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
jjudy@ucla.edu
Abstract – Micromachining and MEMS
technologies can be used to produce complex
electrical, mechanical, fluidic, thermal, optical,
and magnetic structures, devices, and systems
on a scale ranging from organs to subcellular
organelles. This miniaturization ability has
enabled MEMS to be applied in many areas of
biology, medicine, and biomedical engineering –
a field generally referred to as BioMEMS. The
future looks bright for BioMEMS to realize (1)
microsensor arrays that act as an electronic
nose or tongue, (2) microfabricated neural
systems capable of controlling motor or sensory
prosthetic devices, (3) painless microsurgical
tools, and (4) complete microfluidic systems for
total chemical or genetic analyses.
INTRODUCTION
Microelectromechanical systems (MEMS) is a
technology of miniaturization that has been largely
adopted from the integrated circuit (IC) industry and
applied to the miniaturization of all systems (i.e., not
only electrical systems but also mechanical, optical,
fluidic, magnetic, etc). Miniaturization is
accomplished with microfabrication processes, such
as micromachining, that typically use lithography,
although other non-lithographic precision
microfabrication techniques exist (FIB, EDM, laser
machining). Due to the enormous breadth and
diversity of the field of MEMS, the acronym is not a
particularly apt one. However, it is used almost
universally to refer to the entire field (i.e., all devices
produced by micromachining). Other names for this
general field include “microsystems”, popular in
Europe, and “micromachines”, popular in Asia.
For a discussion of the early work in MEMS,
including many of the seminal papers, the interested
reader is directed to reference [1]. For a
comprehensive discussion of micromachining
processes and MEMS devices, the interested reader
is directed to the texts by Kovacs [2] and Madou [3].
MICROFABRICATION
Although many of the microfabrication techniques
and materials used to produce MEMS have been
borrowed from the IC industry, the field of MEMS has
also driven the development and refinement of other
microfabrication processes and non-traditional
materials.
Conventional IC Processes and Materials:
- photolithography; thermal oxidation; dopant
diffusion; ion implantation; LPCVD; PECVD;
evaporation; sputtering; wet etching; plasma
etching; reactive-ion etching; ion milling
- silicon; silicon dioxide; silicon nitride; aluminum
Additional Processes and Materials used in MEMS:
- anisotropic wet etching of single-crystal silicon;
deep reactive-ion etching or DRIE; x-ray
lithography; electroplating; low-stress LPCVD
films; thick-film resist (SU-8); spin casting;
micromolding; batch microassembly
- piezoelectric films such as PZT; magnetic films
such as Ni, Fe, Co, and rare earth alloys; high
temperature materials such as SiC and ceramics;
mechanically robust aluminum alloys; stainless
steel; platinum; gold; sheet glass; plastics such as
PVC and PDMS
The methods used to integrate multiple patterned
materials together to fabricate a completed MEMS
device are just as important as the individual
processes and materials themselves. The two most
general methods of MEMS integration are described
in the next two sub-sections: surface micromachining
and bulk micromachining.
typically the case for surface micromachining).
Exploiting the predictable anisotropic etching
characteristics of single-crystal silicon, many high-
precision complex 3-D shapes, such as V-grooves,
channels, pyramidal pits, membranes, vias, and
nozzles, can be formed [5]. An illustration of a typical
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
LIGA is a German acronym standing for lithographie,
galvanoformung (plating), and abformung (molding)
[6]. However, in practice LIGA essentially stands for
a process that combines extremely thick-film resists
(often >1 mm) and x-ray lithography, which can
pattern thick resists with high fidelity and results in
vertical sidewalls. Although some applications may
require only the tall patterned resist structures
themselves, other applications benefit from using the
thick resist structures as plating molds (i.e., material
can be quickly deposited into the mold by
electroplating). A drawback to LIGA is the need for
high-energy x-ray sources (e.g., synchrotrons or
linear accelerators) that are very expensive and rare
(i.e., only several such sources exist in the U.S.).
SU-8
Recently a cheap alternative to LIGA, with nearly the
same performance, has been developed. The
solution is to use a special epoxy-resin-based optical
resist, called SU-8, that can be spun on in thick
layers (>500 µm), patterned with commonly available
contract lithography tools, and yet still achieves
vertical sidewalls [7].
Plastic Molding with PDMS
Polydimethylsiloxane (PDMS) is a transparent
elastomer that can be poured over a mold (e.g., a
wafer with a pattern of tall SU-8 structures),
polymerized, and then removed simply by peeling it
off of the mold substrate [8]. The advantages of this
process include (1) many inexpensive PDMS parts
can be fabricated from a single mold, (2) the PDMS
will faithfully reproduce even sub-micron features in
the mold, (3) PDMS is biocompatible and thus can
be used in a variety of BioMEMS applications, and
(4) since PDMS is transparent, tissues, cells, and
other materials can be easily imaged through it.
Common uses of PDMS in biomedical applications
include: microstamping of biological compounds (to
observe geometric behavior of cells and tissues) and
microfluidics systems [9][8].
BIOMEDICAL MICROSENSORS
The majority of MEMS used in biomedical
applications act as sensors. Examples include
critical sensors used during surgery (i.e., measuring
intravascular blood pressure), long-term sensors for
prosthetic devices, and highly sophisticated sensor
arrays for rapid lab-quality diagnosis at home. A
comprehensive discussion of all the different sensors
and their applications is beyond the scope of this
paper. Instead, a discussion of several classes of
microsensors and an overview of their applications
will be given.
Microsensors for Biomechanics
Studies of the forces created by and imposed on the
body benefit from increasing the sensitivity of
mechanical stress and strain sensors while also
reducing their size and cost. The following are
examples of microsensors used to study
biomechanics.
Strain Gauges
Strain gauges are used to characterize the forces in
the body. Since silicon is known to be an excellent
piezoresistive material (i.e., it’s resistance changes
as a function of applied force), it can be easily
micromachined to form sub-millimeter multi-axis
strain gauges [10]. Applications of such miniaturized
strain gauges include orthopedic research and the
study of muscles. Although the understanding of
muscle function and structure is well understood at
the whole-muscle and cellular levels, muscles have
not been well characterized in the region in between.
An improved understanding at this level would allow
for the development of improved locomotion
therapies and prosthetic devices.
Accelerometers
One class of microsensors that MEMS technology
has had the most positive impact on are inertial
sensors (i.e., accelerometers and gyros). Since
inertial devices typically consist of a proof mass,
mechanical flexure, and displacement sensor,
MEMS technology is well suited to integrate each of
these sensor elements into a single chip. In fact, it is
also possible to integrate ICs with the micro-
mechanical elements to add signal amplification and
filtration capability to the chip-scale sensor [11].
Inertial microsensors are useful to determine impact
level and patient posture.
Microsensors for Pneumatic Biosystems
Since much of the human body is a complex system
of pumps, valves, vessels, and interconnects,
pressure in many parts of the body is an important
parameter to indicate the health and well being of a
patient. Pressure sensors are used in medicine in
many applications: blood pressure, bladder pressure,
and cerebral spinal fluid pressure to name a few. In
addition to performance requirements, the size of
pressure sensors, particularly those inserted into the
body must be small and ideally disposable. MEMS
technology is well positioned to deliver solutions to
this opportunity. In fact, a good example is the
commercially successful low-cost disposable
medical pressure sensor developed by Lucas
NovaSensor NPC-107 (Figure 3) [12]. In it a silicon
micromachined sensing element is used to meet or
exceed all industry requirements (e.g., sensitivity
within +/-1% and linearity better than 1%). Another
micromachined silicon pressure sensor produced by
NovaSensor is made small enough (1 mm x 0.7 mm
x 0.175 mm thick) to be inserted into a catheter and
inserted into arteries.
Figure 4: Micromachined pressure sensor die with
3
smallest having dimensions (175×700×1000 µm ).
Microsensors for Chemical Biosystems
Since living organisms are extremely sophisticated
chemical processing systems, there are many
biomedical applications for chemical sensors (e.g.,
medical diagnostic instruments, drug screening,
implantable sensors for prostheses, and
environment monitoring). Although the
micromachining of chemical sensors is typically
simple, other components sometimes used in a
complete chemical sensor system (i.e., sample
preparation and delivery, reaction control, and waste
disposal) are more difficult to integrate together.
Impedance Sensors
The conductivity of some materials is affected by the
presence and relative concentration of certain gases
or vapors. Examples of these materials include
polymers doped with conductive particles,
conductive polymers, and some metal oxides. The
challenges common to impedance-based chemical
sensors include identifying single gases, quantifying
gas concentration, dealing with gas mixtures,
sensitivity to water vapor, sensitivity to temperature
changes, and microfabrication of arrays of uniquely
sensitive sensors.
Polymer-Based Gas Sensors
Many polymers will geometrically swell reversibly
when exposed to certain gases. Conductive
polymers, such as polypyrrole, can be used directly
as a viable chemiresistor. To use insulating
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
unique polymers, the integration process must
contend with the large volume of solvent that is
typically present during polymer deposition.
Furthermore, the microfabrication technique must
not damage previously deposited polymers. One
strategy is to use a removable mask to selectively
deposit each polymer into a specific area. This
technique has difficulty forming sub-millimeter
sensors due to poor adhesion to the substrate when
the mask is removed (i.e., the polymers adhere more
strongly to the mask than to the substrate). Another
strategy is to use a permanent microwell structure to
contain the polymer-solvent solution in a well-defined
sub-millimeter area without disturbing previously
deposited polymers. An example of a polymeric
impedance-based gas sensor that uses an SU-8
microwell structure is given in Figure 5.
Metal Oxides
The conductivity of certain metal oxides, most
commonly SnO2, is known to vary as a function of
the concentration of specific gasses (e.g., O2, H2,
CO, CO2, NO2, and H2S) when the metal oxide is
heated sufficiently to induce a chemical reaction that
is detected. There are several mechanisms that
cause the resistance of the metal oxide to vary [2].
The microfabrication of these sensors can be
relatively straightforward, unless additional
micromachined features are added to improve
sensor response and power consumption (i.e.,
integrating microfabricated heaters, thermal isolation
structures (e.g., membranes) that require far less
power to heat, and CMOS signal detection,
amplification, and filtering circuitry.
Figure 5: Microfabricated polymer carbon-black gas
sensor with SU-8 microwell for solvent containment
(from [14]).
Electrochemical Sensors
The oxidation and reduction of chemical species on
a conducting electrode can be observed by
measuring the movement of charge. There are two
primary methods of sensing electrochemical
reactions: potentiometric and amperometric.
Potentiometric sensors can be used to measure the
equilibrium potential established between the
electrode material and the solution, a potential that is
dependent on the chemistry involved. Amperometric
sensors measure the current generated by a
reaction and thus give a measure of reaction rates.
By controlling the potential of the electrode relative to
the solution and measuring the charge flow induced,
the presence of specific ions can be determined by
observing the potential at which they undergo
oxidation or reduction. This is a process known as
voltammetry.
Micromachining processes can be used to
accurately and reliable define the area, number, and
relative position of electrodes that are exposed to
solution. In addition, the simple construction of a
typical electrochemical sensor (i.e., a partially
insulated metal trace on a substrate) allows ICs to be
easily integrated with the electrode. The ICs can be
used to provide on-chip signal processing and
amplification.
Molecular-Specific Sensors
Chemical sensors that respond only to certain ions
or molecules can be extremely selective. Among the
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
electrodes (i.e., gate). If an ionic solution acts as the
gate of a FET, the device will be tremendously
sensitive to the overall ion concentration of the
solution (i.e., not selective to specific ions). A good
pH sensor can be made this way and indeed one
exists [15]. By coating the gate of the FET with a
compound that will selectively bind or allow to pass
only specific ions or molecules, an ion-sensitive FET,
or ISFET, can be realized. Common difficulties with
ISFETs, as with all chemical sensors, are drift and
repeatability.
Resonant Sensors
The resonant frequency of a mechanical element is
strongly dependent on its geometry, mechanical
properties, and mass. By coating a resonating
mechanical element, such as a beam or membrane,
with a compound that will selectively bind to only
specific ions or molecules, the mass of the
mechanical element will increase with their
concentration. The ion-concentration dependent
mass loading can be determined by measuring the
corresponding shift in the resonant frequency.
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

Figure 6: Cell-based biosensor with microelectrode
array [18].
Microsensors for Electrical Biosystems
The central and peripheral nervous systems are the
primary electrical biosystems of interest. Many
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-
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
real-time measurements at the cellular level.
Information from such sensors could be monitored,
analyzed, and used as a basis of experimental or
medical intervention, again at a cellular level.
Another example is the use of micromachined neural
sensors and stimulators to control prosthetic limbs
with processed signals recorded from the brain or
spinal column.
 BIOMEDICAL MICROACTUATORS
Microactuators are useful in biomedical applications
when biological objects or their environment need to
be controlled on the microscopic scale. Furthermore,
the ability to integrate many microactuators as easily
as only one makes it feasible to produce complex
microsystems capable of controlling many
parameters.
Micromanipulators
To manipulate cells, tissues, and other biological
objects, micromanipulators must be driven by a
microactuation mechanism capable of operating in a
conductive solution. Good candidates include
magnetic, pneumatic, thermal, and shape-memory
alloy actuation. The magnetic microactuator shown
in Figure 8 has been used to manipulate single-cell
protozoa in saline [25]. The shape memory alloy
microactuator shown in Figure 9 is capable of
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 8: Magnetic microactuator manipulating a
single-cell protozoa (from [25]).
Figure 9: Surgical microgripper actuated by shape-
memory-alloy forces (from [26]).
Surgical Microinstruments
The capability of most microactuators to surgically
interact with biological tissues is hindered by their
inability to withstand forces on the scale of ~1 mN.
The most successful uses of microactuation in
surgical devices employ high-force small-
displacement stepper motors or resonant
microstructures. MEMS technology can be used to
add a variety of capabilities to surgical
microinstruments (e.g., microheaters, microsensors,
fluid delivery, fluid extraction, feedback and control).
A scalpel driven by a piezoelectric microactuator is
an innovative example of using MEMS technology in
surgical tools (Figure 10) [27]. The piezoelectric
stepper motor allows the position the scalpel to be
precisely controlled. By integrating an ability to
measure the stresses experienced by the scalpel
during cutting, the actual cutting force can be
quantified and controlled.
Figure 10: Piezoelectrically driven force sensitive
scalpel (see [27]).
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 11: Micromachined ultrasonic cutting tool [28].
Micropumps, and Microvalves,
Microfilters, and Microneedles
Clearly the need to precisely control gas and fluid
flow is critical for diagnostic, surgical, and
therapeutic biomedical systems. With this as
motivation, there have been many efforts to develop
viable reliable low-cost high-precision microneedles,
microfilters, microvalves and micropumps.
Microneedles
The reduction in pain caused by needle insertion is
important for patient satisfaction and health. This is
particularly true for patients suffering from diabetes
who inject themselves with insulin at least a few
times a day. It is then no surprise that the smallest
needles presently available are the 30-gauge
needles used by diabetics (Figure 11 - left).
Micromachining and MEMS technology has been
used to produce silicon microneedles that are much
sharper than exisiting needles (Figure 11 - right) [29].
Figure 11: Left: Smallest conventional needle (30
gauge). Right: Microfabricated silicon needle. The
size scale of both images is the same (from [29]).
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 12: Silicon micromachined precision filter
(from [30]).
Microvalves
Several different types of microvalves have been
microfabricated, including normally-open and
normally-closed valves either for controlling gasses
or fluids. A complete discussion of the specifics
involved in the development of each valve type is
beyond the scope of this paper. Instead, the options
and trade-offs of valve design in general will be
described.
A leader in the commercialization of microvalves has
been Redwood Microsystems of Menlo Park, CA
[31]. They have designed many different valves, but
each has many common characteristics. First off, the
actuation mechanism used in each valve is the same
– 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: Microvalves designed by Redwood
Microsystems, Inc [31].
The TiNi corporation has also commercialized a
micromachined pressure sensor driven by shape-
memory alloys. HP and NovaSensor have designed,
fabricated, and tested microvalves driven by the
linear thermal expansion of solid materials. Despite
the good performance, the HP valves have not yet
been commercialized due to business reasons and
the NovaSensor valves are in the final phase of
development.
The performance of microvalves compares favorably
with macroscopic solenoid valves. In particular,
microvalves typically operate faster and have a
longer operational lifetime. However, since
microvalves are typically driven by thermal actuators
their power consumption is still relatively high
(0.1-2.0 W). Care must be taken to prevent the valve
temperature to exceed that tolerated by the fluid or
gas media being controlled.
Micropumps
Several methods of microactuation have been used
to drive micropumps: electrostatic forces, magnetic
forces, and piezoelectric. One example is a
miniaturized gear pump that consists of LIGA
microgears that are magnetically actuated It has
been commercialized by MEMStek Products, LLC, of
Vancouver, Washington [32]. Another example is an
electrostatically driven micropump produced by
bonding multiple bulk micromachined silicon wafers
together. The bonding process creates a pumping
cavity with a deformable membrane and two one-
way check valves.
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 12: Electrostatic micropump with two one-way
check valves (from [33]).
When designing micropumps for biomedical
applications, attention must be paid to the media
being pumped. Some fluids, such as insulin, cannot
tolerate aggressive pumping mechanisms without
degrading.
BIOMEDICAL MICROSYSTEMS
The ability to miniaturize entire biomedical systems,
such as DNA analysis, chemical analysis, drug
development, and neural prosthetics, has the
potential to reduce the cost of health-care
management. For example, reducing the cost and
complexity of performing DNA screening and
chemical analysis to the point that tests can be
performed rapidly on the desktop, would reduce the
infrastructure required for the test without
compromising capability. This would enable remote
or small-scale clinics to offer fast high-quality tests.
Microfluidic Systems
Chemical, pharmaceutical, and genetic analysis
systems require the precise handling of fluids (i.e.,
sampling, mixing, heating, cooling, reacting, and
separating). Conventional fluidic analyses are
typically performed with relatively macroscopic fluidic
systems (>25 µL). Miniaturization and integration of
fluidic systems offers the following advantages: (1)
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
micromachined channels (i.e., pumping and valving)
without any moving parts has enabled the realization
of complex micro total analysis systems [34]. With
multiple independently controlled flow channels,
complex sample preparation, mixing, and testing
procedures can be established. The electrically
controlled pumping and valving mechanism is either
electroosmotic flow or electrophoretic flow [2]. Liquid
chromatography (i.e., a method of separating liquids
based on their different mobility in a long flow
channel) can be used to perform a precise chemical
analysis in microfabricated flow channels. Sensors
integrated at the end of the flow channel will reveal a
time-domain spectrum of the fluid composition.
Micromachined electrophoretic devices have been
used to separate ions and DNA molecules from 70 to
1000 bases in under 2 minutes – much faster than
conventional capillary electrophoresis systems [35].
The detection of each ion or molecule species can
be accomplished with electrochemical measure-
ments, fluorescence, or optical absorption.
Microsystems for Genetic Analysis
The analysis of genetic material typically calls for first
the amplification of the DNA sample and then its
detection. The amplification of a DNA sample can be
accomplished by polymerase chain reaction (PCR).
The PCR process begins by heating the DNA
sample above the temperature at which the two
strands separate or “melt” (~90 to 95ºC). If the DNA
polymerase enzyme and the building blocks of DNA
(i.e., nucleotide triphosphates) are present during
cooling, the DNA polymerase will then reconstruct
each double helix resulting in a doubling of the
number of DNA stands. A major advantage of
miniaturizing PCR systems is the fact that the much
lower thermal mass of the reaction chamber allows
for more rapid heating and cooling and thus a much
faster process overall. Furthermore, it is even
possible to integrate heaters and temperature
Figure Micromachined PCR chamber (from [36]).
Gene Chips
Separation by electrophoresis can be used to detect
the size of a DNA molecule, but another method is
needed to determine its precise code. One method
exploits the highly selective hybridization process
that allows DNA fragments to bind only with their
complimentary sequence. In order to test for many
specific sets of DNA sequences (i.e., for genetic
screening), a large number of unique oligonucleotide
probes need to be constructed and compared to the
amplified DNA. One novel method of constructing
oligonucleotide probes employs the same
lithographic techniques used to construct MEMS.
Specifically, a substrate is coated with a compound
that is protected by a photochemically cleavable or
photolabile protecting group (e.g., nitroveratryloxy-
carbonyl).
When this film is exposed to a pattern of light, the
illuminated regions will become unprotected and can
be conditioned to receive a specific nucleotide /
photolabile protecting group pair. By continuing the
processes with a new mask pattern each time, very
large arrays of unique combinations of nucleotide
can be rapidly formed. The process is repeated until
the desired oligonucleotides are constructed. After
tagging the sample DNA with a fluorescent probe, it
is then distributed over the array of oligonucleotide
probes. Subsequent optical inspection of the
distribution of fluorescence clearly indicates which
oligonucleotides in the array match with a section of
the sample DNA. Miniaturization of this detection
system enabled massively parallel screening (i.e.,
40,000 different compounds can be tested on a
single 1 cm chip with 50 µm oligonucleotide probe
areas. Affymetrix, Inc, has commercialized a DNA
detection scheme based on this technology [37].
 CONCLUSIONS
Micromachining and MEMS technologies are
powerful tools for enabling the miniaturization of
devices useful in biomedical engineering. Although
silicon micromachined pressure sensors presently
possess the largest share of the BioMEMS market in
terms of volume and sales, it is anticipated that the
market share of MEMS-enabled chemical sensing
and microfluidic systems will grow tremendously. In
addition, MEMS will continue to be applied to
biomedical engineering in new research activities
that push our understanding of cells, organs, the
brain, the body, and the world around us.
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