Micro-Measurement And Manipulation Technologies

ISOZAKI Katsumi¹ IMAMURA Makoto² FUKUSHIMA Kazuhisa³ TANAAMI Takeo³

We have been developing original semiconductor and MEMS devices to achieve the functionality of measurement and control equipment that requires much higher quality and performance than consumer-use products. Typical examples are timing generators for LSI test systems, analog-to-digital converters for oscilloscopes, and resonant differential pressure sensors for process use. We are expanding the coverage of MEMS technology to glass, resin and compound semiconductors, as well as to other applications including micro-reactors and biotechnological diagnosis cartridges, though our basic strategies for device development remain unchanged.

1. Advanced Technology Research Center, Corporate R&D
2. Advanced Device Development Div., Corporate R&D
3. Biotechnology Project Dept., Corporate R&D

I PROPRIETARY SILICON KEY DEVICES

INTRODUCTION

Figure 1 Main LSI Test Systems and Timing Generation LSIs of Key Device

With the advancement of semiconductor technologies, the performance and functions of measurement and control equipment have improved dramatically. Most general functions for this type of equipment are achieved by utilizing a wide variety of commercially available LSI's and the other semiconductor devices. However, the key devices that determine the basic performance of measurement and control equipment often cannot be found among commercially available products. Even if such products can be obtained on the market, they often do not satisfy the customers' performance requirements, especially for our equipment. As we consider that the provision of a continuous, reliable supply of our own key devices is our duty as a leading manufacturer of measurement and control equipment, we have for many years devoted our efforts to their in-house development.

Because the requirements for these key LSI devices are diverse, and leading-edge performance is always demanded, it is economically difficult to provide a manufacturing process that satisfies all of these requirements. Therefore, since the 1990's we have established a structure in which key LSI devices can be consistently supplied using leading-edge processes at outside foundries. In contrast, we have developed our unique sensors and high-voltage SSR's (Solid State Relays) utilizing in-house silicon Bi-CMOS (Bipolor and CMOS) / MEMS (Micro-Electro-Mechanical Systems) processes, for which general-purpose foundries are non-existent. This policy of utilizaing both the in- house development and the external fabrication will remain unchanged.

Packaging technologies are also just as important as semiconductor device design technologies. As the packages of sensors and solid-state relays (SSR's) considerably influence performance, we also assemble chips using in-house processes.

In recent years, due to increases in signal bandwidth, conventional wire bonding is no longer capable of maintaining transmission waveform quality. As a result, demand for in-house packaging technologies for high-speed devices, such as A/D converters and LSI's for LSI test systems, has also been increasing. The following describes the development of timing generators for LSI testing systems and A/D converters for digital oscilloscopes. These are key devices for high-speed packaging technologies for high-speed applications, and recent results of SSR's and differential pressure sensors using in-house sensor processes.

TIMING GENERATION LSI'S FOR LSI TEST SYSTEMS

Figure 2 Main Oscilloscopes and A/D Converters of Key Device

The most important characteristic of an LSI test system (tester) is the accuracy of the data rate and timing, which are determined by the timing generator (TG). In recently developed testers, the mainstream configuration of these timing generators uses a per-pin architecture for each measurement pin. This per-pin architecture is effective for increasing timing accuracy. However, tradeoffs for this architecture are system scale, power consumption and cost. As a result, until now it has only been used in high-end models. This is because there are no LSI's commercially available for timing generators, and, moreover, high-grade analog technology requires a timing vernier (TV) capable of generating the minute time of the clock frequency or shorter.

At Yokogawa we have realized the low cost packaging of timing generators, which are key devices for testers, by incorporating them into a single CMOS LSI chip. Thanks to this development, the per-pin architecture can now be adopted even in the low-end LSI test system, TS600. TG's are fully custom designed using processes for general-purpose 1 µm CMOS, and TV's are realized by proprietary technology (which was awarded the Regional Invention Encouragement Prize in 2003). Compared with technology using gate delay, these technologies feature better linearity with lower power consumption and easier span adjustment. Even for TG's in the latest 0.18 µm 1 Gbps memory test systems, TV's use the same method, and existing design assets accumulated thus far have been applied to realize a low voltage TG.

Figure 1 shows the TG's that have been developed so far, and LSI test systems incorporating them. We consistently use the latest processes, and have realized 4 time-interleaved data rates over the past four years. We have also integrated more resources, accompanying the trend for finer patterns, and have expanded the scale. The technological issues we have solved during our developmental research include 1) the design of high-speed, high- accuracy and low-power voltage analog circuits, 2) the design and verification of a low crosstalk layout, and 3) the design and verification of mixed large-scale advanced analog and digital function TG's.

HIGH-SPEED A/D CONVERTERS FOR DIGITAL OSCILLOSCOPES

A/D converters for converting analog input signals to digital signals are key devices for digital oscilloscopes. A/D converters that can handle up to several tens of MS/s of video signals are commercially available; however, the scope of application for characteristics of several hundreds of MS/s or more that are used in oscilloscopes is limited. For this reason, major oscilloscope manufacturers usually develop original A/D converters that are necessary for the production of oscilloscopes. We, too, have developed high-speed A/D converters of 500 MS/s and 2.5 GS/s for our oscilloscopes. Figure 2 shows our main A/D converters and oscilloscopes using these A/D converters.

We have developed a proprietary architecture (Figure 3) called the "cascade architecture" (awarded the Regional Invention Encouragement Prize in 2004)¹. Compared with the parallel type (flash type) that is used for general high-speed A/D converters, this architecture uses far fewer comparators, the basic circuit elements, and therefore features a small scale and low power consumption. As digital codes for the analog input voltage are determined successively, one bit at a time from the uppermost bit, this architecture can, in principle, perform 8-bit A/D conversion using eight comparators.

Figure 3 Cascade A/D Converter

Note, however, that there is a drawback in that logical values are not determined uniquely as comparator gain is limited if the difference between the analog input voltage and the reference voltage to be compared is too small. This is why we devised an architecture for detecting the vicinity of this threshold, and which activates the error suppression circuit only at this time to determine digital codes. As a result, the number of comparators was reduced to 21, one twelfth that of a parallel type converter. This has greatly reduced the circuit scale and power consumption.

This cascade architecture is adopted also in the A/D converter (3 GHz band, 2.5 GS/s 8 bits) for the latest DL9000 Series, in addition to the A/D converter (1.5 GHz band, 500 MS/s 8 bits) for the DL1700 Series. In this way, wide-band, high-speed sampling A/D converters were integrated onto a single chip, using leading- edge bipolar processes.

Also, with the A/D converter (200 MS/s, 8 bits) for the portable oscilloscope DL1600 Series, an analog front-end circuit of 300 MHz input bandwidth has also been integrated onto a single chip. We adopted the CMOS process to reduce size and power consumption. To obtain high-speed and high-precision analog characteristics, we are currently devising means such as the combination of replica circuits with calibration circuits.

HIGH-SPEED PACKAGING TECHNOLOGY

Figure 4 Multichip 10 GS/s A/D Converter

When the signals exceed the GHz level speed, the wire-bond inductance adversely influences the quality of waveforms. In particular, with oscilloscopes, flip-chip (FC) technology that eliminates bonding wires has become mandatory for key devices of digital oscilloscopes, which require rigorously high-fidelity waveforms. Unlike wire bonding, in FC packaging signal interconnection pads are not limited to the chip periphery. Therefore, several advantages, such as the suitable separation of analog and digital signal lines and the requirement of less space for power supply interconnections, enhance signal integrity. Also, as chip mounting and bonding requires less space, multiple chips can be incorporated to improve functionality and performance.

However, a high-speed, multichip FC technology using Au-Sn binding on minute signal interconnection pads has yet to be established in the markets, so we made a proposal NEDO (the New Energy and Industrial Technology Development Organization) to develop multichip FC technology as a subsidized R&D project. This proposal was accepted in 2003. As FC technology can make the pads much smaller, it is suitable for high-speed chip mountings.

Figure 4 shows an example of a multichip, high-speed sampling rate A/D converter produced as a prototype for the NEDO project. Four 2.5 GS/s A/D converter LSI's were mounted with FC technology to achieve a 10 GS/s 8-bit A/D converter². Gold solder is used for the FC bonding. FEM-based simulations were utilized beforehand in the structure and thermal design stages to confirm effects such as the warpage of the substrate. Also, we fabricated prototype daisy-chained test chips to evaluate the long-term reliability of FC bonds.

Using PLL circuits, each A/D converter LSI generates clock signals that have the same interval of 100 ps respectively, and performs time-interleaved A/D conversion, thereby achieving a 4 time-interleaved conversion rate. The prototype that we have produced realizes an S/N ratio of 42 dB for a 100 MHz input sine wave and a maximum conversion rate of 11.3 GS/s.

MEMS SENSOR

Figure 5 Static Pressure Characteristics of Prototype Resonant Type Differential Pressure Sensor

A typical MEMS sensor device is a resonant-type differential pressure sensor. Over 1.7 million of these devices have already been sold, and their performance and quality are applauded globally. Though this device was first developed about ten years ago, it remains potentially capable of meeting newly emerging demands for new functions such as diagnostics and the simultaneous measurement of differential pressure and static pressure. To this end, we are conducting research into implementing methods more suitable for static pressure measurement. Moreover, with regard to processes, we are making efforts to realize more stable, lower cost production by bringing special MEMS processes closer to general LSI processes.

Static pressure is measured by utilizing the change in tension of the resonator, namely the oscillation frequency, caused by changes in the compression stress that the sensor is subjected to. However, the changes in stress on the base supporting the sensor also influence these characteristics. The use of glass bases, though inexpensive, has therefore not been possible due to their slow response to these changes in stress. We discovered that the effect of these changes in stress is expressed by a function of the elastic modulus and the thickness of the silicon and glass, and established a design method that eliminates this effect completely. Figure 5 shows the static pressure characteristics of the prototype sensor that was made based on this design method, and demonstrates the elimination of the influence of changes in stress in glass.

The resonator, gap and shell are continuously formed by self- alignment MEMS processes using low-pressure epitaxy equipment. Although this process involves a small number of production processes, the resonator and shell are connected electrically, the S/N ratio is limited, and the equipment is specialized, requiring a tuning procedure. Therefore, we developed a new process for forming the resonator based on the same diffusion process as that for ICs, and then formed the shell by sandwiching polysilicon between insulation films. As a result, the resonator is insulated by the shell, and we were able to realize a prototype sensor with an S/N ratio improved by three times.

SSR'S FOR SCANNERS

(a) Diode structure and external appearance	(b) Breakdown Voltage Characteristics
(c) Leak Characteristics
Figure 6: 3 kV Dielectric Strength SSR Diode Characteristics

Many relays for switching measurement points are used in recorders, which are typical measurement equipments for performing multi-point measurement. Some measurement points are connected to commercial power supplies, and it is often the case that high insulation and high surge resistance are required, thus mechanical relays are frequently used. However, since downsizing mechanical relays is difficult and their subsequent reliability is insufficient, Yokogawa has been developing SSR's for more than a decade, incorporating them into various types of scanners. Although we can boast that with a surge resistance of 1.5 kV DC, our SSR's are the best in the world, we are developing new SSR's with a voltage resistance of 3 kV that will support even further deteriorated environments.

Device structures have changed from a horizontal DMOS structure to vertical, and we have developed a new process to further combine MEMS processes to maintain chip size at the current level. Due to the prototype diodes we have made, we have been able to limit leak current to 1 nA or less, which is sufficient for measurement applications. Figure 6 shows the external appearance of this diode, and its pressure resistance and leakage current characteristics.

CONCLUSION

It is anticipated that the trends in the basic performance of measurement and control equipment as pertaining to these key devices will continue to strengthen in the future. Therefore, Yokogawa has continually evolved key silicon semiconductor devices. Furthermore, the technology gained through the development of these key devices has been applied to the design of compound semiconductors and to MEMS fabrication using glass and resin. For details of these results, refer to separate articles "II Microplant and MEMS Technology" (pp.11-14), "III Personalized Medicine and Gene Analysis Systems" (pp.15-18).

REFERENCES

1. Irie K., et al., "An 8b 500 MS/s Full Nyquist Cascade A/D Converter," 1999 Symposium on VLSI Circuits, June. 1999, pp.77-78
2. Nagayama H., et al, "Design and Verification Technology for 10 GS/s, 8-bit A/D Converter SIPs for Measurement," No.14 Microelectronics Symposium (MES2004), Oct. 2004, pp.49-152 (in Japanese)

 

II MICROPLANT AND MEMS TECHNOLOGY

INTRODUCTION

Figure 1 Technological Development Strategy of Advanced Technology Research Center

Corporate R&D has two kinds of missions. One is the role of developing discriminated key technologies and devices to strengthen competitiveness of the main products. At our Advanced Technology Research Center, we have developed resonant sensor device using MEMS technology as a key device for new industrial differential pressure transmitters; the high- speed and sensitive scanner using micro-lens arrays as a key technology for confocal fluorescent microscopes for the live organism's observation; and the applied optical technologies as an element technology for in-line near infrared spectrum analyzers. As a result of cooperation with our business divisions, we have succeeded in commercializing these technologies. Continual development is indispensable to maintain and increase a product's competitiveness, and so we are conducting development for further evolving these products. Besides this development, we are researching and developing the optical fiber sensing technology, interferometer measurement technologies for evaluating the NGN (Next Generation Network) devices, and a unique MEMS- VCSEL tunable LD (MEMS vertical cavity surface emission laser tunable light diode) combined our MEMS technologies with compound semiconductor technologies. We would like to discuss these advanced sensing technologies on another occasion.

The other mission is the role of developing new technologies and devices to create new business in the future for Yokogawa. In this respect, strategic management plays an important role in the development, because the likelihood of success in this mission is low, thereby requiring ten to twenty years to achieve success as a business venture. More than anything, the activity is considerably dependent on the abilities and nature of individual researchers, so that training and education of talented personnel is important. Though people tend to focus on new business as an uncharted area where markets and technologies cannot be seen, we have our eyes fixed on either of these as visible areas. We believe that we can make the correct choice and concentrate by "decentralizing" our resources on a specific business area that we have strategically focused on, by coming into contact with new technology and by suffering bitter experiences.

Figure 1 shows our development strategy. We are developing discriminated key devices to be the seeds of Yokogawa's new business and create large value, enhancing added value of the devices themselves by developing modules, systems and content based on the key devices. As a further evolvement, it would be ideal if these key devices become the key devices of other business areas. For our company, one of these technologies is MEMS technology.

At present, at the Advanced Technology Research Center, we have focused on microreactors as a priority theme and have speeded up development. It is our aim to make conventional plants more advanced by bringing the chemical reaction plant into a micro-flow channel, and freely manipulating substances at the micro level. We expect this will lead significant innovation in the chemical industry's manufacturing process. The key technology of this microreactor is MEMS technology, a technology that we focused on at an early stage. The following introduces our activities to microreactors.

BACKGROUND TO YOKOGAWA'S ACTIVITY IN MICROREACTORS

Microreactor technology is a new technology for innovating production methods for pharmaceuticals and fine chemicals that manufacture small amounts of high value-added functional materials. Taking the mixing process by way of an example, it is an extremely difficult task to perform mixing while maintaining a satisfactory balance between uniformity and speed in a conventional large reactor. The basic principle of mixers using microreactors is as follows. The fluids to be mixed are separated into small segments in micrometer units, converged in the state of small segments, and continuously mixed using the diffusion effect. Accordingly, uniform, high-speed mixing can be stably achieved using microreactor. If the effect of this is made use of, emulsions of uniform particle diameter distribution, synthesis of polymers having small molecular weight distribution, and synthesis of chemicals having few by-products becomes possible. High-speed heat exchange also is possible. Exothermic reactions of an explosive nature as typified in Grignard reaction and partial oxidation reaction, that have been difficult to handle up so far, also become controllable by using the microreactor. If these technological developments are advanced, the generation of phenol from benzene at a single stage reaction and the selective and efficient synthesis already acquired by living organisms such as photosynthesis may possibly be achievable in the year 2015. Considering this in terms of a measurement and control standpoint, incorporation of in-line monitoring sensors and introduction of optimum control that have been difficult to implement at existing batch plants will be easily achievable if the reaction site is brought into a chip. This concept is also highly compatible with the PAT (Process Analytical Technology), the process automation technology in the pharmaceutical industry, and we are conducting development of sensors for microreactor, which can be incorporated in a reactor chip^1,2,3.

In the electronic devices industry based on the silicon process, simulation technology for debugging and designing are the generally accepted, and we are providing efficient development environments. Though there is the trend of introducing simulators in the field of chemistry, there are few cases that can be handled with effective results. We consider a cause of this to be the fact that chemical plants have a large flexibility in parameters when the current chemical processes is described as a physical model, so it is difficult to get meaningful calculation results from simulation models. If microreactors are used, each process will be able to be described logically, and variation in parameters can be suppressed to a smaller level. In other words, systems that were too flexible and that relied on experience will be able to be converted to firmer systems that can be logically examined if microreactors are used to restrict flexibility. This is one of the advantages of microreactors.

The introduction of new technology, microreactor, is not entirely plain sailing. It has issues needed to be overcome such as blockages, few techniques for separation suited to microplants, the need for design and making devices to start testing decreases the motivation of chemistry-grounded researchers. It is our intention to solve these problems.

Measurement and control is the core technologies in our business. We have contributed to society by deploying field devices and analyzers for measuring pressure, flow and temperature in large-scale plants in the fields of oil refining and material chemistry, and by connecting these sensors by networks and performing optimum control using control systems. However, we consider our contribution to the fine chemicals and pharmaceutical sectors to be insufficient. We believe that this sector is also the main business for our company and an area that we can contribute to society, thereby devoting efforts to developing microreactors. The following introduces our activities on microreactor.

ADVANCED TECHNOLOGY LABORATORY'S ACTIVITY FOR MICROREACTOR

Figure 2 Microreactor for Electrochemical Reactions and Pillar Structure

1) Development of a Microreactor for Electrochemical Reactions

The core of microreactor is the devices for providing a new reaction site and the content for production using those devices. As our company does not produce chemical-based consumable materials in-house, we do not have information relating to chemical-based information. Accordingly, cooperation with chemical manufacturers is important for producing content using microreactors. Figure 2 shows the structure of a microreactor for electrochemical reactions that is developed jointly with Mitsui Chemicals Material Science Laboratory. The electrical field distribution of the electrochemical reaction concentrates in the range of several tens of micrometers in the vicinity of the electrodes, and substances move by diffusion and agitation. For this reason, in this joint research, we have developed a prototype micro reactor having an electrode structure with a narrower space and a large surface-to-volume ratio for efficient electrochemical reactions.

When the space between electrodes is narrow, the solution resistance can be reduced, thereby not requiring a supporting electrolyte. If there is no supporting electrolyte, by-products derived from the supporting electrolyte can be controlled, and the supporting electrolyte no longer needs to be removed after the reaction.

We selected a dimethyl maleate reduction dual reaction as the model reaction, and demonstrated in testing that an electrochemical reaction can be achieved without the use of a supporting electrolyte. On the other hand, there is also the problem of electrochemical reactions using a microreactor, which involves the mixing of a reaction product as the space between electrodes is narrow. To solve this problem, we made a prototype device with a pillar structure provided in the center to suppress the mixing of products, and are conducting basic tests on this⁴.

For the next step we are developing an on-site fluorine gas generator using an electrochemical microreactor. Fluoric gas is useful as cleaning gas for CVD and etching equipments. At this time fluorine gas is made in a large chemical plant, packed in high pressure gas cylinders, transported to a semiconductor factory and supplied by the high-pressure gas piping. MEMS technology enables an on-site fluorine gas generator that can be set around semiconductor equipments. On-site, on-demand production (ubiquitous production), cost reduction and safety improvement are achievable by our micro reactor. This on-site gas generation based on a microreactor will change the concept of production method.

 

Figure 3 Configuration of Evaluation System for Fuel Cell Catalyst

Figure 4 External View of Evaluation System for Fuel Cell Catalyst

Figure 5 Visualization System for Physical Quantities in a Micro-Flow Channel

Figure 6 Measurement Result of Flow Velocity in a Micro-Flow Channel

2) Development of Catalyst Evaluation System for Fuel Cells

We are developing a catalyst evaluation system for fuel cells jointly with the Aika and Baba Laboratory of Tokyo Institute of Technology. Figure 3 shows the configuration of the developed evaluation system, and Figure 4 shows the external view of the prototype system. This system evaluates the catalyst for reforming methane to generate hydrogen, and can evaluate three types of reforming reactions (water vapor reforming, CO 2 reforming and partial oxidation) individually or in combinations. Currently, we are developing a screening system that achieves the reactor section of this system by microreactors on multiple channels. If this system is used, evaluation by few materials, evaluation of many types of catalysts simultaneously under the same conditions, and evaluation in a short time are possible.

3) Measurement and Control Technologies for Microreactors

In the conventional plants, measurement and control technologies have an important role to maintain the safety, quality and efficiency. The development of measurement and control technologies matched to microplants is also required.

1. Development of visualization technology in a micro-flow channel⁵
   Though microreactors use the behavior of fluid in a micro-flow channel, it is difficult to freely control the flow velocity distribution and temperature distribution. At the current stage, research has begun into a design technology that uses simulation technology. To support this research, we have developed visualization technology in a micro flow channel to link simulation world to the real world and to make use of this as design data. As the saying "Seeing is believing." goes, mankind has a history of attempting to visualize from the DNA level right up to the universe. As a high spatial resolution and non-contact methods are both required to observe an inside of the micro flow channel, we focused on the microscope. We measured the flow velocity distribution and temperature distribution in a flow channel using a confocal microscope that is capable of measuring at a high speed of up to 1 ms/frame. Figure 5 shows the configuration of the measurement system, and Figure 6 shows the results of measuring the flow velocity distribution using fluorescent beads. 3-dimensional measurement of the flow velocity distribution could be achieved in real time. Figure 7 shows the results of measuring the temperature distribution in the flow channel that was measured using the temperature dependency of fluorescent strength. The reaction heat of water and calcium chloride was chosen as the model reaction, two liquids were mixed in a Y-shaped micro-flow channel, and the reaction heat was measured. We were able to confirm that the temperature in the area of several tens of micrometers immediately after convergence rose partially by 50°C even though the flow channel width was 100 µm. These measurement results match the simulation results, and we consider that this is an effective means for the visualization of liquids in a complex structure such as a mixer.
2. Development of a thermal flowmeter for micro-flow rate measurement
   Temperature, pressure and flow are the basic physical quantities for controlling a plant, and do not change even if that is a microplant. However, to use these at a microplant, sensors of a size mountable on a chip must be developed. Figure 8 shows the photograph of a thermal flowmeter chip. The flowmeter is made entirely of glass without wetted parts on the assumption that it will be incorporated in microreactors made of glass. We are also developing 1 x N type micro-flow channel control devices using these flow devices. We anticipate that these will become the main device for numbering up that is required for turning microreactors into actual manufacturing devices.
3. Analysis technology for microplants
   In the same way that gas chromatography and near infrared analyzers have been installed in chemical plants today, it is important that analyzers that are capable of directly measuring chemical quantities and properties are introduced into microplants, too. Microplants often handle liquid phase materials in micro-flow channel of about several hundred micrometers and also often measure organic materials. Therefore, we can consider infrared analysis techniques as being suited for microreactors. Yokogawa has the technology to make high-sensitivity infrared sensors using MEMS technology and infrared analysis technology, and will apply these to this field.

Figure 7 Measurement Result of Temperature Distribution in a Micro-Flow Channel	Figure 8 Thermal Flowmeter for Micro-Flow Rate Measurement

CONCLUSION

Though microreactor research has begun with research into achieving practical applications, we believe that it will put to practical application by the year 2015 and that it will aid production in the fields of chemistry. This research is also a theme well matched to the technologies that have been amassed by our company, and we hope that it will contribute to society in the future. Though this often happens in new fields of research, there still remain numerous issues to make microreactors a viable business and there are many who view this in a negative light. To overcome this, cooperation beyond business sectors is required, and we hope to work in cooperation with external research organizations and other companies.

The technology that supported the 20th century was electronics technology centering on IT technology. We are pressing ahead with research in the belief that it will be chemical technology required for biotechnology and organic material devices that will support the 21st century.

REFERENCES

1. Wolfgang Ehrfeld, Volker Hessel, Holger Lowe, Microreactors: New Technology for Modern Chemistry, CWiley-VCH, 2000
2. Volker Hessel, Steffen Hardt, Holger Lowe, Chemical Micro Process Engineering, Fundamentals, Modeling and Reactions, Wiley-VCH, 2004
3. Volker Hessel, Holger Lowe, Andreas Muller, Gunther Kolb, Chemical Micro Process Engineering, Processing and Plants, Wiley-VHC, 2005
4. Maekawa H., Tamaya H., Sadamoto M., Watanabe T., Suzuki K., "Supporting Electrolyte-Free Dimethyl Maleate Reduction Dual Reaction Using a New Electrochemical Microreactor,' No.11 Chemistry and Micro Nano-System Research Drafts, p-2-06, May 2005
5. Hinouchi T., Kawano M., Satou M., Koyama H., Isozaki K., "Measurement of Three-Dimensional Distributions Inside Microchannels,' AIChE Spring Meeting Conference Proceedings. New York, NY: AIChE, 2005

 

III PERSONALIZED MEDICINE AND GENE ANALYSIS SYSTEMS

INTRODUCTION

The 21st century is being called the "era of bioinformation-based industry" as symbolized by the complete decoding of the human genome in April, 2003. When the Human Genome Project was first started in 1990, it was said that it would take several tens of years to complete decoding. However, ultimately, decoding was completed by considerably bringing the schedule forward. One of the main factors that supported the shortening of this schedule is regarded as being major improvements in biotechnology-support devices.

On the other hand, it is said that the immense volume of genome information obtained by the decoding project has had an enormous affect on many fields of science and industrial technology. 'Personalized medicine' is being given greater attention as a new means of medicine in sight ahead of that innovative reform. However, it is generally regarded that achieving this will be difficult unless the functions of the biotechnology-support devices are improved.

Yokogawa's mission is to provide scientific and industrial sectors with leading-edge support devices and mother tools. The following describes how biotechnology-support devices and next-generation gene analysis systems currently under development will achieve this major advancement in functions required for achieving 'personalized medicine'.

WHAT IS PERSONALIZED MEDICINE?

Figure 1 Past and Future Trends in Biotechnology

The discovery of the double helix structure of DNA by Watson and Crick in 1953 was followed by a succession of new Nobel Prize class discoveries in the world of biotechnology— gene decoding, reforming, splicing, amplification, etc. These achievements finally culminated in the completion of the Human Genome Project. It is said that the immense volume of genome information obtained by this will revolutionize the worlds of medical care and medicine, in particular (See Figure 1). And, it is said that 'personalized medicine,' in the broad meaning of the word, that is in sight ahead of this shows the future shape of medical care in which the three types of medical care shown in Table 1 are integrated.

Table 1 'Personalized Medicine' A New Concept in Medicine

	Present	Future
1. Tailor-made medical treatment Selection of effective, side effect free drugs suited to individuals' constitution will be possible.	It is said that 40% of drugs do not work. (e.g., 100,000 people a year die in the United States due to side effects.)	By investigating the gene type and manifestation circumstances, the effect of drugs and extent of side effects can be known, and drugs suiting individuals will be able to be selected.
2. Evidence-based medical treatment Misdiagnoses will be eliminated, and appropriate treatment will be possible.	Disease can be inferred from symptoms or bio-testing of blood pressure, urine, etc.	By investigating the gene type and manifestation circumstances, the type and condition of the disease can be ascertained, and misdiagnosis- free and appropriate medical treatment will be possible.
3. Preventive medical treatment Effective preventive measures will be possible by early detection.	There are few highly accurate means for early detection.	By investigating the gene type and manifestation circumstances, the type and condition of the disease can be ascertained early, and appropriate preventive measures will be able to be taken

In other words, by 'personalized medicine,' the constitutional (qualitative) state, and environmental factors and physical (quantitative) state of the individual are comprehended. By this, the appropriate diagnosis, treatment and medication can be given. This, in turn, will heighten the QOL (Quality of Life) of patients, and will improve the economy and cost effectiveness of medical treatment. As a part of this, 'tailor-made medical treatment' that enables the selection of drugs matched to the constitution and symptoms of individuals, in particular, forms the core of 'personalized medicine.'

Figure 2 Gene Analysis Systems

At present, it is said that medicine is not effective for an average of 40% of people who require medical treatment. The reason for this lies in the difficulty in the criteria for drawing lines as to whether or not to authorize drugs. In the development of drugs these days, it is unclear why they work. Yet, compounds having some kind of noticeable effect at the cell level are exhaustively investigated, and then modified and optimized. After this, animal tests are conducted to confirm toxicity, stability and efficacy. Then, clinical testing on humans is performed, where numerous hurdles such as stability tests, efficacy tests, and side-effect tests are overcome. After all this, an application for recognition as a drug is made for the last remaining compound if it works on a fixed number of people or more, and the drug is authorized after taking its safety, efficacy, economy, and other factors into account.

In this way, it is in reality difficult to draw lines as there are no selection criteria as to whether or not that drug works, and as to whether or not side-effects will occur. In the United States, 100,000 people allegedly die of drug side-effects annually and the medical cost of side-effects exceeds 700 million US dollars. Statistical data such as this symbolizes the difficulty of this problem even in terms of the economy of medicine.

Yet, on the other hand, in March, 2004, the FDA (Food and Drug Administration) of the United States proposed a draft for guidelines and is in the process of clarifying policy. In this way, a new trend is in the process of emerging. That is, the mainstream of drug design in the future will be such that the drug will not be authorized as a drug unless a means is devised for resolving in concrete terms in what order and for what purpose the drug is to be made, and for what and how it will work, and for diagnosing before it is prescribed whether or not it will be effective for that person, or whether or not side effects will appear.

Figure 3 Principle of Operation of DNA Chip

In actual fact, for drugs to demonstrate pharmacological effect after introduction into the body, the drug must maintain a fixed resident concentration for a fixed length of time in the body. If the concentration drops immediately, pharmacological effect cannot be expected, and if the drug is retained in the body for too long a time at a high concentration, this alternatively will lead to side effects. Yet, it is said that the difference in resident concentration reaches about 10 to 100 times depending on differences in physical constitution.

Figure 4 Prototype Reader

The main cause of this difference in intracorporeal resident concentration of drugs is the difference in quantity and quality of the transporter and the metabolic enzymes which regulate the drugs in and out as well as metabolizing in the cells. It is said that this occurs due to the difference of single base in the genome that determines the physical constitution of each person; the combination of SNPs (Single Nucleotide Polymorphisms) derived from differences in the repetition count of the repetition sequence or differences in natural individual qualitative genome sequence (e.g., deficiencies); or differences in condition based on quantitative qualities over time that occur due to the condition of that person's disease (mRNA profile or methylation of DNA, etc.).

Accordingly, if we can learn the natural genome sequence of each person by diagnosing genes at the individual level, or if we can learn dynamic states based on quantitative qualities over time that occur due to the condition of that person's disease, it is predicted that the appropriate drug concentration can be controlled, and, as a result, the criteria for selecting people who suffer from side effects and those who do not, and people who find the drug effective and those who do not, will become clearer. If the criteria are clear, then appropriate drug selection will be possible. So, for example, in the case of antitumor agent, there will no longer be the need to repeatedly test on a trial-and-error basis which of several tens of types of available possible medicines is effective or produces side effects, and it is predicted that this will create very major advantages in terms of the economy of antitumor agent that are said to exceed more than ten thousands of US dollars per month.

However, for this, gene analysis as described above is necessary, and development of support devices for this is indispensable. The gene analyzers currently used for research are completely dissimilar with gene analyzers required by medical sites. Consequently, this means that personalized medicine can be made a reality only after a so-called "next-generation gene analyzer" has appeared. Five requirements—high repeatability, high precision (conclusiveness), safety, convenience, and cost effectiveness—are required of gene analyzers at medical sites. Of these requirements, the first three are essential, and the analyzer will not be authorized as a medical device that can be used at medical sites unless these are actualized.

On the other hand, the remaining two requirements also are important from the standpoint of popular acceptance. Accordingly, we consider these five requirements to be attained at all costs for realizing personalized medicine. Yet, the hurdles for technologically solving these requirements are extremely high. Though manufacturers in America and Europe have covered the market with many biotechnology support devices, no main players yet exist in the world in the area of gene analysis systems, which makes this a very sparse sector. This is why Yokogawa is applying MEMS technology and its supersensitive fluorescent measurement technology gained in the area of confocal scanners and field devices in challenging technological breakthrough to make personalized medicine a reality.

GENE ANALYSIS SYSTEM

Figure 5 DNA Extraction/Amplification Process

As mentioned so far, gene analysis at medical care sites is one answer for achieving personalized medicine. To achieve gene analysis at actual clinical sites and at inspection and research sites, Yokogawa envisages the "gene analysis system" in Figure 2.

In this system, blood samples and specimens taken from patients are targeted for measurement as samples. The samples are first poured into an exclusive integrated cartridge. Cells, etc. are dissolved in this cartridge, and genetic compounds such as DNA, for example, is extracted. The genes are detected by the DNA chip (described later), and, for detection of these, fluorescent light emitted from the DNA chip is analyzed as genes using an exclusive biochip reader. The results of this analysis are used for medical care and treatment by feeding the results back to the physician.

At this time, security measures for protecting patients' personal information are mandatory. However, networks can also be accessed as necessary to link to the latest medical and genetic information, electronic clinical records, etc.

The following briefly describes the principle of operation of the DNA chip, the core technology for sensing in the "individual's gene analysis system."

Figure 3 shows an outline of the DNA chip. A DNA chip (micro-array) is a device comprising a substrate on which many types of known DNA are attached. DNA from a patient's specimen sample is extracted separately and a fluorescent label is attached to this. When this sample fluid is mixed on the DNA chip, it bonds with DNA of the corresponding nucleic acid array since DNA forms a double-strand by nature. The genes in the sample can be ascertained by a specific spot on the substrate lit by fluorescent light and this being scanned by laser.

BIOCHIP READER

We made a prototype reader for use in DNA chip (biochip) measurement. Figure 4 shows an external view of this prototype biochip reader. Yokogawa's core technology such as the supersensitive fluorescent measurement technology of confocal scanners has been made fully use of in this reader.

A feature of our biochip is that it reads by using a multi-beam laser. With conventional single-beam excitation shown in Figure 3, an elaborate XY-stage and scanning mechanism was required. By adopting multi-beam excitation and sensing by a CCD camera, a highly sensitive, simple, highly reliable and low-cost structure can be achieved.

INTEGRATED CARTRIDGE

Another important core device in a gene analysis system is the integrated cartridge.

Currently, DNA chip pre-processing involves work requiring complicated and highly skilled operations, as shown in Figure 5, and the skill of being able to use dedicated systems. To use these in clinical and other fields, there is the need to ensure safety with respect to viruses, for example, and moreover ensure that sequences can be performed reliably.

Figure 6 shows the integrated cartridge currently under development. When blood, diseased specimen or other sample is injected into the cartridge by a pipette, the complete series of operations—cell lysis, extraction and washing of DNA, gene amplification and fluorescent labeling, refining of amplification products, and detection by the DNA chip—is performed internally.

Figure 7 shows the results of experiment of this operation on a prototype cartridge. Figure 7(a) shows the results of having performed genetic amplification (PCR) internally on the cartridge, and also shows the results using a tube by conventional manual methods. It can be seen from these that the amplification of genes was successful.

Figure 6 Integrated Cartridge

Figure 7(b) shows the results of transferring target DNA fluid to the DNA chip internally on the cartridge, and continuously performing washing and complementary binding (hybridization) as double-strand DNA internally on the same cartridge. It can be seen that each site is spotted with the same gene and that hybridization was successful.

Figure 7 Experimental Results of Prototype Integrated Cartridge

CONCLUSION

Many innovative technological developments are currently being advanced in the field of biotechnology. At the same time, there are many issues in the field of medicine, including a dwindling birthrate and a graying society. Yokogawa hopes to earnestly press ahead with developments so that it can be of service from the standpoints of measurement, control and information.

REFERENCES

1. "NEDO, The drug design and diagnosis fields place priority on 'personalized medicine' and preventive medicine,' http://www.venturewatch.jp/nedo/ 20050627.html
   http://www.nedo.go.jp/roadmap/ data/life_rm1.pdf
2. FDA Workshop, IVT Guideline 2005
3. FDA Pharmacogenome Guideline 2005
4. Takeo Tanaami, Shinya Otsuki, Nobuhiro Tomosada, Yasuhito Kosugi, Mizuho Shimizu, Hideyuki Ishida, "High-Speed 1-Frame/ms Scanning Confocal Microscope with a Microlens and Nipkow Disks," Applied Optics-OT, Vol.41, No.22, August. 2002, pp.4704-4708