Applying Micro-Electro-Mechanical Systems (MEMS) to medicine and drug discovery

A micro device working on individual cells

Micro-Electro-Mechanical Systems (MEMS) refers to the technology whereby micromachining technology is used to fabricate miniaturized devices that integrate electrical and mechanical elements. MEMS came under the spotlight in 1987 when AT&T Bell Laboratories introduced micro gears with diameters ranging from 125 to 185μm at an international conference called Transducers held in Tokyo. Thereafter, the research and development of MEMS has been mainly led by the U.S., Europe, and Japan by using advanced micromachining technology that was developed from semiconductor technology. Nowadays, MEMS technology is used in various devices including acceleration sensors in automobile air bags and smart phones, the inkjet nozzle of printers, the mirror and switch of optic devices and analysis equipment in the field of life sciences.

“Great expectations are placed on MEMS to become a key technology for innovation since its range of potential applications is quite broad. On the other hand, the MEMS technology demanded by each field is different, and therefore MEMS research is progressing in various unique ways adapted to suit the needs of each field. Although we talk about MEMS in general, it actually represents quite diverse fields, and is also constantly evolving through trial and error,” says Professor Takayuki Shibata.

Professor Shibata is applying cutting edge MEMS based research to construct very tiny tools that work on a biological cell, which is the smallest unit of life. “The size of a cell is only 10 to 20μm. Up to now there have been no tools that could handle both individual cells and all the cells at once. If our technology is put into practice, we expect that researchers will be able to control and analyze a large number of cells simultaneously, leading to new findings in life science. Not only that, we would be happy if our technology can contribute to facilitating an acceleration in the process of drug discovery and medicine,” Professor Shibata says.

The applications of MEMS in the medical field have mushroomed since the complete decipherment of the human genome in 2003. More recently their practical implementations have been increasing. In this context, Professor Shibata has received attention by developing a microneedle array for pricking cells - 600,000 pcs of tiny hollow needles made of glass with an outer diameter of 5.6μm and an inner diameter of 3.2μm arrayed on a 1cm² size microchip.

“This needle array is an innovative device that can simultaneously introduce DNA molecules and extract biomolecules into and from 600,000 individual cells . Conventional methods for cell analysis can only provide information on the average value of all the cells since their analysis equipment checks all cell fracture extracts in a large quantity. On the other hand, if we can work on individual living cells in the scale of one million and analyze them, highly accurate statistical analysis will become possible, even as far as understanding the individuality of each cell. Furthermore, since the diameter and spacing of the needles is adjustable in MEMS, we can create various designs depending on its application.”

Using electrical driving force and mechanical oscillation to introduce DNA into cells

To fabricate a needle array, one must first make a circular pattern on silicon substrate using a method known as photolithography and then vertically etch fine holes into the substrate. The next step is to make them react with the water and silicon by exposing them to high temperature steam at 1000°C to form a glass film (SiO₂) in the inner wall of the hole. Finally it is necessary to remove the silicon using an alkaline solution to create a minute glass needle.

“Cells are very small and delicate, so if we try to forcibly prick one with a needle, its cellular membrane may be punctured and destroyed, and the cell would eventually die. You might have seen a microscopic image of pricking an egg cell with a glass needle in IVF (In Vitro Fertilization), but almost all types of cells (so-called somatic cells) that make up our body are only one tenth of the size of the egg cell so it is very difficult to prick them by sucking with a needle under negative hydrostatic pressure. In addition, if you try to introduce a solution into an array of needles by the application of external pressure, but the aperture of needle is too small, the solution would seek whichever individual needle offered the least hydraulic resistance, and only be released from that point. No matter how sophisticated our needle processing, it is impossible to fabricate all needles to precisely the same size.”

To address this problem, Professor Shibata adopted a method using an electric field and mechanical oscillations when penetrating cell membranes and introducing DNA into a cell with a needle. DNA is negatively charged in a solution so if the potential inside the cell is rendered positive by applying appropriate voltage, DNA can be injected into the cell through the tip of the needle. Furthermore, it becomes easier to penetrate cell membranes without causing serious cell damage when mechanical oscillation is applied during the insertion process with a needle. This is due to an increase in the cell’s viscous resistance.

“Think about the suspension in automobiles. It is mechanically composed of a combination of springs and dampers. Springs can be deformed proportional to the applied force. On the other hand, dampers can also be deformed when pressed slowly just like the spring; however, if the damper is pressed quickly, it becomes hard and difficult to deform. It becomes easier to penetrate a cell with a needle, as with the damper, when one applies oscillations to quickly deform its cell membrane. This technology was made possible by applying my knowledge acquired from mechanical engineering and cell-capture, in other words by understanding its mechanical characteristics.”

Application to mass production of iPS cells and genome editing

Moreover, Professor Shibata is aiming to construct a platform for analyzing and manipulating cells by handling various technologies such as hollow microneedle arrays, suction cup type manipulator arrays, piezoelectric type micro cell medium devices, nanoneedle-based sensing probes for capturing dynamic changes of cells, and multi-functional scanning bioprobe microscope with hollow nanoneedle.

“At this point, we are only preparing the necessary tools for analyzing and manipulating cells, but we want to apply these technologies for the mass production of iPS cells in the future. Currently, iPS cells are made manually by skilled personnel, but the success rate of creating iPS cells is only 1%, which is very low in efficiency. If we can use our needle array to establish automatic mass production of iPS cells, the application of iPS cells will progress even further, and it will become more convenient to elucidate the mechanisms of diseases and to study the effects and toxicity of various drugs.”

Professor Shibata says that he wants to accelerate the process of finding practical applications for his work by collaborating with medical institutions. His will continue to strive to develop fundamental technologies for advanced medical research.

Reporter's Note

Professor Shibata, as a former researcher in precision engineering, used to produce diamond thin films and three-dimensional structures for use in devices. In the meantime, he became interested in the mystery of life and turned to the field of BioMEMS research after being involved with the production of microchips for amplifying DNA and analyzing blood. He feels that it is his mission to apply the technologies that he learned in the field of manufacturing, where reproducibility is emphasized, to the progress of life science.

“It is not well known but Toyohashi University of Technology has the one of the best cleanrooms in the world. I am very fortunate therefore to enjoy a research environment which is not only optimum for creating MEMS, but is also supported in such a way that active collaboration with researchers in different fields is made easy. As it happens, my interest in the mass production of iPS cells emerged from a conversation with a researcher in a different field,” Professor Shibata says. It is greatly hoped that this MEMS technology, originating from Toyohashi, will contribute to rapid advancements in medicine and drugs around the world.