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.
Surface Micromachining
(100) Silicon Wafer
p+ Silicon
Silicon Nitride Film
{111 Planes}
Through
Hole
month).
Anchor
Membrane
V-Groove
Sacrificial Layer
Substrate
Substrate Bonding
Structural Layer
Release Etch
Bulk Micromachining
Bulk
micromachining
differs
from
surface
micromachining in that the substrate material, which
is typically single-crystal silicon, is patterned and
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
Non-Silicon Microfabrication
The development of MEMS has contributed
significantly to the improvement of non-silicon
microfabrication
techniques.
Two
prominent
examples are LIGA and plastic molding from
micromachined substrates.
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 m), patterned with commonly available
contract lithography tools, and yet still achieves
vertical sidewalls [7].
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
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., its 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 micromechanical 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.
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.
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,
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
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
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.
Cell-Based Sensors
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.
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
smalldisplacement
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.
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].
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].
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.
BIOMEDICAL MICROSYSTEMS
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, W ashington [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.
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 L). Miniaturization and integration of
fluidic systems offers the following advantages: (1)
smaller typical operating fluid volume, (2) precise
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., nitroveratryloxycarbonyl).
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 m 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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