Research on the Application of Sprout Technologies in otherFields to Micromachine Technology for Fiscal 1999 (Part II)
Since 1992, the Micromachine Center has taken up various seeds of technology as themes for joint research by academic,
governmental and industrial sectors, aiming to reinforce basic technologies by searching for technology seeds, especiallyin the scientific and technological fields, that are necessary to build various micro systems. In fiscal 1999, research has
been carried out on nine themes. Continuing from the last issue, the remaining five themes are summarized below.

Investigation of the Trend Related to the Fusion of Biosensor Technology with Micromachine Technology
Masuo Aizawa
Professor, Graduate School of Bioscience and Biotechnology,
Tokyo Institute of Technology
1. Introduction
The research and development of biosensors has rushed into
an age of upheaval. The main reason for this drastic change may
be found in the rapid diversification of needs for biosensor technology and the progress of related technologies.
In response to these diversified needs, targets of the researchand development of biosensor technology have been clarified as
described below:(1) On-site sensing, (2) massive information sensing, (3) complex information sensing, and (4) ultimate sensing technology. This
paper will describe what can be realized when biosensor technology is fused with micromachine technology, and it will investigate
the current status of the application of micromachine technology
to the foregoing items.
2. Massive information sensing and micromachine technology
The importance of molecular information about DNA andchemical substances has come to be recognized, which in turn has
led to attaching greater importance to massive information sensing technology with which molecular information contained in a
trace amount of sample can be analyzed at one time. Massive information sensing is used for or expected in the detection of DNA,evaluation of substances synthesized by combinatorial chemistry,and detection of environment-related substances. This paper summarizes the trend of massive information sensing related to theanalysis of gene information chiefly on DNA chips, and a report ispresented on the findings of the investigation of micromachinetechnology required in that field. Also summarized are the evaluation of molecular functions in combinatorial chemistry where massive information sensing is expected to develop in the future, thetrend of research in the micro total analysis system, µTAS, in neural network information sensing, and the application of micromachine technology.
3. Ultimate sensing and micromachine technology
Chapter 2 deals with the trend toward research of massive
information sensing and the utilization and technical problems of
micromachine technology. In addition to the micromachine technology chiefly related to processing, another micromachine technology for evaluation and observation is also available. This isprobe microscope technology (SPM), including AFM. In recent
years, SPM has developed rapidly as a technology for sensing
minute targets, and it is beginning to be utilized. Particularly fordeveloping research that delves into the constituents of microorganisms and materials a technology is required that will allow asingle molecule to be observed.
With this background, “a probe microscope”, which enables
topologic information to be obtained by probing for a sample without relying on light or electron rays, is considered essential as a
new technology by which observation and function measurement12

can be made possible on a single molecular level. This chapter
deals with the contribution of micromachine technology in the technology of sensing minute molecules and minute areas with emphasis on various probe microscopes to probe for single moleculesand single cells as their targets.
4. Bio-system microprobe
For those with health problems, the aged and disabled, it isnecessary to routinely monitor their health management information so that they can participate in social activities. For that
purpose, it is most effective to use a sensor embedded in a biosystem for measurement. This makes it inevitable not only to micronize a sensor device, but also to realize the application of thedevice using materials compatible with a living body. This paper
summarized the trends in research of microprobes that can beused directly for a living body along with tasks for which micromachine technology is required.
5. Conclusion
Research and development of biosensor technology has entered a new stage aiming at high performance by micronizationand integration. In a narrow sense, DNA chips and µTAS are notcategorized as sensing devices. With the enlargement of the baseof biosensor technology, however, they have had a strong impact.
In this investigative research, by assuming the future targets ofbiosensor research, the present state of related research was generalized after reviewing how micromachine technology can contribute to the achievement of those targets. Since the related research branches out broadly, its investigation was limited. However, many themes of research and development to be promoted in
the future have come to the fore.
Microprocessing technology is making rapid progress. However, sizes that can be processed at present are considered to be on
the submicron order. It will be necessary to transfer to a processing form unlike the present one if processing to the nanometerorder is required. Further miniaturization is needed, particularly
to permit a sensing device to be embedded in a living body. In
addition, the device should have a structure wrapped in a material compatible with a living body. Developing a technology capable of using various materials compatible with a living body as
the raw materials of micromachines or the importance of developing materials compatible with a living body, suitable formicromachine processing, is expected to grow in importance. Again,
for micronizing sensing devices, it is necessary to develop a method
suitable for modifying molecules (enzymes and antibodies) precisely into minute materials.
Currently, various research themes to be promoted in the future have surfaced. At the same time, it has been demonstrated
that the fusion of biosensor technology with micromachine technology is an important theme for development of future biosensor
technologies.

Investigative Study of Chemical Reactions
and Synthesis Using Microreactors
Jun-ichi Yoshida
Professor, Graduate School of Engineering,
Kyoto University
Microreactor technology has recently become a new andvery promising field within a very short time in the fields
of chemistry, process engineering, and biotechnology. The
application of micromachine technology to chemical synthesis is progressing at a particularly rapid rate. On finding that this technology could be realized, the chemical industries in Europe and the U.S. have aggressively set about
the trial manufacture and operation of microreaction systems in only a few years.
Downsizing as represented by microreactors is expected
to contribute greatly not only to future chemical synthesis
but also to industry and society as a whole. This has
prompted the investigation of chemical reactions and syntheses using microreactors with the emphasis on the nature of reactions, the manufactures of reactors and application to the development of functional materials and drugs.
Several organic reactions using microreactors have already been reported. Particularly noteworthy is the factthat microreactors, characterized by a large specific surface area per unit volume, could realize reactions hitherto
considered impossible to achieve. In addition, heterogeneous
catalytic reactions and electrochemical reactions that takeplace on a solid surface will develop dramatically using
microreactors in the future. Microreactors are also expected
to enable chemical manufacture using hitherto considereddifficult to use due to limitations of process engineeringand safety. What is more, microreactors enable the realization of a comparatively small-scale economical plant easilyand quickly when set in parallel, making it possible to transfer the findings of research and development more promptly
to the manufacture of materials. This will simultaneously
enable more rapid compliance with market demands.
The technology of chemical analysis or biochips, socalled micro-TAS or Lab-on-a-chip, can be used for manufacturing microreactors. However, other technologies will
also be required for the manufacture of microreactors suitable for chemical synthesis because of the great differencein the requirements for organic synthesis and those foranalysis and biotechnology. For example, technologies ofmaterials for reactors, joints and connectors that are resistant to solvents frequently used for organic synthesis will
become increasingly important.
The applications of microreactors to chemical synthesis involve the development and manufacture of functional
materials and drugs. In the former case, it is particularly
worth noting that, by the use of microreactors, the processof manufacturing functional materials, including
microcapsules, dispersion of micro-particles and polymers,
so far considered impossible to manufacture with conventional reactors, will be revolutionized. In the latter case,the development of new drugs by combinatorial synthesis
and their manufacture using microreactors attract our at-

tention. Although not many examples have been reported
in either case, great developments can be expected in those
fields in the future.
Our investigation, which emphasized the above points,
reveals that a potential of microreactors has not yet been
fully utilized, leaving much room for dramatic and revolutionary development in the future. It is, therefore, premature to completely forecast and evaluate the direction of
the development of microreactors. It is beyond doubt, however, that microreactors will bring about a revolution in
research, development and manufacture in the chemicalindustry, presumably wielding great influence on the future shape of the chemical industry as well as our entire
society. Microreactors will bring about a new paradigm ofscience and technology, leading to the creation of new disciplines and new fields of industry. It is indispensable forthe development of microreactors in theory, design, manufacture, reaction, and application to concentrate the intelligence in a variety of fields, including microfluidics,
microfabrication, process engineering, reaction engineering, microanalysis, catalyst and organic synthesis. Since
these fields spread widely over electric and electronic engineering, mechanical engineering, chemical engineering,
analytical chemistry, physical chemistry, and organic chemistry, they should be organized to work together. Although
the research into the application of microreactors to chemical synthesis is not mature in Japan. However, energetic
research and development should be made in the future inview of the growing expectations in this field.

Microreactionengineering

Analyticalchemistry
Syntheticchemistry

Microfluidics
Chemical
synthesis
using
microreactors

Microfabricationµ TAS
Lab on a Chip

Downsizingofchemistry

Biochemistry

Desktop Factory

New paradigm of scienceand technology

Creation of new disciplines
and new fields of industry

How material shouldbe created and how
material should bemanufactured canbe determined.
Medicine

Bio-engineering
Biology

Pharmacy
ChemistryFig. 1 Chemical Reactions and Synthesis Using Microreactors

13Investigative Study of Micro Heat Design
Technology
Takayoshi Inoue
Professor, Department of Mechanical Sciences and Engineering,Tokyo Institute of Technology
It is well known that many problems related to engineering and industry arise from poor heat design andcontrol. This also applies to micromachines, which may
break down unexpectedly as seen in malfunctions andfailures without a prediction of temperature and heatelimination needs based on appropriate heat design, andheat control based on the above prediction. For instance,
deformation due to thermal expansion of component
parts, changes in action characteristics at high temperatures, and the progress of corrosion can be cited. Thismay be attributable to the failure in a temperature prediction for the part that goes out of order and in heat
control stemming from poor temperature prediction. It
is important, however, to include an appropriate heat
design in the design stage.
In the heat design of micromachines as well, it isequally important as in the heat design of conventional
size machines to evaluate local heat value and thermalload along with the quantity of heat to be removed when
considering how to remove the heat generated. However, the distribution of temperature and heat conduction characteristics in an infinitesimal area have notbeen entirely clarified because of the very small size ofthe target machines. This may also explain why no effective cooling system has been satisfactorily established.
This investigative study reports on a technique formeasuring temperatures on an immeasurably shortscale, the importance of which should particularly beconsidered in the heat design and control of micro devices, a method for theoretical and experimental handling of contact and interface heat resistance at the component interface, and a technique for calculating heat
conduction for heat design.
In micro devices, the area in which temperature information is required is incalculably too small to handle
by conventional temperature measurement techniquesin many cases. This area may be characterized by requiring a technique of high-degree space resolution
measurement. Accompanied by progress in micro processing techniques, measuring techniques have also
made progress recently so that it can meet the needs formeasuring temperatures at sites in such micro systems.
In this investigative study, various techniques for measuring temperatures in the proposed micro areas were
investigated for analysis to compile a report on the findings, citing actual examples.
In addition to the foregoing, it is possible to list various problems in thermal engineering as specific to micro devices. Important among these is thermal resistance at the interface of dissimilar materials. Thermal
resistance stands for an index by which the difficulty of

14heat conduction is represented. It may safely be calleda physical volume that controls a rise in device temperature because of a large difference caused in an areawith a large heat resistance. For example, heat is transferred by conduction in device components such as substrates or thin film devices. However, as is clear from
Fourier’s law relative to heat conduction, a temperature difference is sure to be caused in the elements unless a material is present with an infinitely large thermal conductivity. This will result in the presence of athermal resistance, large or small, in those elements.
What is more, a temperature difference is caused at theinterface of the elements because of the presence of athermal transfer resistance that differs from the inside.
As is clear from Newton’s cooling law, no heat can betransferred unless a temperature difference exists between the perimeter of the device and the surrounding
environment as we see in the final removal of heat tothe surrounding environment outside the device. Particularly in the case of micro devices, because of the small
size of each device component, the contribution of thermal resistance arising from the heat of conduction inside those elements becomes relatively smaller andsmaller. Generally, thermal resistance at the interfaceof elements does not depend on the size of the device. It
therefore follows that thermal resistance at the interface comes to be regarded as relatively important. In
this investigative study, the considerations describedabove are classified into the following problems for discussion:
1) A surface-related problem at the interface, whichbecomes important in various film-forming processes.
2) A volume-related problem arising from an incomplete layer near the interface.
3) A problem at the joining interface where respective materials are present as if pasted together.
The surface-related problem is important, particularly at low temperatures. Explanation of this viewpointis therefore given. In addition, a technique for measuring thermal resistance is proposed in various ways forverifying the value of thermal resistance, obtained theoretically. This is also under study.
Further, it becomes necessary to study the techniqueof calculating heat transfer with all of these factors combined. It is possible to select a technique for the respective purposes, ranging from a technique of simple analysis for a basic order estimate to a more exact one thatsolves a three-dimensional energy equation numerically.
Those techniques and related problems are introduced
along with the concept of the thermal resistance.

Investigative Study of the Possibility of Greatly Upgrading
Micromachine Technology by Utilizing Physical Phenomena that Characterize the Mesoscopic Area
Tokio Kitahara
Professor, Mechanical Engineering,
The Faculty of Engineering, Shonan Institute of Technology
1. Introduction
Micromachine component parts are as small, ranging from1 mm to 1 µm, which is larger than an atom or a molecule by 3
to 4 orders of magnitude and smaller than conventional machine parts by 1 to 3 orders of magnitude. This area lies between the area to which a macro physical phenomenon model
can be applied, hitherto used by conventional technology, andthe area to which a micro phenomenon model is applicable,with atoms or molecules used as units, an area that has been
making marked progress in recent years.
The modeling and practical application of physical phenomena in this mesoscopic region is seldom seen except for thetechnology related to hard disk drives. It is indispensable tograsp physical phenomena in this area so as to establish methods for utilizing them so that micromachine technology cangrow into a basic industrial technology.
2. Physical phenomena and related research trends
In this investigative study, physical phenomena related togreatly upgrading macro mechanisms were itemized (Refer toTable 1). The items considered particularly important were
investigated relative to their research trends.
One of them is tribology. The coefficient of friction in themesoscopic region often grows into a large value, and interfacial force or the surface tension of a liquid film are closely related to this value.
Water repellency has much to do with minute surface structure and chemical factors. The contact angle between a liquidand a solid is related with the surface tension of the two.
Water repellency is exhibited when a liquid with a highsurface energy is combined with a solid having a low surface
energy. Again, it has been clarified that water repellency isenhanced when the minute structure on the surface of a solidor an air layer is formed.
The effect of viscosity on macro mechanism components
can be measured by the law of similarity if it is within therange where Newton’s viscosity law holds good. From the
Reynolds numbers of microorganisms, the Reynolds numbersof the micromachine mechanism parts are assumed to be below 1.
Many thin-film parts are used for micromachines. To measure their mechanical properties, it is necessary to make amodel in which the effect of the surface layer is considered. At
present, however, methods for measuring various mechanicalproperties are still in the proposal stage.
3. Application map and the status of research and development
There are physical phenomena that stand out in themesoscopic region work as a positive factor in some cases, andas a negative factor in other cases. Those phenomena were itemized into interfacial force, surface tension, viscous force, adsorption layer, and mechanical strength, and their relationshipto the basic technology and manufacturing technology of
micromachines and device system technology was arranged inorder as their application map.
Various surface forces lead to an increase in friction force
in tribology. It is reported that minute unevenness formed on
the sliding surface reduces friction. On the other hand, an attempt is being made to handle micro parts by taking advantage of the surface force. A traction drive is also considered byutilizing high friction force.
An example is reported in which the minutely uneven functional surface having super water repellency was used for sealing an axis. Viscous force can be considered applicable to simplestructure devices, including torque converters, brakes, and vibration dampers.
Various methods of joining are used for micro application.
Adhesives can be used as a substitute method for separable
thread fastening. An adhesion and tensile strength tester was
manufactured on a trial basis for butt adhesive joint of slenderaxes with a diameter of less than 2 mm. A strength of 18 MPs
was attained with an epoxy adhesive. This enabled confirmation of the possibility of adhering micro parts.
Many prototypes of micro fluid devices were manufactured
by taking advantage of the laminar flow, high heat transfer,and other characteristics of a micro fluid. In the µ-TAS, now
attracting our attention, the above characteristics are integrated.
4. Conclusion
In upgrading micromachine technology to a higher degree,
it is important to utilize and overcome physical phenomena inthe mesoscopic region. There are many cases in which usefulfunctions are exhibited, accompanied by multiple phenomena.
It will be necessary to grasp quantitatively their synergistic
and counterbalancing effects in the future.
Table 1 Main physical phenomena that stand out when micronizing
Items
Interfacial force
Surface tension
Adsorption (layer)
Viscous force

Super water repellency
Mechanical strength

Related matter
Van der Waals forces
Electrostatic force
Capillary phenomenon
LB film, surfactants, Stiction
Electric viscosity effect,
Magnetic fluid,
Low Reynolds number
Surface tension,
minute form on solid surface
Crystal size, crystal anisotropy

15

Summary of Investigative Study of the Possibilityof Innovative Gene Therapy by the Use of MicroKazunori Kataoka
machine Technology
Professor, Graduate School of Engineering,
The University of Tokyo
Interest is growing rapidly in gene targeting to deliver genes into the living body for the purpose of cancer
therapy, and the study of the delivery system is being
actively pursued utilizing liposomes, viruses, and cationic polymers as the carriers of genes. Those carriers
are required to have various functions, such as stability
in blood flow, accumulation inside the targeted cells,
transfer to cellular nuclei, and release of effective genes
inside the nuclei. An additional important point is theneed for those functions to be realized on the micro scale,say, in order of micrometers or nanometers so that they
can be used for a living body. In this sense, the carriers(gene vectors) for gene targeting, applicable to clinicaluses, that surpass the properties of viruses would be
worthy of the term “biomicromachines”. Recently, an accidental death was reported in gene therapy using
adenoviruses in the U.S. This poses a serious problem
for spreading gene therapy in the future. It is urgently
required to develop non-viral vectors with excellent
safety and transfer characteristics without relying onconventional virus vectors if gene therapy is to breakthe category of a hitherto-used special method of medical treatment and grow into a universal method of medical treatment, applicable to a wide range of diseases.
In this case, an active approach is increasingly desired from the fields of medicine and biology as well asfrom the field of engineering. This approach includes
the establishment of a chemical engineering methodology to grasp the trends in the bio-environment beginning with a vector design based on molecular assembly
engineering (artificial viruses), and the development of
new analytical techniques to measure quantitatively and

Design of a micromachine forbio-compatible gene delivery
Investigation items: 1), 2), and 3)

Intravenous
injection

Effective accumulation into targeted sites
Size < 100 nm

Investigation item: 4)

Selective transport
into targeted cells
Investigation item: 5)

Taking into
the liver

Achievement of effective
transfer into nuclei
Investigation item: 6)

Blood vessel system
Reticuloendothelial
system(RES)

Kidneyexcretion

Transfer inside the body avoiding
a mechanism to perceive foreign
bodies to the living bodyAchievement of targeted gene therapy

Investigation items: 1) and 7)

Investigation items: 2) and 4)

Figure Image of a micromachine used for intravenous
in-vivo gene therapy and study items

16

over time the behavior inside the cells.
In this investigative study, therefore, specialists inpolymer synthesis and researchers from the companies
that have succeeded in developing the materials for targeting carcinostatic agents. In addition, researchers who
have been carrying out the study of gene targeting carriers also individually participated in systematic investigation of the merits and demerits of the many trials
carried out thus far with the intention of establishing a
guideline for the design of micromachines for gene targeting.
The major study items are summarized below together with a diagram of the positioning of each item inintravenous in-vivo gene therapy:
1 method for introducing various genes and its commercialization
2 A technique for device surface treatment using biocompatible elements
3 A gene including association based on molecular assembly
4 Polymeric nanocapsules oriented toward gene vectors
5 Structuring of an environment-responsive material
system
6 Clarification of a DNA delivery system in the cell
7 Various technical problems and their solutions in invivo gene therapy
The author believes that a series of important points
as described below can be clarified thus to contribute to
the development of next-generation micromachines forgene delivery by carrying out the investigative study of
the above items.
A series of important points are: 1) structuring of
micromachines for gene delivery, 2) mounting of genes
onto micromachines, 3) grasping of movements inside
the body and accumulation in targeted sites, 4) establishing of routes into targeted genes, 5) clarification of
traffic inside the cells and the routes for transferring to
nuclei, and 6) release of mounted genes and gene expression.