Chapter 1: Introduction.
Université de Lyon, FRANCE
Stansan International Group
Chapter 1: Introduction.
Chapter 2 : Basic principles of Microfluidics.
Chapter 3 : Basis of molecular biology and analytical tools.
Chapter 4 : Micromanufacturing.
Chapter 5 : Lab-on-a-Chip & applications.
Chapter 6 : Cancer diagnostics and monitoring.
WHAT IS « MICROSYSTEM » ?
MICROSYSTEM = microelectronic circuit + sensor(s) and/or
Any engineering system that performs electrical and
« other » functions, with components in micrometer scale is
a MICROSYSTEM. (1 µm = 1/10 of human hair)
MICROSYSTEM products may include :
● Micro sensors (pressure, acceleration, acoustic wave,
biomedical, chemical, optical, radiation, thermal, etc.)
● Micro actuators (valves, pumps and microfluidics; microneedles for blood sampling or drug injection,
electrical and optical relays and switches;
grippers, tweezers and tongs; linear and rotary motors, etc.)
WHAT IS « MEMS » ?
MEMS = Micro Electro-Mechanical
This term is often used in USA and some other countries,
even in connection to systems which do not contain
mechanical parts in sensors and actuators.
e.g. BioMems, BioNems: MEMS/NEMS ‘bio’logical applications
In practice : MEMS = MICROSYSTEM
European Commission uses the abreviation MST for MICROSYSTEMS
or microsystem's technology.
In this lecture we will speak about Bio-Microsystems
MICROSYSTEMS – contain parts in the scale of micrometers
NANOSYSTEMS – contain parts in the scale of nanometers (<100 nm)
What are biosensors?
A biosensor is an analytical device which converts a
biological response into an electrical signal.
Schematic diagram showing the main components of a biosensor.
The biocatalyst (a) converts the substrate to product. This reaction
is determined by the transducer (b) which converts it to an electrical
signal. The output from the transducer is amplified (c), processed
(d) and displayed (e).
What are biosensors?
Biosensors sometimes are broadly defined as any
device designed to gather biological information,
such as the presence of a particular biomolecule, and
convert it into an analytical signal. This report uses
the stricter definition of biosensors used by The
National Research Council (NRC), part of the U.S.
National Academy of Sciences.
The NRC has defined a biosensor as a detection
device that incorporates a) a living organism or
product derived from living systems (e.g., an enzyme
or an antibody) and b) a transducer to provide an
indication, signal, or other form of recognition of the
presence of a specific substance in the environment.
What is a "miner's canary"?
The first bio-chemical sensor !
"Miner's canary" refers to the birds once used by miners to test the purity of the air in the
mines. At least three birds would be taken underground by a group of miners. If any one bird
showed signs of distress, it was taken as an indication that dangerously high levels of carbon
monoxide existed. Today, miners use sophisticated sensing equipment instead of canaries.
Biosensors - transduction
Most Biosensors work on the principle of interactions between the
biomolecules in the sample and the analyte (usually in solution)
in the sensor. Signal transduction is carried out by the sensing
element, which may use a wide range of different techniques.
Diabetes is a metabolic disorder, in which the pancreas underproduces
or does not produce insulin. Because cells need insulin to absorb
blood sugar (glucose) for their energy needs, the cells of people with
diabetes suffer from a shortage of glucose, while glucose levels build
up in the blood.
The disease is a major world health problem. It is estimated that there
are over 150 million diabetics worldwide. Worse still, incidence of the
disease has risen by an alarming 11% over the last five years, and a
further doubling of new cases is predicted in the next 25 years.
There are three types of diabetes:
Type 1 Diabetes of the young. Approximately 10 % of diabetics have Type 1.
Type 2 Diabetes of older patients. 90 % of people with diabetes have Type 2.
Type 3 Gestational diabetes is a temporary condition that occurs during
pregnancy. It affects 4 % of pregnancies with an risk of developing diabetes for
both mother and child.
When left untreated or improperly managed, diabetes is one of the
leading causes of death by disease.
Despite the many technological advances in biosensor and the
introduction of many different biosensors, glucose biosensors still
account for approximately 85% of the current world market, which
has recently been estimated to be around $5 billion.
There are, currently, over 40 blood glucose meters on the market.
The lion’s share of the market is shared between Roche Diagnostics,
Lifescan, Abbott and Bayer.
Many transducers could be used for the measurement of glucose, but
electrochemistry has dominated. This is partially historical, but the
primary reason is that they offer suitable sensitivity, reproducibility
and can be manufactured in great volumes at low cost.
A sensor for measuring the glucose
concentration of a patient.
CNT based Field Effect Transistor
for Glucose Detection
SWNT - single-walled carbon nanotubes
Example of Home Blood Glucose
The main biosensors products sold by Roche are the Accu-Chek
blood glucose monitoring systems. Accu-Chek Active is one of the
fastest meters in the market, requiring just 5 seconds to obtain a
reading. It features an automatic on/off function, a 1 µl blood sample
requirement, 200 value memory storage (with times and dates, 7 and
14 day averaging and an underdosing monitor that detects when
insufficient blood has been applied.
Ion-Selective Field Effect Transistors
Enzyme membranes are coated on the ion-selective gates of
Field Effect Transistors, responding to the electrical potential
change via the current output. Thus, these are potentiometric
devices although they directly produce changes in the electric
current. The main advantage of such devices is their extremely
small size (<< 0.1 mm2) which allows cheap mass-produced
fabrication using integrated circuit technology.
Ion-Selective Biosensor which Use
A chip on your fingertip may someday measure and transmit data on
your body temperature. An array of chips attached to your body may
provide additional information on blood pressure, oxygen level, and
pulse rate. This type of medical telesensor, which is being developed
at ORNL for military troops in combat zones, will report measurements
of vital functions to remote recorders. The goal is to develop an array
of chips to collectively monitor bodily functions.
These medical telesensors would send
physiological data by wireless transmission to
an intelligent monitor on another soldier's
helmet. The monitor could alert medics if the
data showed that the soldier's condition fit one
of five levels of trauma. The monitor also would
receive and transmit global satellite positioning
data to help medics locate the wounded
Biosensors printed directly onto clothing
Joseph Wang and colleagues at the University of California San
Diego, La Jolla have devloped a method for printing biosensors
directly onto clothing. To form the sensors, Wang screenprinted carbon electrode arrays directly onto the elastic bands
of mens' underwear. The tight contact and direct exposure to
the skin allows hydrogen peroxide and the enzyme NADH,
which are both associated with numerous biomedical
processes, to be monitored using the sensor.
sensor + control
The global market for biosensors and other bioelectronics
is projected to grow from $6.1 billion in 2004 to $8.2 billion
in 2009, at an AAGR (average annual growth rate) of about
Learning From the Experiences in Microelectronics
invention of transistors by three Nobel Laureates,
W.Schockley, J. Bardeen and W.H. Brattain of Bell
Laboratories in 1947.
concept of Integrated Circuits (IC) in 1955, and the
production of the first IC few years later by Jack
Kilby of Texas Instruments.
Moore’s law (1964) - number of transistors per chip
doubles every 1.5-2 years
ICs have made possible for miniaturization of many
devices and engineering systems in the last 50
Learning From the Experiences in Mechanical
Microsystems and Microfabrication
1959: Richard Feyman says, “There is plenty of room at the
1969: Westinghouse creates the “Resonant Gate FET.”
1970s: Bulk-etched silicon wafers used as pressure sensors
1982: Kurt Petersen published “Silicon as a Structural material.”
1980s: Early experiments in surface- micromachined polysilicon.
Micromachining leverages the micro-electronic industry in late
1990s: Introductionof new materials (piezoelectric, piezoresistive,
WHAT IS « MICRO/NANOFABRICATION » ?
Micro/nano fabrication: it is a process used to
construct physical objects with dimensions in the
micro/nano-metre to millimeter range.
Micro/nano objects or devices are comprised of a
range of miniature structures, including moving parts
(cantilevers and diaphragms), static structures (flow
channels and wells), chemically sensitive surfaces
(proteins and cells) and electrical devices (resistors
In contrast to planar microelectronic devices,
micro/nanosystemns contains ALWAYS 3-dimmensinal
by machine tools
Evolution of Microfabrication
● There is no machine tool with today’s technology can produce
microsystem components of the size in the micrometer scale (or in mm
● The microfabrication techniques originally developed for producing
integrated circuit (IC) components can help.
● The complex geometry of microsystem components can only be
produced by various complex physical-chemical processes.
● Despite the fact that many microelectronics technologies can be
used to fabricate silicon-based MEMS components, microsystems
engineering requires the application of principles involving
multidisciplines in science and engineering (new materials and new
● Team effort involving multi-discipline of science and engineering is the
key to success for any microsystem industry.
(Courtesy of Denso Research Laboratories,
Denso Corporation, Aichi, Japan)
A micro gear-train
(Sandia National Laboratories)
WHAT IS « MICROFLUIDICS » ?
Microfluidics deals with the behavior, precise control and
manipulation of fluids that are geometrically constrained to a
small, typically sub-millimeter, scale. Typically, micro means
one of the following features:
small volumes (nl, pl, fl)
It is a multidisciplinary field intersecting engineering, physics,
chemistry, microtechnology and biotechnology, with practical
applications to the design of systems in which such small volumes
of fluids will be used. Microfluidics emerged in the beginning of the
1980s and is used in the development of inkjet printheads and in the
beginning of 1990s for bio-chemical analysis. DNA chips, lab-on-achip technology, micro-propulsion, and micro-thermal technologies.
MICROFLUIDICS - key application areas
To date, the most successful commercial
microfluidics is the inkjet printhead.
Advances in microfluidics technology are revolutionizing
molecular biology procedures for enzymatic analysis (e.g.,
glucose and lactate assays), DNA analysis (e.g., polymerase
chain reaction and high-throughput sequencing), and proteomics.
The basic idea of microfluidic biochips is to integrate assay
operations such as detection, as well as sample pre-treatment
and sample preparation on one chip.
An emerging application area for biochips is clinical pathology,
especially the immediate point-of-care diagnosis of diseases.
In addition, microfluidics-based devices, capable of continuous
sampling and real-time testing of air/water or food samples for
biochemical toxins and other dangerous pathogens, can serve as
an always-on "bio-smoke alarm" for early warning.
Annual Microfluidics and Microsystem
publications across all journals
WHAT IS « Lab-on-a-Chip » ?
Lab-on-a-Chip are devices that integrate multiple laboratory
functions on a single chip of only millimeters to a few square
centimeters in size and that are capable of handling extremely small
fluid volumes down to pico liters.
Lab-on-a-chip devices belong to the family of MICROSYSTEMS.
Lab-on-a-chip devices are sometimes called "Micro Total Analysis
Lab-on-a-chip concept extends the simple sensor functionality and
includes the integration of pre-treatment steps, additional cleaning
and separation steps towards a complete laboratory analysis.
Lab-on-a-Chip devices emerged in early 1990s (Manz, A., 1990,
Sensors & Actuators B Chem., B1, 1-6, 244)
Examples of LOC Applications
Real-time PCR ;detect bacteria, viruses and cancers.
Immunoassay ; bacteria, viruses, cancers based on antigen-antibody
Dielectrophoresis : detecting cancer cells and bacteria.
Blood sample preparation ; can crack cells to extract DNA.
Cellular lab-on-a-chip for single-cell analysis.
Lab-on-a-chip technology may soon become an important part of efforts
to improve global health, particularly through the development of pointof-care testing devices.
Many researchers believe that LOC technology may be the key to
powerful new diagnostic instruments. The goal of these researchers is to
create microfluidic chips that will allow healthcare providers to perform
diagnostic tests such as immunoassays and nucleic acid assays with no
Lab-on-a-Chip : Possible Functional Blocks
The detection of protein cancer markers will be obtained here by
the integration on the Chip of the following blocks :
The most general block diagram of the Chip for the detection
of molecular cancer markers is the following :
Miniaturization Makes Engineering Sense !!!
• Small systems tend to move or stop more quickly due to low mechanical
inertia.It is thus ideal for precision movements and for rapid actuation.
• Miniaturized systems encounter less thermal distortion and mechanical
vibration due to low mass.
• Miniaturized devices are particularly suited for biomedical and aerospace
applications due to their minute sizes and weight.
• Small systems have higher dimensional stability at high temperature due
to low thermal expansion.
• Smaller size of the systems means less space requirements.
This allows the packaging of more components in a single device.
• Less material requirements mean low cost of production and
• Ready mass production in batches.
Market breakout for 1 st level packaged
Market breakout for 1 st level packaged
3 products make 70% of the market in 2009
– Read-Write (RW) heads
– Inkjet heads
– MEMS displays
3 other products making each over $1 billion in 2009
– Pressure sensors
– RF MEMS
– Inertial sensors
12 emerging or niche products each < $100m in 2009
Lab-on-a-Chip, Microreaction, chip cooler, inclinometers,
MEMS memories, MEMS fingerprints, liquid lenses,
microspectrometer, wafer probes, micro-mirrors for optical
processing, micro-pumps, micromotors, chemical analysis