Microfluidics and
Their Role in
Biomedical
Applications
May 14th, 2003
ENMA 465
By Susan Beatty, Stacy Cabrera, Saba Choudhary, and
Daniel Janiak
http://www.mae.ufl.edu/~zhf/ResearchInterests-ZHFan.htm
Executive Summary
Microfluidics focus on controlling the flow of liquids and gases in systems with
dimensions on the microscale. These fluids are dealt with in nano and picoliter amounts and are
subject to specific properties at this level. Microfluidic devices are very promising to biomedical
applications and play a key role in the future of laboratory testing. Applications in this area can
range from detecting toxins in the air to identifying DNA sequences. The idea behind “lab-on-achip” processes is that a macroscale laboratory and all of its functions can be downsized to fit on
a microchip. Micro-dosing systems are also being developed for drug delivery with microfluidic
systems that involve channels, pumps, valves, and sensors. In the beginning of the research, the
material of choice was silicon. Because silicon is not completely bioinert and fairly expensive to
process, manufacturers have since moved to plastics. Some of the common materials reviewed
include Polyimide, Parylene, PDMS, and Diamond-Like Carbon films. The primary process for
making the channels of the device is soft lithography, while micromachining is used to create
other features like valves. A key component to a microfluidics system is a valve. The materials
and processes of choice depend on the valve being manufactured and the function of the valve
within the system. One of the main key concepts currently being improved on is mixing
techniques among fluids with only laminar flow properties The future of microfluidics is to
continue to take the processing to a smaller and smaller level with increasing speed, accuracy
and range of tests being conducted on a microchip.
Key Words: Microfluidics, biomedical, valve device., soft lithography
1
Table of Contents
Executive Summary
1
Introduction
3
Biomedical Applications
Overview
4
Lab-on-a-chip
6
Drug Delivery and Micro-Dosing Systems
6
Microfluidic Device Focus: Valves
7
Materials
8
Processes
Overview
11
Fabrication of a Valve
13
Future of Microfluidics
15
References
16
2
The idea is that once you master fluids at the microscale, you can automate key
experiments for genomics and pharmaceutical development, perform instant diagnostic
tests, even build implantable drug-delivery devices—all on mass produced chips. It’s a
vision so compelling that many industry observers predict microfluids will do for biotech
what the transistor did for electronics.
- Rebecca Zacks for Technology Review Jan/Feb 2001
Introduction
In the most general sense, microfluidics is the flow control of tiny amounts of gases or
liquids in a miniaturized system on a microchip (Fluidigm, 2003). This is a growing area of
biotechnology that will attempt to bring an entire lab, all its equipment, and its range of tests to a
single piece built on a microscale. Examples of microfluidics can be found in nature—one
prominent one being the human body’s oxygen transport system. Fluid (plasma carrying tiny red
blood cells) is moved through tiny capillaries bringing the material to all extremities of the body
(Holl et al., 2002). In comparison, microfluidic systems in biotechnology are made up of a
combination of channels, pumps, valves, and sensors and are referred to as Micro Total Analysis
Systems (mTAS). These channels and chambers within the systems are at the dimensions of tens
of hundreds of micrometers (Holl, et al., 2002).
The motivation behind developing microfluidics is the properties of laminar flow that
exist within the system. On a macroscale, laminar, turbulent and random flow exists for fluids
whereas there is only laminar flow on a microscale. Because only this particular type of flow
exists in confined spaces, micro channels create special environments that provide controlled
mixing—a critical step in expediting chemical reactions (Holl et al., 2002). The area of
microfluidics is also looked to for its low thermal mass and efficient mass transport (Holl, et al.,
2002). Finally, these miniature systems are the first step to automating complex experimental
processes (Fluidigm, 2003).
The processing of microfluidic systems is just as important as the inventions of them.
Microfabrication methods from the electronics industry have been adapted to microfluidic
system processing. Methods range from “printing” to soft lithography and everything in between.
Different materials types, such as ceramics and plastics are also used to make the various parts
including the pumps, valves, and channels.
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The future of microfluidics can bring professional, large scale, cumbersome, yet
important tests to an individual, at-home level by building personal microfluidic devices, similar
to the way microcomputing brought a computer into nearly every person’s home. The focus lies
on uses in biotechnology but the possibilities for electronics and more exists.
Biomedical Applications
Overview
Microfluidics studies the behavior of liquids and gasses at the micro level and exploits
these properties, or finds methods of circumventing them, in applications and designs for device
fabrication. Microfluidic devices combine the advantages of the chemical and physical
properties of liquids and gasses at the micro level with the electrical properties of
semiconductors on a single chip. This breakthrough in technology finds great potential in the
biomedical field. Applications range from detecting airborne toxins to analyzing DNA
sequences. Advantages in using these small-scale devices rather than conventional systems
include: compact size, disposability, increased functionality, and they require smaller volumes
of reagents and samples. According to Harold Craighead of Cornell University, himself a
researcher in the area, commercialization of the technology is seen for more rapid DNA
sequencing, chemical analytical systems, manipulating cells, and doing general biological
procedures (Gwynne, 2000).
The optimism surrounding the future of microfluidics is reinforced by the fact that
fabrication of the devices involves techniques compatible with those already used in batch
processing standard semiconductors. “That should allow future microfluidics devices to be made
quickly and cheaply in a microchip factory,” according to Carolyn Matze of the Compound
Semiconductor Research Lab at Sandia National Labs (Gwynne, 2000). According to Dr. David
Beebe of the University of Wisconsin, simple methods have been developed that enable
functionality in microfluidic systems. Using basic physical phenomena of fluids that dominate at
the micro-scale (e.g. diffusion, surface tension), one can create new functionality, elegant system
designs, and low cost manufacturing methods. “The use of liquid phase photopolymerization
allows for the realization of channel networks in a few minutes. Extensions into three dimensions
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are possible by leveraging surface tension effects. Surface tension effects can also be exploited to
achieve sample concentration and pumping schemes as well as the creation of ‘virtual’ and liquid
walls providing new functionality in microfluidic systems. Gel matrices can be used to achieve
filtering and display functions. Autonomous function is possible by utilizing materials that
undergo direct chemical to mechanical conversions enabling elegant system design (e.g. active
valves, closed loop feedback control without electronics). Heating and cooling via chemical
reactions further eliminates the need for electronics and batteries in order to achieve complex
functionality. Further, simple microfluidic systems can enhance in vitro environments and enable
improved study of living systems.” (Beebe, 2002).
Microfluidics has been used in the Gene Chip technology. Gene chips are also known as
DNA chips or DNA microarrays. This technology is used to analyze thousands of genes at a
time. Gene Chips are covered with grid-like patterns of short DNA strands, called probes, each
of which can specifically bind to a different gene sequence. When sample DNA is placed on the
chip, researchers can study which probes bind DNA from the sample to determine which genes
were present in the sample. This is applied in analyzing cancerous cells to discover which genes
are present in the cancerous cells that are not present in healthy cells. Furthermore, cells can be
treated with drugs, and the gene chip can analyze those genes to determine which genes are
turned on or off by the drug. Evidently, using a gene chip can be the equivalent of thousands of
conventional genetic tests since there are hundreds of thousands of probes on a single gene chip.
Hence, gene chips have dramatically accelerated the pace of genetic research (Wikipedia, 2002).
The Neural Engineering Laboratory of the Department of Biomedical Engineering at
Michigan University is researching the possibilities of Neural microfluidic devices for the
intracerebral delivery of neuro-active compounds. Advances in protein and peptide chemistry
provide many neuro-active compounds that have therapeutic potential as neuro-protective
treatments. The challenge lies in systematically delivering these molecules without the
hampering effect of degradation and metabolism. The only option in the past has been to give
large doses of medication, which can have detrimental effect on other parts of the body. In
addition, the blood-brain barrier poses a significant obstacle for the delivery of these molecules.
This challenge can be faced with the advent of microfluidic technology, which is leading into
many novel ideas for drug delivery (Kipke, 2002).
5
Lab-on-a-Chip
Microfluidic lab-on-a-chip systems hold great potential for many laboratory applications.
Labs-on-a-chip can perform the same specialized functions as their macroscopic counterparts,
with the additional advantages of using very small sample size, very short reaction and analysis
time, and high throughput. These chips can perform clinical diagnoses, scan DNA, run
electrophoretic separations, act as microreactors synthesizing novel compounds, and are selfcontained chromatographs (Li, 2002). The gene chip, which was mentioned earlier, is one
example of a lab-on-a-chip.
The typical lab-on-a-chip is a thin glass or plastic plate, a few centimeters on a side, with
a network of microchannels etched into its surface, and strategically placed electrodes on the
chip. Microchannels are about 10 microns deep, 50 microns wide, and several centimeters in
length. A simple experiment begins by injecting a liquid sample, which can be as little as several
picoliters, at one end of a microchannel. Electric fields propel the sample along a predefined
route, past reservoir chambers that squirt measured amounts of reactants, and over detectors
scrutinizing the progress of the reaction. On such a chip, hundreds of different reactions and
analyses can be performed at the same time through hundreds of parallel microchannels (Li,
2002).
In order to manipulate fluids and obtain the desired results, labs-on-a-chip must be able to
perform the following functions on a microscopic scale: pumping, metering, switching flow,
dispensing, mixing, and separating (Li, 2002). This can be done by integrating many devices
(such as pumps, valves, etc.) onto a single chip.
Drug Delivery and Micro-Dosing Systems
Micromechanical dosing systems were the first microfluidic systems to be described. A
dosing system consists primarily of a micropump and flowsensor, and can be used in drug
delivery systems that are needed in the medical field (Koch et al, 2000). One example of a drug
delivery system was mentioned earlier: the research of a drug delivery system for neuro-active
compounds, where the challenge lies in delivering these drugs across the blood-brain barrier, and
into the central nervous system without them being degraded and metabolized on the way there.
Similarly, research has been conducted on drug delivery systems for insulin and painkillers
(Koch et al, 2000).
6
The purpose of the insulin micropump system is to mimic the action of the pancreas by
continuously giving the body a supply of insulin to maintain blood glucose levels within a
normal range, which can work 24 hours a day. In the past, insulin and painkillers have been
given in high doses in order to last for several hours. This high dosage approach gives an initial
high concentration, which is well above the required level being used. This results in a
consequent wastage of insulin or a possible addiction in the case of painkillers, such as morphine
(Koch et al, 2000).
Macroscopic insulin pumps have already been implanted into the human body. However,
these systems contained no closed-loop system to monitor glucose levels and regulate the
injection of insulin on demand. This system can be improved by further development of
microfluidic devices with glucose sensors. This microfluidic device could improve the quality of
life for diabetic patients as it could be implanted in the human body and have the desired
monitoring and regulating characteristics (Koch et al, 2000).
A similar system could be used for painkillers, to inject the medicine locally and not
globally, which reduces the probability of addiction (Koch et al, 2000). In addition, this could
result in much faster relief because the painkillers are being delivered to the desired sight, almost
instantly. Such a system has been developed and tested at the Maternity Hospital in Dublin,
Ireland (Koch et al, 2000).
Microfluidic Device Focus: Valves
A microfluidic system is the product of device integration. Many devices, such as valves,
pumps, flowsensors, fluidic mixers, and biological and chemical sensors are integrated into a
single substrate to design microfluidic systems (Koch et al, 2000). The focus of this section is
the valves used in microfluidic systems. This device is of two types: active and passive (Koch
et al, 2000).
Active valves are complicated structures because they include a form of actuation. In
principle, a flap controls the flow by actively opening or closing the passage for the fluid.
Methods of actuation include thermal actuation, electrostatic actuation, thermopneumatic
actuation, and peizoelectric actuation. On the other hand, passive valves do not include any
7
actuation, and are designed to give a high flow rate in one direction and a small flow rate in the
opposite direction. Passive valves find their main application in mechanical micropumps,
because it is necessary for valves to direct the flow of fluid through these pumps. Passive valves
include cantilever valves, diaphragm valves, bivalvular valves, and diffuser nozzle valve (Koch
et al, 2000).
Cantilever valves generally consist of a thin flap, which controls the flow through the
valve system, sitting on top of a duct. When the pressure is lower downstream from the valve
than upstream, the cantilever bends into an open state, allowing fluids to pass through. However,
when the pressure is higher upstream from the valve, the flap is pressed against the valve seat
and is forced to be in the closed state. Diaphragm valves are similar in principle to the cantilever
valves, but they incorporate diaphragms for controlling the flow. In essence, the fluid must
deflect the diaphragm with sufficient pressure in order to pass through the valve. The bivalvular
valves are made with two flaps, which close on each other to form a “V” shape. This type of
valve is analogous to double doors, which open from the center (i.e. one swings open to the right,
while the other swings open to the left). The diffuser nozzle valve is different because it makes
possible two different flow regimes. If the taper angle is small, the diffuser direction is preferred
compared to the nozzle direction. However, if the angle is enlarged, the flow changes to the
nozzle direction (Koch et al, 2000).
Materials
When intense research into microfluidics began in the early 1990s, the material of choice
for many microfluidic devices was silicon. Silicon was readily available and there was an
abundance of well-understood processing techniques because of the growing interest in
microelectronics. As biomedical uses for microfluidic devices became more apparent, many of
the researchers in the field were drawn to plastics as a low-cost, low complexity alternative to
silicon microfluidic devices. In addition, it was determined that silicon was not entirely bioinert,
making it highly undesirable for use in biomedical applications.
Plastics can be patterned easily through hot embossing and imprinting, both of which are
inexpensive compared to common processes used for silicon. The low cost of plastic devices
8
make them disposable; an important feature considering it is best to use microfluidic devices
only once to avoid contamination. Currently there are a staggering number of different materials
used to build microfluidic devices. The following section gives an overview of some of the more
common materials being used.
Polyimide is a commonly used polymer for microfluidic devices because it is a high
quality substrate into which complex microchannels can be easily machined. In addition, it is
easy to sputter metals such as Al, Ti, or Pt onto its surface. This can be extremely useful for
creating electrical contacts in microfluidic devices to induce flow with the use of an electrical
current (Nguyen, 2002).
Parylene is another polymer that is commonly used as a substrate and coating. Parylene
has desirable physical and electrical properties in combination with a low permeability to
moisture and low susceptibility to corrosion. In addition, a type of Parylene called Parylene D
has the ability to withstand high temperatures. Parylene’s properties make it an excellent
candidate for biomicrofluidic applications (Nguyen, 2002).
PDMS is perhaps the most commonly used polymer in the entire field of microfluidics.
Not only is it used as a structural material for microfluidic devices, but it is also used as a stamp
for microcontact printing and as a replica master for the micromolding processes. PDMS has as
low interfacial free energy, meaning most other polymers and fluids will not have an affinity to
stick to or react with its surface. In addition, PDMS is stable against humidity and a wide range
of temperatures. Its durability and elastic properties make it highly desirable as a stamp, as these
properties allow it to stick to non-planar surfaces (Fujii, 2002). Some of the main drawbacks of
using PDMS for biomicrofluidic devices are that due to its permeability it has the tendency to
swell when it comes in contact with some organic solvents. This puts limitations on the
experiments that researchers can perform using PDMS devices. Another disadvantage of using
PDMS is that its elastic properties can cause problems when the aspect ratio of a structure is too
high or too low. Specifically, regions of high aspect ratios can attach to each other, an effect
known as pairing, while regions of low aspect ratios can sag dramatically (Nguyen, 2002).
Diamond-Like Carbon films (DLC) have been successfully used as structural materials
for microfluidic devices. DLC films have high hardness and are chemically inert, making them
useful for devices where highly toxic or corrosive fluids are being studied (Massi, 2003).
9
Properties of materials used for building devices (valves, pumps, etc.) other than simply
microchannels can vary greatly from one device to the next. In most cases, a material is selected
based on the specific operation of the device. This leads to an enormous number of different
materials being used. For valves specifically, it is an extremely common practice for researchers
to choose materials in which a volume changed can be induced. Conductive polymers, paraffin,
and polythethylene glycol (PEG) are three materials with in which such a volume change can be
induced.
Conductive polymers, also known as conjugated polymers, are gaining the attention of
many researchers as an inexpensive and effective way to create microfluidic devices such as
micropumps and microactuators (Nguyen 2002). Polymers are classified as conjugated when
they have alternating single and double carbon bonds throughout the length of the backbone
chain. The structure of the chain creates a bandgap within the polymer, and for this reason
conjugated polymers are sometimes referred to as “organic semiconductors.” These polymers
have the same behavior as inorganic polymers such as silicon; in other words, the conductivity of
the polymer depends on its doping level. The doping level of a conjugated polymer in turn
depends on its oxidation state. In one specific case, Smela et al. have discovered ways to cause a
polymer to undergo volume changes based on its doping level. The first step of creating a
polymer capable of undergoing volume change is oxidizing (doping) the polymer. To neutralize
the (+) charge on the doped polymer, a large, immobile anion is introduced to the polymer by
placing the polymer in contact with an electrolyte solution. Upon reduction (undoping), a cation
enters the polymer to neutralize the charge. The volume of the polymer increases as a result of
the cation entering. In the case of small immobile anion initially located within the polymer,
there is a decrease in the volume of the polymer upon reduction (undoping). Both of these cases
are represented visually by the figure below. The polymer Polypyrrole was used by Smela et al.
because of the fact that it is highly stable in aqueous environments. In addition, it should also be
noted that the large anion used by Smela et al. was dodecylbenzenesulfonate (DBS). In both
cases, it is the movement of ions into and out of the polymer that create the volume change. This
volume change can be exploited to create valves and actuators suitable for use in microfluidic
devices (Smela, 2003).
10
Large Immobile Anion: P+(A-) + C+ + e-  P(AC)
Small Mobile Anion: P+(A-) + C+ + e-  P + A- + C+
Polyethylene glycol (PEG) (Mastrangelo, 2003) and paraffin (Klintberg, 2003) have been used in
similar ways to fabricate micropumps and actuators. The volume change associated with each of
these materials as result of their respective transformations from solid to liquid phases can be
exploited to create valves in microfluidic devices.
While the exploitation of volume changes in materials is one of the most common ways
to create valves and actuators, many devices are being created using other innovative methods.
Low temperature co-fired ceramic tapes, for example, have been used to induce flow patterns
and create pumps in microfluidic devices. LTCC tapes are highly dielectric and the layered
manufacturing process used to create these films makes it easy to integrate complex conduits and
metallic paths within them. By using magneto-hydrodynamics, a process in which magnets are
used to induce flow, researchers have been able to create complex flow patterns with LTCC
tapes. The complex flow patterns have proven to be useful for mixing and stirring fluids in
microfluidic devices (Zhong, 2002).
As devices built from certain materials prove to be more useful than others, the variation
in materials used for biomicrofluidics will undoubtedly decrease. Until that time, the trend of
using specific materials for specific devices will continue unhindered.
Process Overview
Within a microfluidic device there are channels pumps and valves. For each component
there are a set of processes that are used to create that component. It is the combination of all
these processes that creates the device.
The key element for any microfluidic device is the fluid channels. The channels are
created by a process called soft lithography. Soft lithography begins with a silicon wafer. This
wafer is patterned using a negative photoresist.
11
Patterning of the silicon substrate (Fisher, 2003)
The patterned silicon is then used as a mold for the material to be used. The soft, in soft
lithography refers to the soft polymer material that is used. The polymer is then cured and
peeled from the mold.
Curing and peeling of PDMS (Fisher, 2003)
The product is either then used directly for the device, or is used as a stamp or printing surface.
The method to create the closed channels essential to microfluidics is embedded in the patterned
silicon mold (Fisher, 2003).
Another process used for creating microfluidic systems, especially in valves, is
micromachining. Micromachining consists of both surface micromachining and bulk micro
machining. Both of theses terms describe a family of processes that occur in micro systems.
12
Bulk micromachining affects the profile of the material. Etching is an example of bulk
micromachining because materials are removed from the bulk of the material. Both wet and dry
etching can be used, however, wet etching is more common.
In surface micromachining thin layers are added to the surface of the wafer or other
substrate. Deposition is included in this category as well as other techniques like microcontact
printing (Whitesides, 2003). In microcontact printing, the previously described cured PDMS is
used as a stamp, to deposit thin layers in patterns.
While other more specific processes occur for the production of microfluidic devices,
these processes outline the general method by which these devices are made.
Fabrication of a Valve
Each different type of valve is processed differently. All valves are processed through a
combination of micromachining techniques. The order and number of steps is dependent on the
type of valve. For a detailed explanation of process, the diaphragm check valve will be
discussed.
(a)
(b)
(c)
Examples of diaphragm check valves ((a)Xie, 2001 (b)Whitesides, 1998 (c)Koch, 2000)
This process will focus on valves similar to (a) and (c). Both of these valves begin with
the same step. This step is to etch holes into the silicon on the bottom surface of the valve. This
process is done using double-sided alignment (Xie, 2001). For valve (a) the silicon is not fully
13
etched through, but rather a thin membrane is left. After etching there is a metallic layer,
chromium or gold in this case, evaporated onto the silicon surface. To help with adhesion the
entire surface is lightly etched with BrF3 vapor.
Etched silicon with deposited gold (Xie, 2001)
Next, a photo resist layer is patterned and deposited, and the polymer layer is deposited on top of
that.
Deposited photoresist (pink) and polymer (green) (Xie, 2001)
The final step involves etching the silicon membrane at the bottom surface and dissolving
the photoresist in acetone. For this particular valve the seal between the metal and the polymer
must also be broken to ensure proper functioning.
Valve (c) is processed in a similar fashion with a few differences, the primary difference
being the lack of the metal seal. After the etching of the silicon a phosphosilicate glass is
deposited by chemical vapor deposition. Photoresist is patterned and applied on top of the glass
and dry etched.
Etched glass with photoresist on silicon substrate (Koch, 2000)
Poly silicon is then deposited and a positive photoresist applied on top. The silicon is then
etched.
14
Deposited poly silicon and resist after etching (Koch, 2000)
The last step is etching the sacrificial layers. To protect the polysilicon a nitride is deposited
using chemical vapor deposition. The system is then etched using KOH. Care should be taken
to ensure the etching stops at the glass (Koch, 2000).
Final valve (Koch, 2000)
The specific processes between different types of diaphragm valves change. The overall process
is the same, but the number of steps involved can vary.
Future of Microfluidics
The goal of microfluidics is to take the equipment needed for everyday chemistry and
biology procedures and shrink it to a system the size of a postage stamp. The advantages of this
branch of biotechnology include increased speed, accuracy and ability of testing and decreased
costs. One example of the type of improvements that are waiting science in the field of
microfluidics is with the sorting of DNA-type samples. To sort something like proteins or DNA
into different sizes (when done by electrophoresis) takes about 30 minutes on a bench but less
than 30 seconds on a chip. Also, volume measurements in microfluidic systems are more
accurate, which cuts down on the error involved.
Along with the continuous downscaling of these devices comes an integrated problem of
mixing fluids on the nanoscale. With only laminar flow at this level, liquids want to flow next to
15
each other without mixing. Although this phenomenon is often times desired, processes and
designs are being developed for the times that it is not. One design involves adding ridges to the
sides of the channels to force the liquid to swirl as the center folds in on itself and mixes (Knight,
2002). Another method is done with a shaking of the liquid in the device to induce mixing sooner
than would occur naturally in the system (Knight, 2002).
Small ridges along the channel walls can force mixing by a kneading motion (Knight, 2002).
The future of microfluidics serves not only to bring the size of the lab to be able to exist
on a microchip, but also to bring to skill of the laboratory technician to exist within the properties
and abilities of the device. This branch of research is still in its beginning stage and shows huge
promise with its integration into both science in the lab and science at home. Researchers will
continue to strive to increase the range of tests that can be performed at the micro level and the
accuracy and speed with which these tests are performed.
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