode 31 may be grown by electroplating as needed. In the case that (9) is carried out, the size, speed, invasiveness, directionality, and other attributes of the bubbles can be adjusted by adjusting the height of the electrodes.
[0080] In the manufacturing method described above, because the thickness and inside diameter of the cylindrical photosensitive resin can be set as desired, the extended section 33 is not easily damaged even if the applied voltage is increased. Therefore, the electrodes can be enlarged, and as a result, electricity can be discharged from the electrodes in addition to the jetting of the bubbles by raising the voltage applied to the electrodes. Accordingly, electric discharge processing can be carried out on the processed object in addition to local ablation or injection by bubbles, and the present invention can therefore be used as a device for treating cancer, etc. Also, holes can be opened in plant cells and other biomaterial, as well as a broad range of hard materials such as metals, polymers, etc., and genes, reagents, etc. can also be introduced as needed.
[0081] In the procedure shown in
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[0083] 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.
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[0085] The current, voltage, and frequency of the electricity 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, electricity can be discharged from the electrode 31 as needed, and the bubble-jetting portion 3 is not damaged. For example, the current is preferably 10 mA to 10 A, and more preferably 25 mA to 800 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 10 A, since wear of the electrode may occur. The voltage is preferably 100 V to 100 kV, and more preferably 200 V to 8.0 kV. It is undesirable for the voltage to be smaller than 100 V, since production of bubbles 36 may be difficult, or for the voltage to be greater than 100 kV, since wear of the electrode 31 or damage to the extended section 33 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 33 might be damaged, or for the frequency to be greater than 1 GHz, since it might not be possible to produce bubbles 36. The numerical values given above are standard numerical values and can be changed depending on the size of the electrode 31.
[0086] In the local ablation method, first, the bubble-jetting chip 1 of the local ablation device 6 and the counter electrode 5 are immersed in a conductive solution. A processed object is arranged on the bubble-jetting portion 3 of the bubble-jetting chip 1, and bubbles 36 jetted from the bubble-jetting portion 3 are caused to collide with the processed object, whereby local ablation of the processed object can be performed.
[0087] The processed object 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. When electricity is discharged from the electrode 31, the effects of electric discharge processing are also achieved in addition to those of processing by bubbles; therefore, a harder processed object may be used. Examples include rice, plant cells, and other comparatively hard biological samples, as well as resins, metals, etc. Processing in the present application signifies jetting bubbles on a processed object, as well as performing electric discharge as needed, to open holes in the object or cut a portion of the object.
[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 local ablation using the bubble-jetting chip 1 illustrated in
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[0090] A channel 71 for sending a conductive solution as needed may be formed so as to be connected to the outer shell part 7. A solution containing the first injection material can be sent through the channel 71 to the space between the outer shell part 7 and the bubble-jetting portion 3.
[0091] When the channel 71 is formed, it is permissible to continue to send a conductive liquid that does not contain the first injection material. In such a case, the conductive liquid forms a liquid flow in the direction in which the bubble-jetting portion 3 extends, as shown by the white arrows in
[0092] The outer shell part 7 and the channel 71 can be fabricated by photolithography, nanoimprinting, etching, three-dimensional molding, three-dimensional processing, UV curing, stereolithography, two-photon absorption photo-molding, etc. Also, the material for fabricating the outer shell part 7 and the channel 71 is preferably an insulating material, and should be polydimethylsiloxane (PDMS), parylene, epoxy resin, polyimide, polyethylene, glass, quartz, PMMA, silicon, or another well-known insulating material.
[0093] An injection device can be produced by using the bubble-jetting chip 1 for injection instead of the bubble-jetting chip 1 of the local ablation device 6 mentioned above. Except for filling the space between the outer shell part 7 and the bubble-jetting portion 3 with a solution containing an injection material, the same procedure as the local ablation method can be used to introduce the injection material while performing local ablation on a processed object.
[0094] 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.
[0095] When the outer shell part 7 shown in
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[0099] The formats shown in
[0100] The embodiments are described specifically below with examples, but these examples are provided simply for reference to specific modes for description of the embodiments of the present application. These illustrations do not represent restrictions or limitations on the scope of the present invention disclosed in the present application.
EXAMPLES
Example 1
[0101] [Production of Bubble-Jetting Chip 1]
[0102] (1) Au was formed into a film on a glass substrate using a sputtering device (Vacuum Device MSP-30T) with plasma current value (80 mA) for one minute.
[0103] (2) OFPR-800 LB (200CP) was spun-coated on the glass substrate at 2000 rpm for 30 seconds and 7000 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 a chrome 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.
[0104] (3) 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.
[0105] (4) The glass substrate was immersed in acetone and the remaining OFPR film was removed, with which patterning of the Au electrode portion was completed, as was the counter electrode 5.
[0106] (5) SU-8 3005 was spun-coated at 2000 rpm for 30 seconds on the glass substrate, and the coated substrate was pre-baked on a hot plate at 95 C. for 3 minutes. Photoexposure was performed using a chrome mask, and then the resulting product was post-exposure baked on a hot plate at 95 C. for 3 minutes. Development was performed using PGMEA (2-Methoxy-1-methylethyl acetate; CAS Number: 142300-82-1), and the water was cast off in a spin dryer to allow drying, with which a SU-8 insulating layer was produced.
[0107] (6) SU-8 3050 was spun-coated at 1000 rpm for 30 seconds and at 4000 rpm for two seconds on the glass substrate, and the coated substrate was pre-baked on a hot plate at 95 C. for 50 minutes. Next, photoexposure was performed using a chrome mask, and post-exposure baking was performed on the hot plate at 95 C. for five minutes. Lastly, development was performed using PGMEA (2-Methoxy-1-methylethyl acetate; CAS Number: 142300-82-1), and the water was cast off in a spin dryer to allow drying, with which a shell part 32, a cylindrical structure of SU-8, was produced.
[0108] (7) An electrode was connected to the Au patterned part, and Ni plating was grown to the height (100 m) of the SU-8 pattern along the inner side of the SU-8 shell part 32.
[0109] (8) SU-8 3050 was spun-coated at 800 rpm for 30 seconds and at 4000 rpm for two seconds on the glass substrate, and the coated substrate was pre-baked on a hot plate at 95 C. for 50 minutes. Next, photoexposure was performed using a chrome mask, and post-exposure baking was performed on the hot plate at 95 C. for 5 minutes. Lastly, development was performed using PGMEA (2-Methoxy-1-methylethyl acetate; CAS Number: 142300-82-1), and the water was cast off in a spin dryer to allow drying, with which a cylindrical structure of SU-8 (a shell part 32 and an extended section 33) was produced over the shell part 32 produced in (6).
[0110] (9) An electrode was connected to the Au patterned part, and Ni plating was grown along the inner side of the SU-8 cylindrical structure to 30 m from the top of the SU-8 cylindrical structure.
[0111]
Example 2
[0112] [Production of Local 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 means, and a local ablation device and injection device were thus produced.
[0114] Next, PDMS was used to produce a frame 41 large enough for the bubble-jetting portion 3 and at least part of the counter electrode 5 to be disposed therein, and the frame 41 was affixed to the bubble-jetting chip 1, as shown in
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Example 3
[0116] [Jetting of Bubbles Containing Plasma]
[0117] Bubbles were jetted in the same manner as in example 2, except that the solution used in the local ablation device and injection device prepared in example 2 was a 0.15M NaCl solution, the electricity output conditions were a current of 5.0 A and a voltage of 6.2 kV, the output frequency was 450 kHz, the sampling frequency for impedance matching was 450 kHz, and feedback was performed at 3.5 kHz. The formation of bubbles was captured using a VW 600 M (Keyence Corp.) at a frame rate of 230,000 fps.
KEY
[0118] 1, 1: Bubble-jetting chip, 2: Substrate, 3: Bubble-jetting portion, 4: Energizing portion, 5: Counter electrode, 6: Local ablation device, 7: Outer shell part, 8: Photoresist, 10: Processed object, 31: Electrode, 32: Shell part, 33: Extended section, 34: Space, 35: Bubble-jetting outlet, 36: Bubble, 37: Insulating layer, 41: Frame, 42: Solution, 51: Cap, 52: Support, 53: Movable frame, 54: Urging means, 56: Variable frame, 61: General commercial AC power supply device, 62: Electric wire, 63: Non-dielectric resistor, 64: Voltage amplification circuit, 71: Channel