BN4404 - BioMEMS, Yong Zhang, NUS

Course description
This module will provide students with background and basic knowledge of
biomedical microelectromechanical systems (BioMEMS) and introduce some
useful techniques as well. Students will have a basic understanding of the
principles, current state and prospects of BioMEMS and will be able to tackle
simple problems in BioMEMS using what they have learned. The module will
focus on major topics such as microfabrication technologies, biological
materials, surface modification, biochips, and the frontiers in BioMEMS. At the
end of this module, the students will gain an understanding of standard
microfabrication techniques used in BioMEMS and know the major classes,
components, and applications of biomedical microsystems and demonstrate an
understanding of the fundamental principles.
 BN4404 - BioMEMS, Yong Zhang, NUS

Text & Readings

Author Madou, Marc J.
Title Fundamentals of microfabrication : the science of
miniaturization Imprint Boca Raton, FL : CRC Press, 2001.
Edition 2nd ed.

Supplementary

Grading
Grades are based on quizzes and final exam. Exam materials come
from lectures and reading assignments (if any).

CA, 40% (2 quizzes)

Final exam, 60%.
 BN4404 - BioMEMS, Yong Zhang, NUS

Introduction to BioMEMS
 BN4404 - BioMEMS, Yong Zhang, NUS

Outline

 Why Small

 Introduction of MEMS (Micro-Electro-Mechanical

System)

 From MEMS to BioMEMS (MEMS for biomedical

applications)
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is beautiful

Metal oxide on silicon Stained glass Feather

Fly eyes Honeycomb

 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
Biomimetics: Lotus effect
• most efficient self-cleaning plant
• mimicked in paints and other surface
coatings

water
repellant?
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
Biomimetics: Butterfly Wings
• Butterflies have irridescent colours
formed by photonic crystals.

Butterfly Nanostructure Inspiration

• To reflect visible, UV and IR radiation for cooling or transmit
certain wavelengths of light for warming.
• To be used in solar cells
• To be used for bar coding or other functions
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
Biomimetics: Desert Beetle
• Water vapor harvesting: The wing covers of the Namib desert
beetle gather water from the air using nanoscale bumps
https://www.youtube.com/watch?v=Lyz8xuMCcOg
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
Biomimetics: Gecko
• Self-cleaning, re-attachable dry adhesives, named ‘gecko tape’
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful

Security lock
Enabled code wheel -- One of six code wheels is shown here in
an enabled position after the correct code was entered. The wheel
is 300 microns in diameter, about the size of the period at the end
of a sentence in a standard newspaper.
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful

The Incredible Shrinking Transistor

Scientists have already shown that carbon nanotubes can operate as
transistors—electrical switches—when shrunk down to fewer than 10
nanometers, about 1,000 times smaller than a human hair. And the thinking is
that we can shrink these tiny tubes much further. But below the 10nm range,
carbon nanotubes haven’t maintained the performance of larger transistors—
until now. IBM has shown that it can build 10-nanometer carbon nanotubes
without sacrificing speed.
With the Tools of the Nanotechnology Trade Becoming Better Defined, the
Ability to Create New Materials And Devices By Placing Every Atom and
Molecule in the Right Place Is Moving Closer to Reality. - Ralph C. Merkle
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
First integrated circuit General Microelectronics1964
1958 J.S. Kilby (Nobel prize 2000)

The first integrated circuit, made by Texas 4 MOS IC BCD-Binary Converter (TL);
Instruments, contained a grand total of six Dual 20 Bit Shift Reg (TR); Dual 4-Input
components. (very primitive!) Gate (BL); Dual J-K Flip-Flop (BR)
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
Electronic devices are becoming smaller !!

Past
Shared computing thousands of
people sharing a mainframe computer

Present
Personal computing

Future
Ubiquitous computing thousands of computers sharing each and
everyone of us; computers embedded in walls, chairs, clothing, light
switches, cars….; characterized by the connection of things in the
world with computation.
 BN4404 - BioMEMS, Yong Zhang, NUS

Small is useful
The incredible shrinking disk drive

1956 IBM Ramac 305 2000 IBM Microdrive

5 MB 1 GB
50 x 24” dia. Disks 1 x 1” disk
weighs “a ton” < 1 oz.
$50,000 $500

Control over materials nanostructure

Sensitivity and resolution of heads

Magnetic storage GMR heads

Nanostructured medium
 BN4404 - BioMEMS, Yong Zhang, NUS

MEMS Applications

Automobiles, Biotechnology,
Aerospace, Communication…
 BN4404 - BioMEMS, Yong Zhang, NUS

Market
 BN4404 - BioMEMS, Yong Zhang, NUS

What is MEMS

Other names: Microdevices, Micro Systems, Micromachines, …

 BN4404 - BioMEMS, Yong Zhang, NUS

Why MEMS
There’s Plenty of Room At the Bottom
Richard P. Feynman, APS Meeting, Caltech, 1959
 … I’d like to describe a field, in which little has been done, but in which enormous
amount can be done.
 … What I want to talk about is the problem of manipulating and controlling things
on a small scale.
 … it would have an enormous number of technical applications.
 … equipment won’t simply be scaled down; it has to be redesigned.
TECHNOLOGY
 … how to make such a device? One possibility would be to evaporate the
materials.
 … We can reverse the lenses of the electron microscope in order to demagnify as
well as magnify. A source of ions, sent through the microscope lenses in reverse,
could be focused to a very small spot.
 … why can’t we drill holes, cut things, solder things, stamp things out, mold
different shapes all at an infinitesimal level?
 BN4404 - BioMEMS, Yong Zhang, NUS

Why MEMS
 Advantages:  Challenges
• Miniaturization • Packaging
 low per-unit cost, reduction of  very diversified – no
power budget, faster device, standard packaging
increased selectivity and method
sensitivity, wider dynamic • Testing
range, minimal invasive (e.g.,
• Power sources
microfabricated needles)
• Multidisciplinary (collaboration)
• Potential to integrate with circuits
• The ability to fabricate arrays of
devices
• Batch fabrication processing
• New functions There’s plenty of room at the
• MEMS has been proven to be bottom! (R. Feynman)
commercially viable
 pressure sensors, ink-jet
nozzles
 BN4404 - BioMEMS, Yong Zhang, NUS

Scales & Dimensions

 BN4404 - BioMEMS, Yong Zhang, NUS

The Incredible Tininess of Nano

A million nanometers Nanometers
The pinhead sized Ten shoulder-to-shoulder
patch of this thumb is a hydrogen atoms span 1
million nanometers nanometer. DNA molecules
across. are about 2.5 nanometers
wide.

Thousands of Less than a

Billions of nanometers nanometer
nanometers Biological cells have Individual atoms are up
A two meter tall male is diameters in the range of to a few tenths of a
two billion nanometers. thousands of nanometers. nanometer in diameter.

A human hair is approximately 100,000 nm.

 BN4404 - BioMEMS, Yong Zhang, NUS

From MEMS to BioMEMS

‘Miniaturization engineering’ is a
more appropriate name than
MEMS, but the name MEMS is
more popular. It involves a good
understanding of scaling laws,
different manufacturing
methods and materials. Initially
it involved mostly Si and
mechanical sensors (e.g.,
pressure, acceleration, etc).

Miniaturization engineering or MEMS applied to biotechnology is

called BIOMEMS.
 BN4404 - BioMEMS, Yong Zhang, NUS

Advantages of Micro System

 Small length scale

 Close to some biological length scale
 Less sample / reagent required
 High surface-to-volume ratio
 Small thermal mass
 Shorter processing time
 Parallel operation possible – high throughput
 Integration possible
 Automation possible
 Disposable
BN4404 - BioMEMS, Yong Zhang, NUS
 BN4404 - BioMEMS, Yong Zhang, NUS

BioMEMS Applications
 Medical diagnosis and treatment
‒ Implantable sensors and computers for health monitoring,
Minimally invasive microsurgery instruments
 Biological analysis
‒ Microtools for study at cellular scale
‒ DNA amplification (PCR)
‒ DNA microarrays
 Chemical analysis and synthesis
 Drug discovery, synthesis and delivery
 BN4404 - BioMEMS, Yong Zhang, NUS

Microarray Chips
 BN4404 - BioMEMS, Yong Zhang, NUS

Microarray Chips

Test tubes Microwell plate Microarray Microsphere-based

array

• The ability to simultaneously detect multiple biomarkers

• Antibodies are most often used in a sandwich immunoassay fashion and
are immobilized on chips as “planar arrays” or conjugated to micro beads
as “suspension arrays.”
 BN4404 - BioMEMS, Yong Zhang, NUS

DNA Microarray

 Control Cells (left) and Target Cells (right)

 Harvest mRNA from both cell groups
 Make fluorescently labeled cDNA, with green
and red dyes
An array of oligonucleotide  Hybridize the cDNA with oligonucleotide probes
 Reading the result using a scanner
(20~80-mer oligos) probes
 BN4404 - BioMEMS, Yong Zhang, NUS

DNA Microarray

Array Labeled Sample

(Probe) (Target)
Hybridization

Hybridized Array

Scanning

Images

Quantification

Raw Data
 BN4404 - BioMEMS, Yong Zhang, NUS

DNA Microarray Biochips

Microarray chip #1
(How to fabricate oligo microarrays)
(how many masks?)

https://www.youtube.com/watch?v=Z_KNhD1jz-k
 BN4404 - BioMEMS, Yong Zhang, NUS

DNA Microarray Biochips

Microarray chip #2
 BN4404 - BioMEMS, Yong Zhang, NUS

DNA Microarray Biochips

Microarray chip #3
 BN4404 - BioMEMS, Yong Zhang, NUS

Protein Microarray

Protein microarrays
Small molecule – protein interactions
Protein – protein interactions
High throughput screening of compounds
 BN4404 - BioMEMS, Yong Zhang, NUS

Bead Microarray

1. Bead with capture antibody

2. Capture antibody binds analyte

3. Fluorescence labelled reporter

antibody binds to capture analyte Laser
A

Laser
4. Bead ID and reporter quantity B
determined by laser detector
 BN4404 - BioMEMS, Yong Zhang, NUS

Bead Microarray
 BN4404 - BioMEMS, Yong Zhang, NUS

Bead Microarray

Beads in Optical Fiber Bundle

solution

Encoding and decoding technology  positional registration of probes

 BN4404 - BioMEMS, Yong Zhang, NUS

Microfluidics
Microfluidics deals with the behavior, precise control and manipulation of fluids
that are geometrically constrained to a small, typically sub-millimeter, scale.

Filter animation
 BN4404 - BioMEMS, Yong Zhang, NUS

Microfluidics

Can make valves, pumps, etc.

“lab-on-a-chip”
 PCR reaction
 Gel electrophoresis
 Sensors and actuators
 …

DNA analysis chip (M.A. Burns, U Mich, 1998)

 BN4404 - BioMEMS, Yong Zhang, NUS

MicroReactors

Glass Microreactor. The channels

of the chip in the picture are 150
µm wide and 150 µm deep

Why microreactors?
Small volume
Laminar flow (reproducible results)
Rapid mass diffusion
Rapid heat transfer
 BN4404 - BioMEMS, Yong Zhang, NUS

Liquid-phase reactor with heat exchangers and temperature sensors

 BN4404 - BioMEMS, Yong Zhang, NUS

Microreservoirs for drug delivery

 BN4404 - BioMEMS, Yong Zhang, NUS

http://www.biochipnet.com/
 BN4404 - BioMEMS, Yong Zhang, NUS

PCR Microchips

PCR animation
 Continuous
 3 temperature zones
 High temperature to split
strands
 Medium temperature to
extend
 Low temperature to
anneal (primers in high
concentration)
 Repeat
 BN4404 - BioMEMS, Yong Zhang, NUS

With channels, chambers, valves, pumps,

heaters, …
 BN4404 - BioMEMS, Yong Zhang, NUS

Microfluidics
 BN4404 - BioMEMS, Yong Zhang, NUS

µm
10
3 Input channels

3 Output
channels
 BN4404 - BioMEMS, Yong Zhang, NUS

Microbubble formation
Applications: Cell encapsulation (tissue engineering, diabetes
treatment), Drug delivery, Lab-on-a-bead (bubble), etc.
http://www.youtube.com/watch?v=lnVB9MauOrU
http://www.youtube.com/watch?gl=SG&v=1Pj9pH24NF0&hl=en-GB
http://www.youtube.com/watch?v=NwXiwNgNRXQ
BN4404 - BioMEMS, Yong Zhang, NUS
BN4404 - BioMEMS, Yong Zhang, NUS
 BN4404 - BioMEMS, Yong Zhang, NUS

Classification

Analyte

Bioreceptor

Bioreceptors Transducers
Molecular
recognition

Electrochemical

Mass-based
Antibody

Enzyme

Protein

Tissue
Transducer

Optical
DNA

Other
Cell
Signal detec-
tion & analysis
 BN4404 - BioMEMS, Yong Zhang, NUS

Biosensors

Requirements
 High degree of selectivity and
sensitivity
 Rapid response
 Repeatability/reproducibility
 Rapid recovery
 Stability
 Long lifetime
 Internal calibration and referencing
 Reagentless – no auxiliary reagents
required
 No sample preparation
 BN4404 - BioMEMS, Yong Zhang, NUS

Biosensors

Immuno-biosensor Toxin Assay

Antigen-antibody Nanosensors
interaction
 BN4404 - BioMEMS, Yong Zhang, NUS

Milestone
 BN4404 - BioMEMS, Yong Zhang, NUS

Milestone
DRAM 1/2 pitch, 3-yr cycle DRAM 1/2 pitch, 2-yr cycle MPU gate length
100
nm

10
nm

Soon, all microchips will be nanoscale devices

1
nm1999 2003 2007 2011 2015 2019 2023 2027 2031 2035 2039 2043 2047

CONCLUSION: The semiconductor industry already has a large effort underway for producing devices
whose minimum design features are 100nm. It is only a matter of time before nearly all chips are nanotech
devices. Hence, there is substantial value in synchronizing the large research effort already funded by
industry & driven by the International Technology Roadmap for Semiconductors (ITRS), with the large
research effort expected to be funded worldwide. Semiconductor Research Corporation