BIOMEDICAL APPLICATIONS OF MEMS

Jack W. Judy
University of California, Los Angeles
68-121 Engineering IV, Box 159410
Los Angeles, CA 90095-1594
Tel: (310) 206-1371
[email protected]

Abstract – Micromachining and MEMS For a discussion of the early work in MEMS,
technologies can be used to produce complex including many of the seminal papers, the interested
electrical, mechanical, fluidic, thermal, optical, reader is directed to reference [1]. For a
and magnetic structures, devices, and systems comprehensive discussion of micromachining
on a scale ranging from organs to subcellular processes and MEMS devices, the interested reader
organelles. This miniaturization ability has is directed to the texts by Kovacs [2] and Madou [3].
enabled MEMS to be applied in many areas of
biology, medicine, and biomedical engineering – MICROFABRICATION
a field generally referred to as BioMEMS. The
future looks bright for BioMEMS to realize (1) Although many of the microfabrication techniques
microsensor arrays that act as an electronic and materials used to produce MEMS have been
nose or tongue, (2) microfabricated neural borrowed from the IC industry, the field of MEMS has
systems capable of controlling motor or sensory also driven the development and refinement of other
prosthetic devices, (3) painless microsurgical microfabrication processes and non-traditional
tools, and (4) complete microfluidic systems for materials.
total chemical or genetic analyses.
Conventional IC Processes and Materials:
INTRODUCTION - photolithography; thermal oxidation; dopant
diffusion; ion implantation; LPCVD; PECVD;
Microelectromechanical systems (MEMS) is a evaporation; sputtering; wet etching; plasma
technology of miniaturization that has been largely etching; reactive-ion etching; ion milling
adopted from the integrated circuit (IC) industry and
applied to the miniaturization of all systems (i.e., not - silicon; silicon dioxide; silicon nitride; aluminum
only electrical systems but also mechanical, optical,
fluidic, magnetic, etc). Miniaturization is Additional Processes and Materials used in MEMS:
accomplished with microfabrication processes, such - anisotropic wet etching of single-crystal silicon;
as micromachining, that typically use lithography, deep reactive-ion etching or DRIE; x-ray
although other non-lithographic precision lithography; electroplating; low-stress LPCVD
microfabrication techniques exist (FIB, EDM, laser films; thick-film resist (SU-8); spin casting;
machining). Due to the enormous breadth and micromolding; batch microassembly
diversity of the field of MEMS, the acronym is not a
particularly apt one. However, it is used almost - piezoelectric films such as PZT; magnetic films
universally to refer to the entire field (i.e., all devices such as Ni, Fe, Co, and rare earth alloys; high
produced by micromachining). Other names for this temperature materials such as SiC and ceramics;
general field include “microsystems”, popular in mechanically robust aluminum alloys; stainless
Europe, and “micromachines”, popular in Asia. steel; platinum; gold; sheet glass; plastics such as
PVC and PDMS
The methods used to integrate multiple patterned typically the case for surface micromachining).
materials together to fabricate a completed MEMS Exploiting the predictable anisotropic etching
device are just as important as the individual characteristics of single-crystal silicon, many high-
processes and materials themselves. The two most precision complex 3-D shapes, such as V-grooves,
general methods of MEMS integration are described channels, pyramidal pits, membranes, vias, and
in the next two sub-sections: surface micromachining nozzles, can be formed [5]. An illustration of a typical
and bulk micromachining. bulk micromachining process is given in Figure 2.

Surface Micromachining
(100) Silicon Wafer
Simply stated, surface micromachining is a method p+ Silicon
of producing MEMS by depositing, patterning, and
etching a sequence of thin films, typically ~1 µm Silicon Nitride Film
thick. One of the most important processing steps
that is required of dynamic MEMS devices is the
selective removal of an underlying film, referred to as
a sacrificial layer, without attacking an overlaying
film, referred to as the structural layer, used to create
the mechanical parts. Figure 1 illustrates a typical {111 Planes}
surface micromachining process [4]. Surface
micromachining has been used to produce a wide
variety of MEMS devices for many different
applications. In fact, some of them are produced
commercially in large volumes (> million parts per
month). Through Membrane V-Groove
Hole
Anchor Sacrificial Layer

Substrate Figure 2: Bulk micromachining.

Structural Layer Substrate Bonding

Silicon, glass, metal and polymeric substrates can be
bonded together through a variety of processes (i.e.,
fusion bonding, anodic bonding, eutectic bonding,
and adhesive bonding). Typically at least one of the
Release Etch bonded substrates has been previously
micromachined. Substrate bonding is typically done
to achieve a structure that is difficult to form
otherwise (i.e., large cavities that may be
hermetically sealed or a complex system of enclosed
channels) or simply to add mechanical support and
protection [2].
Figure 1: Surface micromachining and the sacrificial
layer technique.
Non-Silicon Microfabrication
Bulk Micromachining The development of MEMS has contributed
significantly to the improvement of non-silicon
Bulk micromachining differs from surface microfabrication techniques. Two prominent
micromachining in that the substrate material, which examples are LIGA and plastic molding from
is typically single-crystal silicon, is patterned and micromachined substrates.
shaped to form an important functional component of
the resulting device (i.e., the silicon substrate does
not simply act as a rigid mechanical base as is
LIGA comprehensive discussion of all the different sensors
and their applications is beyond the scope of this
LIGA is a German acronym standing for lithographie, paper. Instead, a discussion of several classes of
galvanoformung (plating), and abformung (molding) microsensors and an overview of their applications
[6]. However, in practice LIGA essentially stands for will be given.
a process that combines extremely thick-film resists
(often >1 mm) and x-ray lithography, which can Microsensors for Biomechanics
pattern thick resists with high fidelity and results in
vertical sidewalls. Although some applications may Studies of the forces created by and imposed on the
require only the tall patterned resist structures body benefit from increasing the sensitivity of
themselves, other applications benefit from using the mechanical stress and strain sensors while also
thick resist structures as plating molds (i.e., material reducing their size and cost. The following are
can be quickly deposited into the mold by examples of microsensors used to study
electroplating). A drawback to LIGA is the need for biomechanics.
high-energy x-ray sources (e.g., synchrotrons or
linear accelerators) that are very expensive and rare Strain Gauges
(i.e., only several such sources exist in the U.S.).
Strain gauges are used to characterize the forces in
SU-8 the body. Since silicon is known to be an excellent
piezoresistive material (i.e., it’s resistance changes
Recently a cheap alternative to LIGA, with nearly the as a function of applied force), it can be easily
same performance, has been developed. The micromachined to form sub-millimeter multi-axis
solution is to use a special epoxy-resin-based optical strain gauges [10]. Applications of such miniaturized
resist, called SU-8, that can be spun on in thick strain gauges include orthopedic research and the
layers (>500 µm), patterned with commonly available study of muscles. Although the understanding of
contract lithography tools, and yet still achieves muscle function and structure is well understood at
vertical sidewalls [7]. the whole-muscle and cellular levels, muscles have
not been well characterized in the region in between.
Plastic Molding with PDMS An improved understanding at this level would allow
for the development of improved locomotion
Polydimethylsiloxane (PDMS) is a transparent therapies and prosthetic devices.
elastomer that can be poured over a mold (e.g., a
wafer with a pattern of tall SU-8 structures), Accelerometers
polymerized, and then removed simply by peeling it
off of the mold substrate [8]. The advantages of this One class of microsensors that MEMS technology
process include (1) many inexpensive PDMS parts has had the most positive impact on are inertial
can be fabricated from a single mold, (2) the PDMS sensors (i.e., accelerometers and gyros). Since
will faithfully reproduce even sub-micron features in inertial devices typically consist of a proof mass,
the mold, (3) PDMS is biocompatible and thus can mechanical flexure, and displacement sensor,
be used in a variety of BioMEMS applications, and MEMS technology is well suited to integrate each of
(4) since PDMS is transparent, tissues, cells, and these sensor elements into a single chip. In fact, it is
other materials can be easily imaged through it. also possible to integrate ICs with the micro-
Common uses of PDMS in biomedical applications mechanical elements to add signal amplification and
include: microstamping of biological compounds (to filtration capability to the chip-scale sensor [11].
observe geometric behavior of cells and tissues) and Inertial microsensors are useful to determine impact
microfluidics systems [9][8]. level and patient posture.

BIOMEDICAL MICROSENSORS Microsensors for Pneumatic Biosystems

The majority of MEMS used in biomedical Since much of the human body is a complex system
applications act as sensors. Examples include of pumps, valves, vessels, and interconnects,
critical sensors used during surgery (i.e., measuring pressure in many parts of the body is an important
intravascular blood pressure), long-term sensors for parameter to indicate the health and well being of a
prosthetic devices, and highly sophisticated sensor patient. Pressure sensors are used in medicine in
arrays for rapid lab-quality diagnosis at home. A many applications: blood pressure, bladder pressure,
and cerebral spinal fluid pressure to name a few. In polymers doped with conductive particles,
addition to performance requirements, the size of conductive polymers, and some metal oxides. The
pressure sensors, particularly those inserted into the challenges common to impedance-based chemical
body must be small and ideally disposable. MEMS sensors include identifying single gases, quantifying
technology is well positioned to deliver solutions to gas concentration, dealing with gas mixtures,
this opportunity. In fact, a good example is the sensitivity to water vapor, sensitivity to temperature
commercially successful low-cost disposable changes, and microfabrication of arrays of uniquely
medical pressure sensor developed by Lucas sensitive sensors.
NovaSensor NPC-107 (Figure 3) [12]. In it a silicon
micromachined sensing element is used to meet or Polymer-Based Gas Sensors
exceed all industry requirements (e.g., sensitivity
within +/-1% and linearity better than 1%). Another Many polymers will geometrically swell reversibly
micromachined silicon pressure sensor produced by when exposed to certain gases. Conductive
NovaSensor is made small enough (1 mm x 0.7 mm polymers, such as polypyrrole, can be used directly
x 0.175 mm thick) to be inserted into a catheter and as a viable chemiresistor. To use insulating
inserted into arteries. polymers, they are doped with conductive particles to
reduce their impedance (e.g., carbon black). When
doped, the overall resistance of the doped polymer
will change as a function of the chemically specific
and concentration-dependent swelling [13]. One
difficulty is that the polymers will swell to a greater or
lesser extent when exposed to a variety of gases. To
identify specific gases, the response pattern of many
different polymers is needed. In addition to resistive
measurements of geometric swelling, configurations
that capacitively detect swelling have also been
used. In these sensors the insulating polymers are
not doped. Since it is known that certain diseases
cause the body to generate specific gases that are
not normally present, gas sensors have been used to
help diagnose patient health.

In order to microfabricate arrays of sensors with

Figure 4: Micromachined pressure sensor die with unique polymers, the integration process must
3
smallest having dimensions (175×700×1000 µm ). contend with the large volume of solvent that is
typically present during polymer deposition.
Furthermore, the microfabrication technique must
Microsensors for Chemical Biosystems not damage previously deposited polymers. One
strategy is to use a removable mask to selectively
Since living organisms are extremely sophisticated deposit each polymer into a specific area. This
chemical processing systems, there are many technique has difficulty forming sub-millimeter
biomedical applications for chemical sensors (e.g., sensors due to poor adhesion to the substrate when
medical diagnostic instruments, drug screening, the mask is removed (i.e., the polymers adhere more
implantable sensors for prostheses, and strongly to the mask than to the substrate). Another
environment monitoring). Although the strategy is to use a permanent microwell structure to
micromachining of chemical sensors is typically contain the polymer-solvent solution in a well-defined
simple, other components sometimes used in a sub-millimeter area without disturbing previously
complete chemical sensor system (i.e., sample deposited polymers. An example of a polymeric
preparation and delivery, reaction control, and waste impedance-based gas sensor that uses an SU-8
disposal) are more difficult to integrate together. microwell structure is given in Figure 5.

Impedance Sensors Metal Oxides

The conductivity of some materials is affected by the The conductivity of certain metal oxides, most
presence and relative concentration of certain gases commonly SnO2, is known to vary as a function of
or vapors. Examples of these materials include the concentration of specific gasses (e.g., O2, H2,
CO, CO2, NO2, and H2S) when the metal oxide is solution. In addition, the simple construction of a
heated sufficiently to induce a chemical reaction that typical electrochemical sensor (i.e., a partially
is detected. There are several mechanisms that insulated metal trace on a substrate) allows ICs to be
cause the resistance of the metal oxide to vary [2]. easily integrated with the electrode. The ICs can be
The microfabrication of these sensors can be used to provide on-chip signal processing and
relatively straightforward, unless additional amplification.
micromachined features are added to improve
sensor response and power consumption (i.e., Molecular-Specific Sensors
integrating microfabricated heaters, thermal isolation
structures (e.g., membranes) that require far less Chemical sensors that respond only to certain ions
power to heat, and CMOS signal detection, or molecules can be extremely selective. Among the
amplification, and filtering circuitry. most selective are the interactions between complex
organic molecules, such as antigens and antibodies.
One caveat is that often very selective sensors are
also less reversible and thus may require special
packaging to protect the sensors until they are
needed. A prominent example of a molecularly
sensitive amperometric sensor is one that uses a
glucose oxidase enzyme to detect glucose. The
enzyme, which is typically immobilized on or near
electrodes, reacts with glucose and alters the local
pH, oxygen concentration, and hydrogen peroxide
concentration – events that can be electrochemically
detected.

ISFETs

Field effect transistors (FETs) are very sensitive to

variations in the amount of charge on their controlling
Figure 5: Microfabricated polymer carbon-black gas
electrodes (i.e., gate). If an ionic solution acts as the
sensor with SU-8 microwell for solvent containment
gate of a FET, the device will be tremendously
(from [14]).
sensitive to the overall ion concentration of the
solution (i.e., not selective to specific ions). A good
Electrochemical Sensors pH sensor can be made this way and indeed one
exists [15]. By coating the gate of the FET with a
The oxidation and reduction of chemical species on compound that will selectively bind or allow to pass
a conducting electrode can be observed by only specific ions or molecules, an ion-sensitive FET,
measuring the movement of charge. There are two or ISFET, can be realized. Common difficulties with
primary methods of sensing electrochemical ISFETs, as with all chemical sensors, are drift and
reactions: potentiometric and amperometric. repeatability.
Potentiometric sensors can be used to measure the
equilibrium potential established between the Resonant Sensors
electrode material and the solution, a potential that is
dependent on the chemistry involved. Amperometric
The resonant frequency of a mechanical element is
sensors measure the current generated by a
strongly dependent on its geometry, mechanical
reaction and thus give a measure of reaction rates.
properties, and mass. By coating a resonating
By controlling the potential of the electrode relative to
mechanical element, such as a beam or membrane,
the solution and measuring the charge flow induced,
with a compound that will selectively bind to only
the presence of specific ions can be determined by
specific ions or molecules, the mass of the
observing the potential at which they undergo
mechanical element will increase with their
oxidation or reduction. This is a process known as
concentration. The ion-concentration dependent
voltammetry.
mass loading can be determined by measuring the
corresponding shift in the resonant frequency.
Micromachining processes can be used to
accurately and reliable define the area, number, and
relative position of electrodes that are exposed to
The most common resonant chemical sensors use gram (ERG). These bioelectrical signals are typically
acoustic waves driven along surfaces of a solid (i.e., transduced with either external or internal electrodes.
surface acoustic waves, SAW) or in a thin With MEMS technology, many electrodes can be co-
membrane (i.e., flexural plate waves, FPW) [2],[16]. fabricated onto a single substrate so that both
Acoustic-wave sensors have been used to detect precise temporal and spatial information can be
liquid density, viscosity, specific gas vapors. Design obtained. MEMS technology can also be used to
challenges include (1) temperature sensitivity of the shape the substrate into either arrays of microprobes
mechanical flexure, (2) selectivity of the binding capable of penetrating neural tissue (Figure 7)
compound, and (3) reversibility of the binding and [19][21] or into a perforated membrane through
mass loading process. MEMS technology impacts which regenerating neural tissue can grow and then
resonant chemical gas sensors by allowing miniature be monitored [20]. In the U.S. the University of
sensors to be produced at low cost. Michigan [22], Stanford University [23], and the
University of Utah [24] have spent years developing
Cell-Based Sensors and improving various MEMS-based neural-
electronic interfaces.
An innovative microsensor uses a cell as the primary
transduction mechanism. An advantage of using
cells to detect chemicals is that cells are microscopic
chemical laboratories that can amplify a chemical
signal (i.e., the detection a few molecules can lead to
the production of many so called “second
messanger” molecules) – essentially biological gain
[17]. The amplified cell signal can be monitored by
either detecting a chemical change within the cell or
inferring the change by monitoring other parameters,
such the electrical activity. One sensor uses chick
myocardial cells to detect the presence of
epinephrine, verapamil, and tetrodotoxin in the cell
environment (Figure 6) [18]. Limitations of cell-based
sensors include the lifetime and robustness of the
cells.

Figure 7: Microfabricated silicon neural probe arrays.

Top: Close-up of the probes and electrodes [19].

The implications of MEMS technologies for

neuroscience are revolutionary. We now have the
potential to develop arrays of microsystems, which
can be tailored to the physical and temporal
dimensions of individual cells. Neuroscientists can
now realistically envision sensing devices that allow
Figure 6: Cell-based biosensor with microelectrode real-time measurements at the cellular level.
array [18]. Information from such sensors could be monitored,
analyzed, and used as a basis of experimental or
medical intervention, again at a cellular level.
Microsensors for Electrical Biosystems Another example is the use of micromachined neural
sensors and stimulators to control prosthetic limbs
The central and peripheral nervous systems are the with processed signals recorded from the brain or
primary electrical biosystems of interest. Many spinal column.
sensors and probes have been used to measure the
electrical signals generated by neural tissue.
Example include electrocardiogram (ECG),
electroencephalogram (EEG), electroneurogram
(ENG), electromyogram (EMG), and electroretino-
 BIOMEDICAL MICROACTUATORS Surgical Microinstruments
Microactuators are useful in biomedical applications The capability of most microactuators to surgically
when biological objects or their environment need to interact with biological tissues is hindered by their
be controlled on the microscopic scale. Furthermore, inability to withstand forces on the scale of ~1 mN.
the ability to integrate many microactuators as easily The most successful uses of microactuation in
as only one makes it feasible to produce complex surgical devices employ high-force small-
microsystems capable of controlling many displacement stepper motors or resonant
parameters. microstructures. MEMS technology can be used to
add a variety of capabilities to surgical
Micromanipulators microinstruments (e.g., microheaters, microsensors,
fluid delivery, fluid extraction, feedback and control).
To manipulate cells, tissues, and other biological
objects, micromanipulators must be driven by a A scalpel driven by a piezoelectric microactuator is
microactuation mechanism capable of operating in a an innovative example of using MEMS technology in
conductive solution. Good candidates include surgical tools (Figure 10) [27]. The piezoelectric
magnetic, pneumatic, thermal, and shape-memory stepper motor allows the position the scalpel to be
alloy actuation. The magnetic microactuator shown precisely controlled. By integrating an ability to
in Figure 8 has been used to manipulate single-cell measure the stresses experienced by the scalpel
protozoa in saline [25]. The shape memory alloy during cutting, the actual cutting force can be
microactuator shown in Figure 9 is capable of quantified and controlled.
grasping tissues during endoscopic surgical
procedures [26]. A second-generation device
constructed with polymers is being commercialized
by Micrus, Inc. and is presently in human trials.

Figure 10: Piezoelectrically driven force sensitive

scalpel (see [27]).

Figure 8: Magnetic microactuator manipulating a

single-cell protozoa (from [25]). An ultrasonic cutting tool fabricated by bulk
micromachining is another good example of using
MEMS technology in surgical devices. Again,
piezoelectric material is attached to the cutter to
resonante the tip of the tool at ultrasonic frequencies.
Only when activated will the device easily and rapidly
cut through even tough tissues (e.g., the hardened
lenses of patients with cataracts) [28]. The devices
shown in Figure 11, includes a imbedded
microchannel through which fluid and surgical debris
can be extracted while cutting .

Figure 9: Surgical microgripper actuated by shape-

memory-alloy forces (from [26]).
 Microfilters
The process used to produce conventional filters
capable of screening micron-scale objects results in
an unacceptably broad statistical distribution of the
size of objects that can pass. Micromachining and
MEMS technology has been used to realize filters
that are precisely and uniformly machined, which
greatly reduces the statistical variation in objects that
pass through [30].

Figure 11: Micromachined ultrasonic cutting tool [28].

Micropumps, and Microvalves,

Microfilters, and Microneedles
Figure 12: Silicon micromachined precision filter
Clearly the need to precisely control gas and fluid (from [30]).
flow is critical for diagnostic, surgical, and
therapeutic biomedical systems. With this as Microvalves
motivation, there have been many efforts to develop
viable reliable low-cost high-precision microneedles, Several different types of microvalves have been
microfilters, microvalves and micropumps. microfabricated, including normally-open and
normally-closed valves either for controlling gasses
Microneedles or fluids. A complete discussion of the specifics
involved in the development of each valve type is
The reduction in pain caused by needle insertion is beyond the scope of this paper. Instead, the options
important for patient satisfaction and health. This is and trade-offs of valve design in general will be
particularly true for patients suffering from diabetes described.
who inject themselves with insulin at least a few
times a day. It is then no surprise that the smallest A leader in the commercialization of microvalves has
needles presently available are the 30-gauge been Redwood Microsystems of Menlo Park, CA
needles used by diabetics (Figure 11 - left). [31]. They have designed many different valves, but
Micromachining and MEMS technology has been each has many common characteristics. First off, the
used to produce silicon microneedles that are much actuation mechanism used in each valve is the same
sharper than exisiting needles (Figure 11 - right) [29]. – a small quantity of inert fluid is heated with an
integrated resistor until a phase change is induced
that exerts a tremendous force (Figure 11). Although
the microfabrication process that precisely traps a
fluid inside a microcavity is not trivial, it can be
commercialized. The performance of microvalves
compares favorably with macroscopic solenoid
valves. In particular, microvalves typically operate
faster and have a longer operational lifetime than
macro-scale valves.
Figure 11: Left: Smallest conventional needle (30
gauge). Right: Microfabricated silicon needle. The
size scale of both images is the same (from [29]).
 The electrodes are fabricated inside a second
isolated cavity formed above the deformable
pumping membrane so that they are sealed away
from the conductive solutions being pumped
(Figure 12). Although the micropump works well,
high voltages (>100 V) are required for significant
pumping to occur [33].

Figure 11: Microvalves designed by Redwood

Microsystems, Inc [31].

The TiNi corporation has also commercialized a

micromachined pressure sensor driven by shape- Figure 12: Electrostatic micropump with two one-way
memory alloys. HP and NovaSensor have designed, check valves (from [33]).
fabricated, and tested microvalves driven by the
linear thermal expansion of solid materials. Despite When designing micropumps for biomedical
the good performance, the HP valves have not yet applications, attention must be paid to the media
been commercialized due to business reasons and being pumped. Some fluids, such as insulin, cannot
the NovaSensor valves are in the final phase of tolerate aggressive pumping mechanisms without
development. degrading.

The performance of microvalves compares favorably BIOMEDICAL MICROSYSTEMS

with macroscopic solenoid valves. In particular,
microvalves typically operate faster and have a The ability to miniaturize entire biomedical systems,
longer operational lifetime. However, since such as DNA analysis, chemical analysis, drug
microvalves are typically driven by thermal actuators development, and neural prosthetics, has the
their power consumption is still relatively high potential to reduce the cost of health-care
(0.1-2.0 W). Care must be taken to prevent the valve management. For example, reducing the cost and
temperature to exceed that tolerated by the fluid or complexity of performing DNA screening and
gas media being controlled. chemical analysis to the point that tests can be
performed rapidly on the desktop, would reduce the
Micropumps infrastructure required for the test without
compromising capability. This would enable remote
Several methods of microactuation have been used or small-scale clinics to offer fast high-quality tests.
to drive micropumps: electrostatic forces, magnetic
forces, and piezoelectric. One example is a Microfluidic Systems
miniaturized gear pump that consists of LIGA
microgears that are magnetically actuated It has Chemical, pharmaceutical, and genetic analysis
been commercialized by MEMStek Products, LLC, of systems require the precise handling of fluids (i.e.,
Vancouver, Washington [32]. Another example is an sampling, mixing, heating, cooling, reacting, and
electrostatically driven micropump produced by separating). Conventional fluidic analyses are
bonding multiple bulk micromachined silicon wafers typically performed with relatively macroscopic fluidic
together. The bonding process creates a pumping systems (>25 µL). Miniaturization and integration of
cavity with a deformable membrane and two one- fluidic systems offers the following advantages: (1)
way check valves. smaller typical operating fluid volume, (2) precise
control of sample volumes, (3) ability to perform sensors into the same chip to allow for improved
massively parallel tests, (4) take advantage of the temperature control.
effect of scaling on fluidic, electrical, and thermal
behavior, (5) possible reduction in system size, and
(6) possible reduction in system cost. One important
caveat with miniaturizing fluidic analysis systems is
the fact that reducing the sample size requires a
corresponding increase in sensor sensitivity. In
addition, micro-scale fluid flow is almost completely
laminar (i.e., there is very little turbulence and thus
mixing can be problematic).

Micro Total Analysis Systems (µTAS)

The ability to electrically control fluid flow in Figure Micromachined PCR chamber (from [36]).
micromachined channels (i.e., pumping and valving)
without any moving parts has enabled the realization Gene Chips
of complex micro total analysis systems [34]. With
multiple independently controlled flow channels,
Separation by electrophoresis can be used to detect
complex sample preparation, mixing, and testing
the size of a DNA molecule, but another method is
procedures can be established. The electrically
needed to determine its precise code. One method
controlled pumping and valving mechanism is either
exploits the highly selective hybridization process
electroosmotic flow or electrophoretic flow [2]. Liquid
that allows DNA fragments to bind only with their
chromatography (i.e., a method of separating liquids
complimentary sequence. In order to test for many
based on their different mobility in a long flow
specific sets of DNA sequences (i.e., for genetic
channel) can be used to perform a precise chemical
screening), a large number of unique oligonucleotide
analysis in microfabricated flow channels. Sensors
probes need to be constructed and compared to the
integrated at the end of the flow channel will reveal a
amplified DNA. One novel method of constructing
time-domain spectrum of the fluid composition.
oligonucleotide probes employs the same
Micromachined electrophoretic devices have been
lithographic techniques used to construct MEMS.
used to separate ions and DNA molecules from 70 to
Specifically, a substrate is coated with a compound
1000 bases in under 2 minutes – much faster than
that is protected by a photochemically cleavable or
conventional capillary electrophoresis systems [35].
photolabile protecting group (e.g., nitroveratryloxy-
The detection of each ion or molecule species can
carbonyl).
be accomplished with electrochemical measure-
ments, fluorescence, or optical absorption.
When this film is exposed to a pattern of light, the
illuminated regions will become unprotected and can
Microsystems for Genetic Analysis be conditioned to receive a specific nucleotide /
photolabile protecting group pair. By continuing the
The analysis of genetic material typically calls for first processes with a new mask pattern each time, very
the amplification of the DNA sample and then its large arrays of unique combinations of nucleotide
detection. The amplification of a DNA sample can be can be rapidly formed. The process is repeated until
accomplished by polymerase chain reaction (PCR). the desired oligonucleotides are constructed. After
The PCR process begins by heating the DNA tagging the sample DNA with a fluorescent probe, it
sample above the temperature at which the two is then distributed over the array of oligonucleotide
strands separate or “melt” (~90 to 95ºC). If the DNA probes. Subsequent optical inspection of the
polymerase enzyme and the building blocks of DNA distribution of fluorescence clearly indicates which
(i.e., nucleotide triphosphates) are present during oligonucleotides in the array match with a section of
cooling, the DNA polymerase will then reconstruct the sample DNA. Miniaturization of this detection
each double helix resulting in a doubling of the system enabled massively parallel screening (i.e.,
number of DNA stands. A major advantage of 40,000 different compounds can be tested on a
miniaturizing PCR systems is the fact that the much single 1 cm chip with 50 µm oligonucleotide probe
lower thermal mass of the reaction chamber allows areas. Affymetrix, Inc, has commercialized a DNA
for more rapid heating and cooling and thus a much detection scheme based on this technology [37].
faster process overall. Furthermore, it is even
possible to integrate heaters and temperature
 CONCLUSIONS [10] Y. Kanda, “Piezoresistance Effect of Silicon”,
Sensors and Actuators A, vol. 28, 1991,
Micromachining and MEMS technologies are pp. 83-91.
powerful tools for enabling the miniaturization of [11] B. Boser, “Electronics for Micromachined Inertial
devices useful in biomedical engineering. Although Sensors”, Proceedings of International Solid-
silicon micromachined pressure sensors presently State Sensors and Actuators Conference
possess the largest share of the BioMEMS market in (Transducers '97), Chicago, IL, USA, June,
terms of volume and sales, it is anticipated that the 1997, pp. 1169-1172.
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