Translation of award-winners and finalists (Japanese-to-English Contest)
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[Heading 1] Introduction [Heading 1]
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Along with advances in fields like regenerative medicine and genetic engineering, the medical world has recently seen a growth of interest in medical engineering research concerning the development of `micronano` technologies, a division of micro devices capable of manipulating and processing cells. In order to create devices that are capable of operating in the sorts of extremely tiny environments that are comparable to the approximate 100µm diameter of a single human hair, expertise spanning the fields of mechanical engineering, biology, chemistry and electrical engineering among a great many others is required.
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[Heading 2] Electric-Field-Induced Bubble Knife [Heading 2]
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The electrosurgical knife is a time-tested and comparatively inexpensive technology that sees regular use in surgical procedures. Contact pressure and arc discharges occurring at the knife’s tip upon the application of a high frequency electrical current to the tissue result in joule heating. Thereupon, an incision is created as the cell liquid is rapidly heated resulting in evaporation and the explosion of the cell itself. Although this sort of electrosurgical technology has remained mostly unchanged since its invention almost a century ago, laser surgery which was developed some 30 years ago continues to be perfected with comprehensive research into the interaction between cell and laser making precise ablation at the cellular level possible. It was this notion that led us to the conception of a new, minimally invasive and high resolution electrosurgical knife capable of performing cellular surgeries. Thereafter, we set about fashioning a micro-electrode encased in a glass insulation film and decreased the output power of the device to work on the cellular level before moving onto experimentation.
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In the early stages of our research we were met with a series of failures as our cell-cutting micro-electrosurgical knife would cause thermal damage to the cells and generate errant gas bubbles as a result of electrolysis. Additionally, the electrode would become worn, and suffered degradation due to contact with protein materials that would accrete on it after making incisions. However, during an instance in which we were trialing a design that was equipped with a small aperture in the tip of the electrode that functions as a bubble reservoir, we discovered a newfound directionality to the gas bubbles that had previously been generated in a disorganized fashion (Figure 1). Upon using a high speed camera to confirm, we observed that the gas bubbles were all of equal size and moved at high velocity in an organized line. We now know that we can use these bubbles to manipulate the surface of cells, and we are currently in the midst of proceeding with research into a device that we have named the `Bubble Knife` which is capable of using gas bubbles to dissect cells. When the return electrode of this device is made to contact the target cells, voltage is applied to the area intervening it and the glass electrode, which functions as the active electrode of the pair. This causes a rapid and successive discharge of extremely small gas bubbles through the needle aperture. These bubbles undergo a sudden change in pressure producing a crushing force capable of cutting through a cell. This method has the advantage of avoiding the propagation of thermal damage to the target surface, whilst still affording the device the necessary power to manipulate relatively hard substances.
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[Heading 3]From Cell Manipulation to Needle Free Injector[Heading 3]
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The gas bubbles collapse as a result of the violent pressure fluctuations they experience, enabling the formation of a cavitation in the targeted area. This allows perforation to be conducted in a minimally invasive and highly precise manner. The frequency oscillator adds non-inductive resistance to a general purpose medical grade electrosurgical knife, and uses an output power suitable for operation at the cellular level.
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During experimentation, a porcine oocyte suspended in a culture medium was used as a test target and brought into contact with the device`s return electrode.
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In addition to the latest advancements in regenerative medicine and genetic engineering, health care professionals have turned their attention to the medical uses of nanotechnology, where the devices developed and researched can manipulate and process cells at the microscopic and nanoscopic levels. The invention of such devices, which can operate at even at the width of a human hair (about 100µm), has established technical knowledge which can be utilized across a variety of fields including mechanical engineering, biology, chemistry, and electrical engineering.
2 The Electrically-Induced Bubble Knife
The electric knife is a reliable and relatively inexpensive technology that is widely used in surgical procedures. A high-frequency electrical current is first distributed throughout the body. Then, the arc discharge from the tip of the electric knife and the resulting contact resistance causes resistive heating. This heat instantly causes detonation and radiation of the targeted cells, allowing for surgical incision. The technique described above has remained mostly unchanged since its invention about 100 years ago. On the other hand, the mechanics of the laser knife created 30 years ago have often been improved upon and the interaction between the laser and the targeted cells has been researched extensively. Once accurate single-cell ablation via laser knives had become possible, minimally-invasive high-resolution surgical cell removal via electric knives had reached a conceptual phase and experiments aiming to localize the discharge of the knife using glass-insulated micro-electrodes were conducted.
In early studies, cell ablation via electric knives had a series of shortcomings. These included thermal damage to surrounding cells, occurrence of multi-directional bubble streams, electrode abrasion, and deterioration of electrodes due to adhesive proteins. However, it was found that linear bubble stream dispersals could be achieved when electrical discharge from the knife was released into the bubble reservoir structure, a space established between the glass-insulated electrode tip and the targeted cells (Figure 1). When using high-speed cameras to confirm the existence of this discovery, researchers were able to determine the size and speed of the bubbles in the linear stream. It was then discovered that these bubbles could also manipulate cell surfaces. The discovery of this device, known as the “bubble knife” for its ability to cut through cells using bubbles, resulted in the advancement of electric knife research. One such advancement involves a method where a cell is forced to come into contact with the space between the active glass-insulated electrode and the counter-electrode. Subsequently, voltage is applied and a continuous stream of very small bubbles is discharged from the tip of the knife. These bubbles manipulate cells by crushing them with the impact of the sudden pressure change. While this method has the strength to process even relatively hard materials, it is advantageous in that it does not induce collateral heat damage in the targeted area.
3 From Manipulation-and-Injection to Needle-Free Injection
Minimally-invasive yet highly-precise perforation can be achieved due to the cavitation that occurs in the targeted area when micro-bubbles are crushed by a sudden change in pressure. An oscillator is used to add non-inductive resistance to the universal medical-use electric knife and apply output to the cellular level. The manipulation target, an oocyte present in the culture fluid, is put in direct contact with the counter-electrode.
Along with the expansion of research in regenerative medicine and genetic engineering fields, medical engineering research is garnering recent attention in the world of medicine with its development of micro devices that manipulate and alter cells in the exceptionally small spaces of the micro/nano world. In order to create micro devices that can operate in such minute units of physical space (picture a space the width of an average human hair at about 100 micrometres), scientists must draw from knowledge that transverses various academic fields not limited to mechanical engineering, biology, chemistry, and electric engineering.
2 Surgical Knives Using Electrically-Induced Bubbles
The electrical scalpel is a solid and comparatively low-cost technology often used in surgical procedures. A high-frequency electric current is run through the patient's body and joule heat is generated via arc discharge and contact resistance produced at the tip of the knife. The heat increases cell temperature instantaneously, and the subsequent cell explosion and transpiration cause an incision to occur. This mechanism has virtually remained the same since its invention nearly 100 years ago. Meanwhile, the degree of perfection in the laser knife invented approximately 30 years ago continues to improve, and thanks to thorough research on the interaction between cells and lasers, an ablation with accuracy at the cellular level is now a possibility (1). However, at the pinnacle of innovation surrounding non-invasive, high-resolution surgical knives, scientists have created and experimented with a knife whose tip consists of a glass-insulated microelectrode and whose electrical output is adjusted at the cellular level (2).
This cell-slicing micro knife faced a run of setbacks at the initial stages of research including thermal damage to cells, formation of disorderly air bubbles via electrolysis, electrode abrasion, and electrode deterioration from coagulation of protein post-incision. Nevertheless, it was discovered that upon discharge using a design in which a bubble reservoir was built into the electrode tip, an element of directionality was present in the bubbles that had previously behaved chaotically (Image 1). Using a high-speed camera to confirm the observation, scientists observed a single line of uniformly-sized, high-speed bubbles. Understanding that through use of these bubbles even the surface of cells could be altered, scientists are making headway into research regarding the "bubble knife," a device that uses these bubbles to cut through cells. With the glass electrode as the working electrode, the targeted cell is brought into contact with the counter electrode and voltage is applied. This produces a continuous high-speed discharge of nano bubbles from the electrode tip, but due to the radical change in pressure the bubbles immediately collapse. It is the force of this violent impact that penetrates the targeted cell. One advantage is that while powerful enough to alter even relatively hard substances, the method does not cause thermal damage.
3 The Advent of the Needle-Free Injector
These nano bubbles disintegrate under the intense fluctuation in pressure and cause cavitation at the targeted area, making it possible to perform non-invasive, yet high-precision perforations. To the traditional electrical scalpel, the output oscillator applies non-inductive resistance, utilizing an object whose electrical output is dropped at the cellular level. The targeted oocyte resides in the culture solution and is in contact with the counter electrode.
Recently within the world of medical care there has been an increasing focus on medical engineering research to develop micro-devices. Coupled with the advancement of techniques such as regenerative treatments and genetic engineering, these devices enable the manipulation or modification of cells within extremely small spaces referred to as the “micro-nano” level. Creating micro-devices that can be utilized in such a small unit of space as a single human hair, with a thickness of approximately 100µm, demands knowledge that spans over a variety of fields such as mechanical engineering, biology, chemistry, and electrical engineering.
2. Electrically Induced Air Bubble Scalpel
The electric scalpel is a firmly established and relatively low cost technology that is often used for surgical procedures. It works by running high frequency electric current through the tissue and generating ohmic heating by means of contact resistance and electrical arcing that occurs at the tip of the scalpel. This effect heats up the tissue cells instantaneously, and produces a cutting action as the cells burst open and evaporate. Since its invention about 100 years ago, the electric scalpel's operating mechanism remains virtually unchanged. In contrast, the laser scalpel which was invented about 30 years ago continues to be improved to higher levels of refinement. As a result of intense research into the interplay between the laser and the cell, it has become possible to accurately remove tissue at the cellular size level(1). This led to the concept of a new minimally invasive, high resolution electric scalpel that can perform surgery at the cellular scale. This device was constructed with its output reduced down to the cellular level and using a specially prepared micro-electrode wrapped in glass insulating film, and was then subjected to experimentation(2).
During the early part of the research, the micro-electric scalpel used to cut the cells experienced one failure after another. The scalpel inflicted heat damage to the cells, air bubbles were generated in an unpredictable manner due to electrolysis, wearing of the electrode took place, and the electrode deteriorated after performing an incision due to the buildup of protein material. However, at a certain time it was discovered that if the electrode is constructed with a vacant space (bubble reservoir) at the tip, then during electrical discharge there is a directional quality to what had previously been an unpredictable occurrence of air bubbles (figure 1). When inspected using a high speed camera, it was found that the scalpel produces a single file line of bubbles with uniform size and proceeding at high-speed. It was discovered that these bubbles can even be used to ablate the surface of a cell, and as a result, research has progressed for the device which can cut cells using bubbles under the moniker “bubble scalpel.” With the glass electrode serving as the active electrode, extremely tiny bubbles are fired continuously at high speed from the tip, by applying a voltage across this electrode and an opposite electrode that is brought into contact with the target cell. This is a method wherein the bubbles ablate the cell by means of a crushing force caused by rapid pressure fluctuations. While this force is sufficient to ablate even a relatively hard substance, the method has the benefit of not inflicting heat damage on the working surface.
3. From Ablation and Injection to a Needleless Syringe
Because the bubbles have the ability to generate cavitation at a target position through crushing action caused by rapid pressure fluctuations, it is possible to punch a hole in a a minimally invasive and highly precise manner. For the output oscillator, a general purpose medical unit for an electric scalpel is used, with non-inductive resistors added in order to reduce the output current down to a level suitable for cells. An oocyte cell that is the target of ablation is contained within a culture solution, and brought into contact with the opposing electrode.
Recently in the world of medicine, developments in regenerative medicine and genetic engineering are accompanied by a growing interest in medical engineering research on microdevices for modifying and manipulating cells. Creating these microdevices, which can be used in the space of the thickness of a human hair (approx. 100μm), requires knowledge transcending many fields such as mechanical and electrical engineering, biology, and chemistry.
2 Electrically Induced Bubble Scalpel
Electric scalpels are durable and relatively inexpensive, and are commonly used in surgical operations. As high frequency electrical current is passed through the human body, joule heating occurs at the tip of the scalpel due to arc discharge and contact resistance. This causes cells to heat rapidly, explode, and vaporize, creating an incision. The mechanism for this technology has not changed since its invention approximately 100 years ago. In contrast, laser scalpel technology has shown continuous improvement since its invention approximately 30 years ago. The effects of interactions between lasers and cells have been studied extensively, and the technology has made accurate ablation possible at the cellular level.1 In this study, a new, low invasion, high resolution scalpel for cellular surgery was conceived. Experiments were conducted by reducing the output of an electric scalpel to cellular levels and using fabricated microelectrodes covered with glass insulation film.2
At first, there were many problems with the micro-electric scalpel such as damage to cells by heat, chaotic bubble generation due to electrolysis, electrode wear, and deterioration of electrode due to protein residue. However, when a structure with a bubble reservoir at the tip of the electrode was implemented during discharge, the bubbles that had been generated chaotically until then became orderly (Figure 1). By using a high-speed camera, it was found that the bubbles are a single row of fast-moving bubbles that are uniform in size. It was also discovered that the surfaces of cells can be modified using these bubbles, and the device is now being studied under the name “bubble scalpel.” With the glass electrode as the active electrode and the target cell connected to the return electrode, the device repeatedly fires extremely small bubbles from the tip at high speed when a voltage is applied across the electrodes. The target cell is modified by the force of bubbles collapsing due to the sudden change in pressure. This method allows for modification of relatively hard substances without damaging the modified surface with heat.
3 From Modification/Injection to Needleless Syringes
When bubbles from the scalpel collapse due to the sudden change in pressure, cavitation occurs at the targeted position. This makes it possible to make holes with high accuracy and low invasion. A power source for an electric scalpel is used with a non-inductive resistor to reduce the output to cellular levels. The sample to be modified, an egg cell, is in a culture medium and in contact with the return electrode.