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BioMEMS
EECS 509, Fall 2019
Course Introduction, Motivation, Administration

Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Class Information
 Lectures: M, W: 1:30-3:00pm, 3433 EECS

 Instructor:
Professor Euisik Yoon
Rm. 2400 EECS Building
Tel: (734) 615-4469
e-mail address: [email protected]
Office Hours: Fridays 3:00-4:00pm
Or by Appointment

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Course Pre-requisites
 College-level Physics, Biology, and Chemistry.
 Basic knowledge of microfabrication technology and MEMS
devices (EECS 414 or equivalent).
 It is expected that students who take this course have already
taken EECS 414 or equivalent courses. However, due to the
interdisciplinary nature of BioMEMS, we would like to allow
students from MANY engineering or science disciplines to be
able to take this course. This prerequisite requirement can be
waived from the permission of the lecturer.
 This course is intended for graduate students, as a part of five
MEMS course series offered in a comprehensive MEMS
educational program developed by the Engineering Research
Center in Wireless Integrated MicroSensing and Microsystems
(WIMS2, http://wims2.org/).

EECS 509 BioMEMS 3

Curriculum on MEMS/Microsystems
• Train students from different
disciplines in Microsystems Engineering & Science
• Modular courses
Students (Grad & UG)
Key:
• Multi-department, multi- Undergraduate
university curriculum
• Distance learning
EECS 414: Graduate
• Students will get both
technology and analytical Introduction to MEMS
Fall
training (at all levels)

EECS 425 EECS 514 EECS 515

MEMS/IC Lab Adv. MEMS Dev & Tech. Integrated µSystems
Winter Winter Fall

EECS 509
BioMEMS • Non-Si Tech. Other Courses:
• RF MEMS Manufacturing
EECS 510 • Optical Projects
RF MEMS
MEMS Business
EECS 830 • BioMEMS Misc. Technical
Societal Impact
Fall (every other year)
• Etc.
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Text and Reference Books

Optional textbook (Strongly recommended but not required):
- Albert Folch, Introduction to BioMEMS, CRC Press, 2013
- Ellis Meng, Biomedical Microsystems, John Wiley & Sons, Inc., New York,
2011
•Lecture Notes: Lecture notes and other supplementary materials
provided through the web.
Reference textbooks:
- Gregory T.A. Kovacs, Micromachined Transducers Sourcebook, McGraw Hill,
1998
- Stephen D. Senturia, Microsystem Design, Kluwer Academic Publishers, 2000
- S. M. Sze, ed., Semiconductor Sensors. New York: John Wiley, 1994.
- R. S. Muller, et.al., Microsensors. New York: IEEE Press, 1991.
- M. Madou, Fundamental of Microfabrication, CRC Press, Inc. Boca Raton, FL.,
1997
- M. Elwensoek, H. Jansen, "Silicon Micromachining," Kluwer Academic Publishers,
2001
- J.W. Gardner, “Microsensors – Principles and Applications,” John Wiley & Sons,
1994

EECS 509 BioMEMS 5

Journals and Other Reading Materials

 K.D. Wise, ed., Micromachined Sensors and Sensing Systems, IEEE Proceedings, Special issue, August
1998.
 Lab on Chip, especially review papers.
 Nature Biotechnology, Nature Methods, PNAS, Science, Anal Chem, etc. Some issues contain many of the
seminal papers in the field.
 IEEE Transactions on Biomedical Engineering. You can find good implantable biosensor papers.
 Digest of Technical Papers, International Conferences on Minaturized Systems for Chemistry and Life
Science (MicroTAS). You can find good papers on microfluidic technologies and bioassay chips
 Digest of Technical Papers, International Conferences on Solid-State Sensors and Actuators (Transducers).
This conference is held every other year. 1985 to 2011.
 Digest of Technical Papers, Solid-State Sensor and Actuator Workshop (Hilton Head, SC Series), 1984
through 2012, every other year.
 Proceedings, IEEE Micro Electro Mechanical Systems Workshop (MEMS Conference), 1987 to 2013
 Digests of Technical Papers, IEEE International Electron Devices Meetings (IEDM). This conference
contains many of the seminal papers on solid-state sensors and tracks the development of this and some of
the other sensor technologies over the years.
 Digests of Technical Papers, IEEE International Solid-State Circuits Conference (ISSCC). This conference
has also served as the focal point for leading edge work, particularly on implantable microsystem
implementations.
 IEEE/ASME Journal of Micro Electro Mechanical Systems (IEEE JMEMS), published by the Institute for
Electrical and Electronics Engineers. See IEEE website at www.ieee.org
 Sensors and Actuators Journal [A (Physical), B (Chemical), and C (Materials)], published by Elsevier
Publishing, http://www.elsevier.com/inca/publications

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Course Web Site

 All course materials will be accessible through the web for all
registered students.
 Please check the website often and read instructions.
Discussions
and answers to many questions will be posted as necessary and
you are responsible to check this out.
 The course website is handled through the University of
Michigan Canvas, and you can access the website through the
following link:

https://umich.instructure.com/courses/319321

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Assignments, Exams
 Problem Sets:
- Maybe two to three problem sets
- Course will emphasize more on projects and class participation
 Pop Quizzes:
- 2-3 pop quizzes during the class time without notice (10 minutes)
- Quiz problems will be very simple and straightforward.
- The purpose of pop quizzes is to evaluate class participation and
attendance in addition to testing the understanding of lecture materials.
 Midterm Exam:
- Tentatively scheduled on Oct. 23, 1:30-2:50pm during the class time.
 Midterm Report
- Short literature survey paper on a given specific topic of your choice
- The topic can be related to your final project but not necessarily.
- Each person will submit a 10 page report (not a group report).
 Midterm Report Presentation
- Each student will give a presentation of his/her studies conducted for
midterm report during the class time. It will be peer reviewed.

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Final Project
 The final proposal will be based on existing NIH exploratory grant proposal
guidelines (R21).
 The number of page limit will be 12 pages similar to R01 proposal, although
the content of the proposal will be following the R21 mechanism.
 You will work on this in a group. (Group size will be announced soon,
depending on the class size.)
 The preproposal (2 page) should be submitted together with the midterm
report, and I will give you my feedback on your preproposal.
 All the submitted proposals will be posted in Canvas and three primary
reviewers will be assigned to review each proposal.
 You are submitting the score and review results based upon the NIH
evaluation guidelines (anonymous evaluation).
 Based upon all the scores, I will rank the proposals and we will emulate an
NIH review panel in the Evaluation Meeting on December 11.
 The detail of the procedure will be given in the class later.
 This will be fun and you will learn a lot from this experience.
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Detailed Outline (1)

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Detailed Outline (2)

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Grading Policy
 Tentative grading policy is as follows:

 Problem Sets 10%

 Pop Quizzes 10%
 Midterm Report 20%
 Midterm Presentation and/or Exam 20%
 Final Project (NIH style proposal) 40%

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Other Issues
 There will be seminars held by the Solid-State Electronic Laboratory
(http://www.eecs.umich.edu/ssel/) and MBSTP (Microfluidics in
Biomedical Sciences Training Program,
http://www.umich.edu/~ufluids/about.html), and other talks related
with BioMEMS. Announcements on time and topics will be posted
on the web and you are strongly encouraged to attend whenever
possible.
 The course outline, and all of the course policies are subject to
change. The course will evolve as I teach it. Expect the
unexpected.
 If you have any questions or face any problems please do not
hesitate to contact me.
 Office hours will be changed and adjusted. If you have a problem
making any of the office hours please let me know immediately.

EECS 509 BioMEMS 13

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What Are MEMS Microsystems?!

• Micro Electro Mechanical Systems

Are Miniature, Multifunctional Microsystems Consisting
of Sensors, Actuators, and Electronics. They Are Built
Using Micromachining Technologies.

• Micromachining Is an Enabling Technology That

Allows Formation Of Physical, As Well As Electronic,
Devices.

• Micromachining Uses Many of the Standard

Silicon IC Fabrication Techniques.

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Where Is Micromachining Come From?

Subset of Some special

fabrication process for Technologies
microelectronics (micromachining)

Fabrication process for miniaturized transducers and

special functional microsystems

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Surface-Micromachined Acceleration Sensor (Accelerometer) For

Air Bag Deployment, Manufactured by Analog Devices, Inc.
~1-2mm

• Undercut polysilicon shuttle mass

• Differential capacitance sensing
• Force-balanced operation
ADXL05:
±5g operating range
1000g survivability
0.5mg/√Hz noise floor
Photos Courtesy Analog Devices, Inc. Only a few $!
EECS 509 BioMEMS

MEMS Inside : Inkjet Printers

 Thermally Activated Print Head in the 1970’s
 Inkjet Print Heads in the late 1980’s
 Major enabler in low-cost color printing

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MEMS Inside : HD DLP TV

 Research by Larry Hornbeck started in mid 1970’s
 Research Intensified in mid 1980’s
 Production in late 1990’s
 Major business for TI, >$1B/yr.

Samsung HLN617W 61" Widescreen DLP TV

• Electrostatically-steered Al mirrors
• Mirror dimensions: 16µm x 16µm
• Two-level structure with hinged bottom
plate and center-yoked top mirror
• Array Size: 800 x 600 Elements
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BioMEMS

• Implementation of MEMS (Micro Electro Mechanical Systems)

to Bio-related areas
• Fluid delivery system at micro/nano-liter scale
• Multi-physics, multidisciplinary and cross-fields

www.calipertech.com BioMEMS, Lab-on-a-chip

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BioMEMS
- Biology Perspective -

• Biomedical MEMS • Biotechnological MEMS

• Biosensors • Gene sequencing
• Biotelemetry • Functional genomics
• Drug delivery • Drug discovery
• Precision surgery • Pharmacogenomics
• Minimally-invasive therapy • Diagnostics
• Physical sensors • Pathogen detection

Deals in vivo with the host Deals in vitro with the

anatomy biological samples of the host

Future BioMEMS: Combination of MEMS for in vitro

Diagnostics with in vivo Therapy

EECS 509 BioMEMS

Applications of BioMEMS
 Advancement in molecular biology  Have
brought medical research into molecular level
 Advancement in nanotechnology 
Manipulation of scale in molecular size possible
 The applications
- Biological analysis
- Medical diagnosis
- Antigen/Antibody screening
- Chemical analysis and synthesis
- Drug discovery
- Drug screening
- ••••

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Biomedical Applications of MEMS

 Implantable Systems - MEMS & Microsystem Perspective -
 Functional muscular stimulation (restore limb movement)
 Auditory, and Visual Prostheses
 Overcome disabilities such as Parkinson and Epilepsy
 Pain control, Bladder control, Drug Delivery Systems,
 Biological Fluid Analysis Systems
 DNA Analysis
 Blood Testing/Typing
 Chemical/Biological Analysis
 Cell-Based Assay Chips
 Patient Health Monitoring
 Measure Patient Health Signs (Activity, breathing, chemistry,…)
 Patient Health Service (drug delivery, …)
 Environmental Sensing
 Air quality
 Water quality, and drug dosing

EECS 509 BioMEMS 23

Integrated DNA Analysis

SEPARATE
DETECT
GEL
LOADING
THERMAL
REACTION

DROP
METERING

SAMPLE
LOADING

• Multiple components
• Multiple reactions/separations
• Decrease size/volume

Courtesy of Prof. Carlos Mastrangelo

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Examples of BioMEMS Device

 Detection and diagnosis Nanogen
 Synthesis and analysis
 Interaction
 Treatment

Aclara

Calipertech Microarray Based Biochip

EECS 509 BioMEMS

Microfluidics on a CD

 Gyros Inc.
 Centrifugal forces
 Metering, fluidic delivery and
protein analysis

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Single-Cell Assay Microsystem

High-throughput Parallel Cell Assay at Single Cell Resolution
- Optimal stem cell culture & transplantation
- Cancer drug screening

Actuation membrane
Capture site

Captured cell
Flow direction

Prof. E. Yoon, University of Michigan

Peristaltic
Pump
Microchamber
Selection Logic
Concentration
Generator

Microfluidic Logic Network Microchamber Array for Single-Cells

EECS 509 BioMEMS

Neuro Implant
 Neuro-circuit interaction
 Chemical delivery
 Issues with long term implant
– bio compatibility

Robo-hobo: A rat instructed

via a wireless receiver and
brain implant to walk along
a railroad track.
IEEE Spectrum, Aug., 2002

Stanford

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What can be done?

University of Utah

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Portable Clinical Analyzer

http://www.istat.com/

Detection with single

chip/single analysis

•pH
•PCO2
•PO2
•Sodium
•Potassium
•Hematocrit
•Ionized Calcium
•Glucose
•Bicarbonate
•Total Carbon Dioxide
•Base Excess
•O2 Saturation
•Hemoglobin

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Integrated Microfluidic System for Bio-

Chemical Assay

DARPA : BioFlips
EECS 509 BioMEMS

Drug Delivery

Nature 1999, MIT

Science 2001, MIT

http://web.mit.edu/cheme/langerlab/

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Portable Medical Device

Intelligent Microsystem Center, KIST

EECS 509 BioMEMS

Future Point-of-Care Service

KIST, Korea

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Standoff Chemical Sensing

 Spectrometer based on a MEMS diffraction grating

 Miniature, programmable remote chemical detection
system for field use
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Smart Endoscope

Intelligent Microsystem Center, KIST

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微系统的优势 Advantages of Microsystems

 Small samples
- Nanoliter quantities without evaporative loss
 Multiplexing
- Discovery biotech puts a premium on high throughput, enables
genomics, proteomics
 Integration, Performance, Speed
- Highly integrated systems possible
- Many analysis method work better as they are scaled down
- Scaling down dramatically improves speed of analysis
 Portability (small size), Low reagent and power
consumption (low cost)
 New types of analysis, new effects to exploit
- Serial chromatographies, dielectrophoresis, surface tension

EECS 509 BioMEMS 37

微系统的局限 Limitations of Microsystems

 Techniques dependent on inertia are problematic
- Centrifugation, mixing
 Physical state of analytes and carrier solvents can’t change
- Liquid only or gas only systems - solids clog, bubbles unstable and
irreproducible
- No precipitation allowed
 Interface with macro world
- Reagent reservoirs, sample introduction, detection
 Mass transfer rates are tiny
- Mixing generally only occurs by diffusion
 Non specific binding - high surface area to volume ratio 体积比表面
 Microscale phenomena not fully understood
积大 不易结
合
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生物微电子领域对材料的选择

Alternative Materials

 Materials requirement for BioMEMS is

different from those for typical MEMS.
 Desired properties of BioMEMS materials
- Biocompatible 生物相容性
- Chemically modifiable
- Surface modifiable
- Easy to fabricate
- Economically viable
- ….
 Si, glass and now more toward polymers…

EECS 509 BioMEMS 39

Core Technologies of BioMEMS

 Fabrication technology
 Microfluidics
 Microactuators and Microsensors
 Surface Modification/Control
 Biosensors and biochips
 Biocompatibility analysis
 Biosystems
 Manufacturing Facilities
 Materials advances
 Wide range of validated analytical techniques

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生物微系统分类

Types of BioMEMS Devices

Biomaterials Cell chip

Microorganism, animal cell, neuron

DNA chip Protein chip

cDNA, oligomer Enzyme, antibody, antigen

Microfluidics
Applications Biosensor
Diagnostics, analysis

Lab-on-a-chip Implantable chip

-TAS, screening Prosthetic device, bioinstrumentation

Bio-electronic device
Biocomputing, bio-memory

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Micro Total Analysis System (TAS)

•Blood
•Bacteria
•Cells •Sequence analysis
•Antigens Microsystems •Genetic analysis
•Proteins Based on microfluidics •Pathogen identification

Sample Reaction Detection

Preparation /Process / Analysis

Material Material Material

•Water
I/O I/O Optical
•Air
Electrical
I/O

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lab on a chip
的优势和特点 Lab-On-A-Chip

The functions of an entire laboratory as for people,

processes, and equipment are integrated into miniaturized,
microfluidic “laboratories on a chip”.
 Desired functions of conventional analysis
- People – labor
- Process – complicated processes
- Equipment – large & expensive
- High cost, low throughput
 Compress all functions into “laboratories on a chip”
- Miniaturized
- Microfluidics
- Small volume of reagents
- Less human error and faster analysis
- Improved accuracy and productivity
- Low cost, high throughput
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Microfluidic Device

Function
Active
Pump Fluid
Valve
Filter Nature Gas Liquid
Reactor
Mixer
…..
Passive

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微流控的一些基本特点

Microfluidics
 Low Reynolds’s Number
- Laminar flow
- Difficult to mixing
 Large surface to volume ratio
- Surface effect dominant – biosurface modification
- Microchannel – pressure drop
 Small fluid volume: pL to mL
- Nano or micro dispenser
- Diffusion
 Fluidic driving
- Electroosmotic force
- External pressure force

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Review of Microfabrication &

MEMS Technologies
Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Benefits of microfabrication

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Essential Microfabrication Steps

 Briefly discussed in
EECS 414
 Other courses, like
EECS 423/425, provide
more detail

EECS 509 BioMEMS

Basic Fabrication Steps

 Photolithography 光刻
 Oxidation
 Doping
- High-temperature Diffusion
- Ion Implantation
 Film Deposition
- Physical Vapor Deposition
 Evaporation
 Sputtering
- Chemical Vapor Deposition (CVD)
 Pyrolytic CVD
Atmospheric Pressure CVD (APCVD), Low Pressure CVD (LPCVD)
 Plasma Enhanced CVD (PECVD)
 Etching
- Wet Etching
刻蚀
- Dry (Plasma) Etching

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Typical Materials Used in MEMS

 Insulators:
- Silicon nitride (Si3N4), Silicon Oxide (SiO2)
- Others: Al2O3, Ta2O5,
 Semiconductors:
- Single-crystal silicon (SCS): in bulk or epitaxially-grown forms
- Polycrystalline silicon (poly-Si)
- Amorphous silicon (a-Si)
- Other semiconductors like GaAs
 Metals:
- Al, Au, Cu, Ti, W, Ag, Cr, Ni, Ir, Mo, Ta, NiFe, ...
 Polymers:
- Polyimides, photoresists, Parylene, plastics, paraffin wax
 Others:
- Ceramics, poly-diamond, SiC, Glass (Pyrex), ….

We need to know how to deposit these materials in thin-film form,

and we need to know their material properties.
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Discussion On Use Of Photoresist 光刻胶

For Patterning Biological Material

Clean room requirements: biological solutions?

Substrate requirements: plastic? glass?

Compatible with proteins?

Compatible with cells?

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Silicon
 Semiconductor, group IV
 Diamond Lattice unit cell
 Each atom shares its 4 valence electrons with
4 neighboring atoms
 There are 5x1022 atoms/cm3 in the Si lattice
 The crystalline nature of Si influences many
of its properties
Tetrahedral Bonding of Si

Face-Centered Cubic
(FCC) unit cell
Diamond Lattice
From Fundamentals of Microfabrication by M. Madou
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Miller Indices for a Simple Cubic Structure

 (xyz) values are the inverse of the coordinate of the intercepts of a given
plane with the three axes;
 For example (100) represents the plane that intersects the x axis and runs
parallel to the yz plane.
 [xyz] is a given crystal direction and represents the direction of the vector
perpendicular to the plane (100).
 As we will see later, properties of Si change along these different planes.
z z z
1 1 1

(xyz)
(100) (110) (111)
Plane y Plane y Plane y
1 1 1
x x x
1 <100> 1 <110> 1 <111>
Direction Direction Direction
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Si Wafer Marking and Designation

 Standard designations have been developed by creating “flats” on Si wafers to
represent their doping type (n- or p-), and wafer orientation. There are two types of
flats: major flat (typically at the bottom of the wafer, and the minor flat, which may
be present on the side of the wafer, as illustrated below.

EECS 509 BioMEMS 9

Why Do We Care About Orientation?

<110>
Create a pattern in a mask on a (100) wafer. The
mask edge (assume rectangular shape) is aligned
(100)
to the <110> direction.

(111) (100)
Planes Surface

54.7°

Slight undercutting under

the mask

If the etch proceeds for a long time, Because (111) planes etch much slower, the
the 4 {111} planes meet in an inverted etch front practically stops on these planes,
pyramid shape. while other planes continue to etch.
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Photolithography
 The process of printing a given 2D pattern onto a thin film layer
 This is a photographic process that requires a photosensitive material
“photoresist”, and a “mask” that permits exposure of only defined regions to the
incident radiation
 The mask:
- Typically made of a glass plate (soda lime or quartz glass) that is transparent to UV
light
- The pattern of interest is created on the glass using a thin (<1µm) metal film such as
chromium (Cr) or gold (Au)
- The mask plate has the pattern of interest repeatedly printed on it.
- Mask polarity can be designed to either allow incident radiation pass through the
patterned regions (i.e., dark field), or pass through the field regions outside of the
patterned areas (I.e., clear field)

Step &
Repeat

Pattern of Interest
Pattern Generation (PG)
Pattern repeated on a glass plate
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Photolithography
 The photoresist (PR) :
- A polymer whose chemical properties change when it is exposed to incident
radiation, typically UV light. Note that PR cannot be exposed to temperatures
above about 200°C because it burns (note that this is a polymer like plastic).
- The PR can be then developed in a “developer” like the standard photographic
process;
- Two different results can be obtained depending on the type of PR used:
 Positive PR: This type of PR is removed (etched away) in the developer solution
only in areas that have been exposed to UV radiation
 Negative PR: This type of PR is hardened (and therefore cannot be removed) in the
developer solution in areas that have been exposed to UV radiation.
- PR is typically in liquid form that can be spun onto a silicon wafer at speeds of a
few thousand RPM’s. This spinning process creates a uniform film thickness in
the range of 1-10’s of microns.
- After application, the PR is baked
at 90-100°C to remove the solvents
- The PR is now ready to be exposed
and developed.

EECS 509 BioMEMS 12

对于正胶，被光照射部分可以溶解于显影剂中（即没有
被mask遮盖的部分）。
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Photolithography 这种就是
负光刻胶
Si Wafer Align mask
on wafer

Deposit/Grow
Film
Expose PR to
UV thru mask

Spin and Soft Develop PR,

Bake PR hard bake
(100-120°C)

EECS 509 BioMEMS 13

区分正胶和负胶的实例
Photolithography: Positive vs. Negative PR
Clear-Field Mask Dark-Field Mask

+ve PR +ve PR
-ve PR

Positive PR’s are typically used because they are easier to work with
and use less corrosive developers and chemicals

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Lift-Off

• Noble metals
• Image Reversal

EECS 509 BioMEMS

3-D Photoresist Structures

Prof. Euisik Yoon, University of Michigan (Lab Chip 2008)

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这是一种负光刻胶

High-Aspect Ratio Patterning: SU-8

Photoplastic “SU-8”
• Photosensitized epoxy
• Negative photoresist

• 750 rpm ~ 50 µm
• 30 s exp. @ 365 nm
• 20 min. dev.
• Aspect ratios > 5:1
• Vertical sidewalls

Depth = 53 µm
Courtesy of Prof. Alber Folch, University of Washington
EECS 509 BioMEMS

SU-8 Micropen Array for Biological Assay

Patterning
 Integrated with a microchannel and a sample reservoir (~45 nl).
 Actuated by Lorentz force induced on an integrated metal actuator
Prof. Euisik Yoon, APL 2007

 Capillary force as a function of microchannel height

at the fixed width of 15 m
 Surface of SU-8 before and after plasma treat-
ment: Roughness increase from 0.318 to 2.627 nm
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SU-8 Micropen Array and Patterning

Prof. Euisik Yoon, APL 2007

 Length: 500 m
 Width: 120 m
 Thickness: 6 m
 Reservoir: 300 m x 300 m
(Capacity: 45 nl)
 Micropen spacing: 240 m
 Red dot ink of 11 m in
diameter

EECS 509 BioMEMS 19

SU-8 Gripper from Thermal Actuation

 Consists of two “hot-and-cold-arm” actuators
 High thermal expansion coefficient of SU-8 (52 ppm/oC)
 Average temperature elevations (10 – 32 oC) at low voltages (1–2 V)

Prof. Nikos Chronis, JMEMS 2005

EECS 509 BioMEMS 20

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SU-8 Gripper Actuation

 In Air: 4.7 mW
 In D-PBS (Dulbecco’s phosphate-
buffered saline): 90.5 mW
 Tmax ~ 55 oC
Prof. Nikos Chronis, JMEMS 2005

EECS 509 BioMEMS 21

Tilted Exposure

Prof. S. Lee, KAIST (JMM 2007)

EECS 509 BioMEMS

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Biocompatible photoresists
Photocleavable copolymer of thermoresponsive polymer, poly-NIPAM

Dr. S. Diez, Max Planck Institute (JACS 2009)

EECS 509 BioMEMS

Maskless Photolithography (1)

Laser Writer
• Raster Scanning of SU8

Courtesy of Prof. Alber Folch, University of Washington

EECS 509 BioMEMS

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Maskless Photolithography (2)

Digital Micromirror Device
• Texas Instruments

Prof. X. Zhang, UCLA, Sens.Actutors A:Phys. 2005

EECS 509 BioMEMS

High-Temperature Oxidation
 Wafers are first cleaned and then placed inside a furnace whose
temperature can be controlled accurately (better than 1°C).
Clean Quartz Tube
Heating Elements

Carrier Gas N2 &

Mixed w/ Oxygen

Si Wafers Carrier
Boat

 A carrier gas (typically nitrogen) is flown through the furnace. Oxygen is

introduced into the furnace by the carrier gas through several means:
- Liquid sources
- Gas sources

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Oxidation
 Si, like many other materials, reacts with oxygen, and forms a very
stable and high quality dielectric, silicon oxide SiO2.
 This ability to form a high quality dielectric is perhaps one of the most
important properties that has enabled Si to become the material of
choice for integrated circuits (IC’s).
 SiO2 has a wide range of uses in both ICs and MEMS
 At room temperature the silicon oxidation process is extremely slow.
Therefore, a high-temperature process is used to facilitate silicon
oxidation in a timely manner.
 The volume of oxide formed is 2.2 times the volume of silicon used in
the process.
Si Thickness Used = 0.44x
Initial surface of silicon
wafer before oxidation
SiO2
Thickness = x
Silicon
Final surface of
silicon after
Wafer
oxidation

EECS 509 BioMEMS 27

Physical Vapor Deposition

 The material to be deposited is placed in a vacuum chamber, it is
somehow converted into a gas phase. The gas phase molecules land on
the target wafer and form the desired layer. The longer the deposition
goes the thicker the film gets.
 Three basic techniques can be used to go from the solid material into a gas
phase:
Vacuum Chamber
- Evaporation Target Wafer
- Sputtering
- Ion Beam Deposition Deposited Film

Source

To Vacuum Pump
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Physical Vapor Deposition: Evaporation

 The material to be deposited is placed in a vacuum chamber, it is somehow
heated so it melts and evaporates. The vapor phase molecules land on the target
wafer and form a thin film.
 Two basic approaches to evaporation are:
- Thermal Evaporation
- Electron-beam (E-beam) evaporation
 Thermal evaporation is the easiest of all and requires the simplest system. The
film to be deposited is placed inside a crucible inside a vacuum chamber. The
crucible is heated until the material evaporates.
 Heating of the crucible can be done in several ways, including resistive and
inductive heating.
 The temperature required to evaporate the material depends on the vapor
pressure of the material and on the pressure.
 Typically the material should have a vapor pressure of more than 10mTorr.
 The pressure in the chamber typically ranges from 0.1-1 µTorr
 Vapor pressure of different materials is shown on the next page.

EECS 509 BioMEMS 29

Physical Vapor Deposition: Evaporation

 In e-beam evaporation, the material is heated and melted using a high-energy
electron beam.
 With e-beam, higher temperatures can be achieved. Therefore, a wider range of
materials can be deposited.
 Because of the higher temperatures possible with e-beam, in addition to refractory
metals with low vapor pressure, it is possible to deposit some insulators such as
oxides and glass.
 The evaporation rate is higher at lower pressures.
 Since the crucible is not heated as much, there is less contamination possibility
using e-beam evaporation than thermal evaporation.
 Most materials used in the IC industry these days, use e-beam evaporation.
 Evaporation in general does not have a very good step coverage and the process
is “line of sight”, as illustrated below.
Arriving Atoms
Deposited Film

Thinner (or discontinuous)

Si Film On Edge
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Step Coverage

Conformal

=180o =270o

=90o

Arrival Angle

EECS 509 BioMEMS 31

Physical Vapor Deposition: Sputtering

 A plasma is generated by applying a RF signal 5-15kV in a pressure range of 10-
100 mTorr. The gas used is typically Ar.
 The plasma creates Ar ions and electrons.
 Ar ions bombard the source knocking off source atoms.
 The source atoms get deposited on the substrate (target).
 Features:
- Wide variety of materials, including metals, insulators, and semiconductors
- When deposited in a reactive environment with oxygen, oxides can be deposited
- One can deposit multiple materials in a single pump down (meaning we do not need to
break vacuum for next material) since multiple sources can be placed in the same
chamber. It is also possible to deposit alloys and compounds like silicides (MoSi, TaSi)
- The films are deposited with better step coverage than e-beam so there is film continuity
going over steps.

Target
Vacuum

Wafer + RF Source
Plasma 13.56MHz
-
Source

EECS 509 BioMEMS 32

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Thin Film Issues

• Adhesion
• Diffusion Barrier/Interface
• Ohmic Contacts
• Step Coverage
• Electromigraion

EECS 509 BioMEMS

Chemical Vapor Deposition (CVD)

 Chemical vapor deposition is used to deposit thin films from a gas phase.
 A number of CVD techniques are available and include:
- Low-Pressure CVD (LPCVD)
- Plasma-Enhanced CVD (PECVD)
- Photo-CVD
 Most of these deposition techniques require temperature in excess of
300°C, so these are higher temperature processes than the PVD
techniques discussed before.
 CVD techniques are mostly used to deposit thin films of insulators and
semiconductors, such as:
- SiO2
- Si3N4
- Polycrystalline and amorphous silicon
- Some metals such as W

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Chemical Vapor Deposition (CVD)

Formation of non-volatile solid film on a substrate by

reaction of vapor phase chemicals (reactants)

Reactants •Uniformity
Carrier Gas •Purity + Density
Reactor
•Stoichiometry
•Mechanical Property
(Stress, Young’s modulus)
•Electrical Property
•Adhesion
•Step Coverage

1) Reactants absorb on substrate

2) Migration & chemical reaction
3) Gaseous by-products desorb
• Heterogeneous Reaction (Wafer surface)
• Homogeneous Reaction (Gas phase)  particulates

EECS 509 BioMEMS

Low-Pressure Chemical Vapor Deposition (LPCVD)

 Typical gases used and the reactions that produce the desired films are:
(the pressure is usually in the range of several 100mTorr)
- SiH4 + N2 + N2O ====> SiO2 + N2 + H2O (for silicon dioxide)
- SiH4 + N2 + NH3 ====> Si3N4 + N2 + H2 (for silicon nitride)
- SiH4 + N2 ====> Si + N2 + H2 (for polycrystalline Si, Poly-Si)
 Several features of LPCVD films:
- The deposited films are typically of very high quality and uniformity
- The deposition rates are in the range of a few tens of Å per minute
- The substrates are usually heated and the reaction takes places as gas
species hit the substrate. Therefore the process is quite uniform
- Because of the low-pressure environment, the gas species usually reach all
areas, even narrow gaps and channels, and the film is quite conformal.
- This also causes the film to be deposited everywhere on the chamber walls.
Therefore, the chambers need to be cleaned rather frequently.
- The LPCVD silicon oxide is not quite as high quality as the thermally grown
silicon oxide and is less dense, but it is still preferred for many applications
because of the lower temperature and because it can be deposited on non-Si
surfaces.
EECS 509 BioMEMS 36

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Plasma-Enhanced CVD
 In PECVD, the energy required for the reaction is provided through a
plasma.
 An RF field is used to excite a plasma over the substrate to aid in the gas
decomposition process.
 Deposition temperatures here are in the range 300-400°C. This is an
important difference with LPCVD, and is one of the principal advantages
of PECVD.
 The lower deposition temperature allows PECVD films to be deposited
over metal films, and over substrates such as GaAs that cannot withstand
high temperature processing.
 PECVD film quality is not as high as LPCVD films.
 A variety of films, including oxide, nitride, poly-Si and amorphous Si, and
doped oxides and nitrides can be deposited using PECVD.
 Deposition rates vary in the range 10-100 nm/minute, depending on the
temperature, pressure, flow rates, etc.
 PECVD film are finding increasing use in a variety of MEMS applications

EECS 509 BioMEMS 37

Isotropic vs. Anisotropic

 Some etchants are purely isotropic (i.e., they etch the material at the
same rate in all directions). This is undesirable since there will be
considerable reduction in line width (feature size), especially as the
thickness of the film becomes larger.
 Anistropic etchants are desirable because one can transfer the exact
pattern and dimension of the PR onto the thin film material.
 Mask erosion is also important and one should select masking materials,
such as PR, that can withstand the etchants for the length of time needed.

Isotropic Anisotropic Mask Erosion

& Undercut
Etcant Under
PR the PR
Film h

x
Undercut x
Si
EECS 509 BioMEMS 38

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Isotropic Silicon Etching (ISE)

 Si can be etched isotropically (equal etch rate in all directions) in a mixture of
HF+HNO3, and some acetic (vinegar) acid (this mixture is sometimes referred to as
HNA) This etch was developed in the 1960’s as the solid-state circuits industry was
working on the development of beam-lead technology for building high-density


circuits.
搅动
The etch removes n- or p-type silicon in all directions at about the same rate.
 The etch does depend on agitation. The more agitation there is during the etch the
larger the undercut under the masked regions.
 The etch attacks most materials (HF is nasty acid that attacks many materials).
For shallow etches, silicon nitride can be used as a mask, for deep etches
sometimes it is required to use Cr/Au. HF does not significantly attack silicon
directly but the HF+HNO3 mixture is a strong etchant of Si.

Mask
(usually nitride)

Si substrate Si substrate

With Agitation With No Agitation

EECS 509 BioMEMS 39

Hemispherical Shells Fabricated Using ISE

• Fabricate hemispherical shells
• Use boron doping and p++ etch stop
• Release shells in concentration-dependent etchant

Si substrate

Etch Si using HNA and a nitride mask

Boron Doped

Boron dope shells to desired depth

Released
Shells Released Si Shells
Release shells in EDP/KOH ~2µm in thickness
Photos Courtesy of Prof. Ken Wise
University of Michigan

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Bulk-Micromachining of Silicon

<111> <111>

thickness
54.7°

Bottom of etch pit

Etch reaches bottom of wafer when
If etch stops early, the wafer will the mask opening is wide
have tapered sidewalls.
EECS 509 BioMEMS 41

MEMS Silicon Pressure Sensor

(111) Plane

(100) surface

Etched Surface
Transmitted light

Top view of a piezo-resistive pressure Scanning Electron Micrograph (SEM) of

sensor. Diaphragm formed using ASE. an etched pit, showing the (111) and (100)
Note that the etched surface is not planes.
perfectly polished.

Photos courtesy of Prof. Ken Wise, University of Michigan

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Surface Micromachining
•Deposited Thin Films Are Used For Both Mechanical and Sacrificial Layers
•A Variety of Films Used in Standard CMOS Can Be Used.

Support Microstructure
Anchor Material

Deposit the Mechanical

Layer Over a Sacrificial CMOS Sacrificial
Layer, and Anchor the Layer
Microstructure to the Silicon Substrate
Substrate.

Free-Standing Undercut Microstructure

Etch the Sacrificial Layer, CMOS

and Release the
Mechanical Microstructure. Silicon Substrate

EECS 509 BioMEMS 43

Surface-Micromachined Microaccelerometers

• Undercut polysilicon shuttle mass

• Differential capacitance sensing
• Force-balanced operation
ADXL05:
±5g operating range
1000g survivability
0.5mg/√Hz noise floor
Photos Courtesy Analog Devices, Inc.

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Dry (Plasma) Etching

 Dry etching is also a chemical etching technique, but employs gases
instead of liquids. The gases are ionized in an RF glow discharge
(plasma) and the specific chemical species are used to etch the thin film.
 The gases used to create the plasma determine the etch rate, etch profile,
and selectivity. Many gases are used to etch different thin films. A few of
them, and the material they can etch are listed below.
 One of the main disadvantages of dry (plasma) etching is the worse
selectivity it has with respect to both the mask (typically PR), and to
different layers.
 Dry etching is now very Chamber
commonplace.

Material Etch Gas

Si/Poly-Si CF4, SF6, .. Plasma
SiO2 CHF3, CF4/H2, CF4/O2
Si3N4 CF4/O2 RF
Organics O2, O2/CF4, O2/SF6 Power
Al BCl3
Wafers
EECS 509 BioMEMS 45

Comparison of Dry Etching Techniques

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可以进行窄而深的刻蚀（相比于RIE）。
Deep Reactive Ion Etching (DRIE)
 Reactive Ion etching ca be used to etch Si as we discussed before. However, it is
often desired in MEMS applications to fabricate very narrow and tall structures or
grooves. To do this, the standard RIE process cannot be used.
 A new process, called DRIE is used. This process uses the same basic RIE
technology, but it utilizes special gas chemistry to form a polymer on the sidewalls of
the trench as it is being etched.
 The thin layer of polymer prevents lateral undercutting and etching of the Si on the
sidewall. The result is a very high aspect-ratio etch.
PR or
Oxide
有效防止硅侧壁腐蚀

Si

EECS 509 BioMEMS 47

DRIE Etch & Passivate Steps lead to

Scalloping

Scallopin
g

EECS 509 BioMEMS 48

各向同性的刻蚀与钝化层的形成
是交替进行的，
并且初期刻蚀完成以后，
后续的刻蚀是定向底部，
侧侧面不会受到影响。
刻蚀对钝化层也同样有效， 24
不过会大大缓解硅的被刻蚀。
 9/7/2019

A Leaf Spring Fabricated Using DRIE

 Combination of fusion bonding

(with pre-etched cavities) and
deep RIE (DRIE).

FUSION BONDING
THINNING

PATTERNING DEEP ETCH

200 µm

Slide from Prof. G. Kovacs, Stanford University, and Locas Novasensor

EECS 509 BioMEMS 49

Comb Finger Test Results

EECS 425 Project Device (2011)
Parameter Pull‐in (V) k (N/m)
Simulated 3.81 14.19
Actual 4.93 22.00

EECS 509 BioMEMS 50

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Thermally-Actuated Optical Shutter

EECS 425 Class Project (2010)

Mechanically
Amplifying the
Displacement Using
Transmitted Spring
Buckling

EECS 509 BioMEMS

Electrothermal Actuation
EECS 425 Project Device (2010)

EECS 509 BioMEMS 52

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Soft Lithography

Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Photolithography vs. Soft Lithography

Use of photons for Use of a “soft” (flexible) mold
patterning for patterning
(Optical process) (Physical process)

Soft lithography

EECS 509 BioMEMS

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First paper on microcontact printing

First paper on microfluidic patterning

Kim, E., Xia, Y., and Whitesides, G.M. Nature 376, 581-584 (1995)

EECS 509 BioMEMS

1.17. Micromolding
PDMS PDMS micromolding
Process
2. Pour polymer precursor(s)
1. Photolithography and cure

3. Peel off and cut 4. Apply

EECS 509 BioMEMS

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1.17.Master
SU-8 PDMS&micromolding
PDMS Replica
PDMS
Replica

Photoresist (SU8)
master

• Inexpensive
• Multiple replicas 30 µm

EECS 509 BioMEMS

Structural integrity of PDMS walls

• Typically, structures with a high aspect ratio (>5:1 height/width)

do not replicate well.
• Some features smaller than 100nm can be replicated.

EECS 509 BioMEMS

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PDMS参数 Structure Collapse of PDMS

下垂

 Lateral collapse: Commonly known as “pairing” when H/L > 5

 Sagging: Recessed structure when H/L <0.5
Delamarche, et al., Adv. Mater. (1997)
EECS 509 BioMEMS 7

PDMS特点 Properties
1.17. of PDMS
The magic of PDMS
(Polydimethyl Siloxane)
 Polymer with a backbone of Si-O-Si or “siloxane”
 Inexpensive CH3 CH3
 Very elastic and soft O O O
Si Si
 Optically transparent down to 300 nm
 Surface is hydrophobic
CH3 CH3
 Self-seals by conformal contact Two Methyl
Groups on
 Inert, but can be oxidized, etched, and derivatized
Silicon
 Biocompatible
 Swells when exposed to solvents
 High permeability to gases and fluids
 Expands a lot with temperature (100 times more than silicon)

EECS 509 BioMEMS

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Patterning Techniques Using

Soft Lithography

 Replica Molding (REM)

 Micro Contact Printing (CP)
or Microstamping
 Micromolding in Capilaries (MIMIC)
or Microfluidic Patterning
 Microtransfer Molding (TM)
or Stencil Patterning

EECS 509 BioMEMS 9

Replica Molding (REM)

 Additional duplication of pattern transfer from a soft mold

Prof. Whitesides, Harvard (Science 1996)

EECS 509 BioMEMS 10

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Microcontact printing (CP)

Material is “added” where stamp contacts surfac
e
PDMS as a transparent rubber

1. Ink

2. Transfer

EECS 509 BioMEMS

Selective Inking of a Flat Stamp

Chemical patterns with flat stamps – prevent lateral diffusion of

ink molecules on the surface of the stamps
Geissler, JACS 2000
EECS 509 BioMEMS

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Microfluidic Patterning
or Micromolding in capillaries (MIMIC)
Material is added where stamp does not contact the surface
microchannels

1. Fill
• Deposit or etch

2. Remove microchannels
• Immobilization of material
固定
• Procedure for removal of microchannels
EECS 509 BioMEMS

Polyurethane Structures on Si/SiO2

• UV-curable polyurathane prepolymer introduced in capillary channels.

• Connected patterns (b), multiple thicknesses mold (c), free standing film after being
dissolved in HF Prof. Whitesides, Harvard (JACS 1996)
EECS 509 BioMEMS

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Microfluidically-Patterned Polyurethane
3D Structures

• Channels filled with UV-curable polyurathane precursor, ant then exposed to UV to

cure the precursor into polyrurthane
• Manually stacking 3D structures
Prof. Albert Folch, Biomed. Microdevices, 2000
EECS 509 BioMEMS

Microfluidic Patterning of Biomolecules

Science 276, 779 (1997)

Microchannels filled by capillarity

EECS 509 BioMEMS

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Railed Microfluidic Fabrication

Prof. S. Kwon, SNU (Nat. Mater., 2008)

EECS 509 BioMEMS

Lock-Release Microfluidic Lithography

• A very think roof is “inflated”
to release the micro-
structures.
• Sequential filling of micro-
channel with different
chemistries allows for
fabricating composite
particles

Prof. P. S. Doyle, MIT (Lab Chip, 2009)

EECS 509 BioMEMS

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MicroTransfer Molding (TM)

Fabrication of PDMS Stencils

Prof. Whitesides, Harvard (Adv. Mater. 1996)

EECS 509 BioMEMS

Fabrication of PDMS Stencils

MicroTransfer Molding (TM)

Prof. A. Folch, U. of Washington (Langmuir 2002)

EECS 509 BioMEMS

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Fabrication of PDMS Stencils by

Exclusion Molding

Prof. A. Folch, U. of Washington (Lab Chip 2004)

EECS 509 BioMEMS

Tunable Micromolding

Prof. A. Folch, U. of Washington (Adv. Mater 2004)

EECS 509 BioMEMS

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Microfluidic Photomasks for Grayscale

Photolithography

Prof. A. Folch, U. of Washington (PNAS 2003)

EECS 509 BioMEMS

PDMS/PDMS Bonding
 Using Partially Cured PDMS

PDMS

Partially-Cured
PDMS

 Using Uncured PDMS as Adhesive

Uncured
PDMS
PDMS

PDMS or
Glass

 Oxygen Plasma
EECS 509 BioMEMS 24

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Oxygen Treatment of PDMS

 Reactive oxygen radicals (O+) attack mythyl groups (Si-CH3) on the surface.
 Condensation reaction between silanol groups (Si-O-H) will form siloxane
(Si-O-Si) to bond two PDMS layers.
EECS 509 BioMEMS 25

Multi-Level Microfluidic Channels

plasma bonding

M. Zhang, Lab Chip 2010

EECS 509 BioMEMS

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Multiple-Stacking of PDMS - Tactile Sensors

Pressure

A
C0
Bump Bump
Membrane

C0+C
A Electrode B
Air Gap Post
Operation Scheme
Short Protection Layer
Support Layer

Cross Section View

Prof. E. Yoon, JMEMS 2006
EECS 509 BioMEMS

Unit Cell Structure

Force
Bump (PDMS)

100m Upper PDMS `

1200m
Electrode (Cu)
5m Spacer (PDMS)
5m
800m
Insulator (PDMS)
800m
1200m
2000m Lower PDMS

Cross section view of one cell

3D exploded view

Prof. E. Yoon, JMEMS 2006

EECS 509 BioMEMS 28

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Fabricated Tactile Sensor Module

22mm 22mm

1mm
Electrode

Bump Spacer

Air channel

Prof. E. Yoon, JMEMS 2006

EECS 509 BioMEMS 29

Mesoscale Self-Assembly

Prof. Whitesides, Harvard (Science 1999)

EECS 509 BioMEMS

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Surface Properties and

Modifications
Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Surface of Cells
 Cell is a basic structural and functional unit of all living organisms.
 What is the surface property of cells? Is it hydrophobic? Or hydrophilic?

TEM image of a bacterium: The furry

appearance on the outside is due to
a coat of long chain sugars attached
to the cell membrane. This coating
helps trap water to prevent the
bacterium from becoming
dehydrated.
EECS 509 BioMEMS 2

脱水

1
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Lipid Bilayers
脂质双分子层  Lipid bilayer is a thin polar membrane made of two layers of lipid
molecules. These membranes are flat sheets that form a continuous barrier
around cells.
 Impermeable to most water-soluble (hydrophilic) molecules
 Barrier of ions, proteins and other molecules.
磷脂  Composed of phospholipids, which have
a hydrophilic head and two hydrophobic tails
each.
Hydrophilic

Hydrophobic

EECS 509 BioMEMS 3

Self-Assembly of Phospholipid Layer

 http://mw.concord.org/modeler/showcase/biology/monolayer.html
 Hydrophobic Effect : Hydrophilic phosphate heads point “out” to the water
and the hydrophobic tails point “in” to the core of the bilayer.
泡泡的微观情况是，
水夹在表面清洗剂之间，  Similar to soap bubble: In the case of a soap bubble, the two soap
所以亲水端在里面夹着水， monolayers coat an intervening water layer. The hydrophilic heads are
疏水端朝着空气。 oriented “in” toward this water core, while the hydrophobic tails point “out”
to the air.
Hydrophilic

Hydrophobic

Hydrophilic

EECS 509 BioMEMS 4

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Cross-Section of Lipid Bilayer

 There are three distinct regions: the fully hydrated headgroups, the fully
dehydrated alkane core and a short intermediate region with partial
hydration.
 Although the head groups are neutral, they have significant dipole
moments which influence the molecular arrangement.
 Hydrophilic headgroup:
completely hydrated and is 水合
typically around 0.8-0.9 nm thick.
 Intermediate region: partially
hydrated, approximately 0.3 nm
thick. Within this short distance,
the water concentration drops
from 2M on the headgroup side
to nearly zero on the tail (core)
side.
 Hydrophobic core: typically 3-
4 nm thick.
EECS 509 BioMEMS 5

Lipid Bilayer Formation in Microfluidic Chip

Prof. Takeuchi, U. of Tokyo (AC Research 2006)

EECS 509 BioMEMS 6

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驱动力是减少表面自由能， Protein Surface Interaction

氨基疏水，蛋白亲水。
 Hydrophobic interactions are essentially entropic interactions basically due
to order/disorder phenomena in an aqueous medium. The free energy
associated with minimizing interfacial areas is responsible for the reason
that hydrophobic amino acid side chains are oriented away from water,
minimizing their interaction with water. The hydrophilic groups on the
outside of the molecule result in protein water solubility. Accordingly, one
can think of the driving force of these interactions as the minimization of
total interfacial free energy, i.e. minimization of surface area.
Hydrophobic
region

Hydrophilic
region

Isolated Protein in
Protein Aqueous Solution

EECS 509 BioMEMS 7

莲花效应 Lotus Effect: Can You Wet Lotus Leaves?

 You can try…. But probably not.

表皮  Why? The epidermis of the lotus plant possesses papillae with 10 to 20 µm

in height and 10 to 15 µm in width on which the so-called epicuticular
waxes are imposed.
一种具有双重结构，
具有疏水功效的表皮。  The cause of self-cleaning properties is the hydrophobic water-repellent
double structure of the surface.
EECS 509 BioMEMS 8

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Hydrophilic vs Hydrophobic Surface

 Hydrophilic: from the Greek (hydros), meaning water, and
φιλια (philia), meaning love.
- Hydrophilic substances can seem to attract water out of the air, the way
salts (which are hydrophilic) do. Sugar, too, is hydrophilic, and like salt
is sometimes used to draw water out of foods.
- A hydrophilic molecule or portion of a molecule is one that is typically
charge-polarized and capable of hydrogen bonding, enabling it to
dissolve more readily in water than in oil or other hydrophobic solvents.
 Hydrophobic: from the Attic Greek (hydro), meaning water,
and phobos, meaning fear.
- Hydrophobicity is the physical property of a molecule (known as a
hydrophobe) that is repelled from a mass of water.
- Hydrophobic molecules tend to be non-polar and, thus, prefer other
neutral molecules and non-polar solvents.

EECS 509 BioMEMS 9

Contact Angle
 Contact angle is the angle, conventionally measured through the liquid,
where a liquid/vapor interface meets a solid surface.
 It quantifies the wettability of a solid surface by a liquid via the Young
equation.
 A given system of solid, liquid, and vapor at a given temperature and
pressure has a unique equilibrium contact angle.
 If the solid–vapor interfacial energy is denoted by SG, the solid–liquid
interfacial energy by SL, and the liquid–vapor interfacial energy (i.e. the
surface tension) by LG, then the equilibrium contact angle C is determined
from these quantities by Young's Equation:

0 = SG – SL + LGcos C

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Typical Contact Angles

 Contact angles are extremely sensitive to contamination; Values
reproducible to better than a few degrees are generally only obtained under
laboratory conditions with purified liquids and very clean solid surfaces.
 Bare metallic or ceramic surfaces: ~0o
The liquid molecules are strongly attracted to the solid molecules, then
the liquid drop will completely spread out on the solid surface.
 Hydrophilic: < 90o
Silicon dioxide, silicon nitride, etc.
 Hydrophobic: > 90o
Silicone, most polymers, etc.
氟化，聚四氟乙烯。 Highly hydrophobic surfaces made of low surface energy (e.g.
fluorinated) materials may have water contact angles as high as ~120°
 Some materials with highly rough surfaces may have a water contact angle
even greater than 150°, due to the presence of air pockets under the liquid
drop. These are called superhydrophobic surfaces.

EECS 509 BioMEMS 11

Hydrophilic vs. Hydrophobic Channel

Surface Tension Driven Selective Drug Injection
Hydrophobic Hydrophilic
(c>90o) (c<90o)
Cell media

Drug

Pressure
EECS 509 BioMEMS 12

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How to Change the Surface Property

 By coating and patterning a layer of film, you can change the surface
property, especially inside a give microfluidic channel.

 Hydrophobic surface formation – By depositing teflon or SAM (self-

assembled monolayer) coating such as FDTS. Also by patterning the
surface to customize hydrophobicity.

 Hydrophilic surface formation – By plasma treatment of the surface, you

PDMS是疏水 can change the surface from hydrophobic to hydrophilic (e.g. plasma
treatment of PDMS). However, the surface property change is typically
temporal and its property degrades over time.

EECS 509 BioMEMS 13

Channel Patterning - Superhydrophobicity

 Wetting Wenzel regime are ‘‘sticky’’ in that drops of water tend to adhere to
them more than a flat surface of the same type.
 Those following the regime of Cassie and Baxter are ‘‘slippy’’ and allow
drops of water to roll off more easily than an equivalent flat surface.

 Hierarchical structure is necessary to have high contact angle but also

essential for the stability of the composite interface (water-solid and water-
air).

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Superhydrophobic Surfaces in Biology

 a) Lotus leaf (Nelumbonucifera), b) Hillock bush leaf, (Melaleuca hypericifolia), c)

Middle of upper side of a common pond skater (Gerris lacustris), and d) Lichen
Lecanora conizaeoides showing high roughness with inset showing water drop
WCA 155 +/- 4o. (Source: Soft Matter 2008, 4, 224-240)
EECS 509 BioMEMS 15

Lithographic Surface Modification

 (a) Photolithographic towers, (b) Indented square posts, (c) Diced silicon wafer, (d)
Photolithographic towers, (e) Silicon nano-towers, (f) Laser-modified SU8 surface,
(g) SU8 towers, (h) Silicon islands and (i) Silicon nanowires grown on those silicon
islands. (Source: Soft Matter 2008, 4, 224-240)
EECS 509 BioMEMS 16

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PDMS Surface Contact Angle

1) Silicon wafer 2) Photoresist coating 3) Photolithography

4) Silicon DRIE with 5) PDMS casting over 6) PDMS peeling-

photoresist masking the etched silicon off from the silicon
mold

10l droplets on PDMS hydro-phobic

surfaces with droplet contact angles.
Growth of a SUM159 sphere shown
over the course of 6 days culture.
Prof. Euisik Yoon, University of Michigan
White circles outline the growing
(MicroTAS, 2011) SUM159 cells.
EECS 509 BioMEMS 17

Channel Coating

Hydrophilic microchannel of Hydrophobic microchannel of PDMS

PDMS and silicon dioxide and FDTS SAM coated silicon surface
Prof. Euisik Yoon, University of Michigan (Biomed Microdevices, 2005)
EECS 509 BioMEMS 18

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Capillary Force in Microchannel

 Surface 1: PDMS, Surface 2: SiO2

 Channel can be either hydrophilic
or hydrophobic, depending on
channel width.
 W > 5m, channel becomes
hydrophilic.(Channel depth is
20m.)

Prof. Euisik Yoon, University of Michigan (Biomed Microdevices, 2005)

EECS 509 BioMEMS 19

Drug Injection Microchannels

 Drug can be introduced into the

channel without generating
bubbles because the air leaks out
through a hydrophobic ventilation
channel while drug is injected to
the hydrophilic channel.
Prof. Euisik Yoon, University of Michigan (Biomed Microdevices, 2005)
EECS 509 BioMEMS 20

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Drug Injection Chip

FDTS疏水

Prof. Euisik Yoon, University of Michigan (Biomed Microdevices, 2005)

EECS 509 BioMEMS 21

Proposed Chip for Single-Cell

Positioning/Nanoliter Drug Injection
Cell positioning
Cell site
suspension Outlet
media

Buffer drain
channel

Hydrophobic
region

■ Autonomous single-cell positioning

■ Nano/picoliter drug injection Electrodes
Opened to
– No diffusion of Injected liquid atmosphere Drain channel
– Leaking-out of air Drug injection channel

EECS 509 BioMEMS 22

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Experimental Result: Cell Positioning

Polystyrene bead (d=15m)
100 μm
Bead (d = 15m)
170nL/min

Living cell
(CHO DG44 cell)

EECS 509 BioMEMS

Experimental Results: Injection Testing

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Micropatterning of Biomolecules
 Can we use photolithography to pattern biomolecules (such as proteins)
using the traditional liftoff process?
图章粘贴生物分子的限制  Two major problems in the application of photolithography to biopatterning:
- Most chemicals used in standard photolithography are toxic to cells and
denaturants* to biomolecules.
- Biological solutions are not compatible with clean-room facilities (not CMOS
compatible) because of rich ionic and molecular contents.

 Interaction of biomolecules and cells with a surface of devices plays a

significant role in the device’s functions.
 Surface engineering combined with microfabrication is crucial to achieve
adequate adhesion of biomolecules on the surface through
physicochemical, biochemical, and biophysical interaction.

光刻需要除水，这一过程 *Denaturation: Organic solvants used in photolithography will exclude water

可能会使生物大分子失活 around proteins and biomolecules and make drastic changes to its natural
变性。 shape, which may result in a loss of activity.
EECS 509 BioMEMS 25

Physisorption of Biomolecules
 Van der Waals Force: Biomolecules are invariably polar and their dipole
moment is attracted to the charges and surrounding dipoles on the surface.
Fluctuating, dipole-induced dipole interaction is known as van der Waals
force, which is always attractive. (Molecular interaction, range of ~ a few
nm)
 Electrostatic Force: Biomolecules are invariably charged, so are most
surfaces in physiological fluids. This force is sensitively affected by ionic
concentration present in solution.
 Hydrogen Bonding Force: Hydrogen atoms can dissociate partially from
donor (electronegative) atoms and be shared with another electronegative
atoms, forming a hydrogen bond.
 Hydrophobic Force: Non-plolar groups (e.g., solvents) and water tend to
repel each other; thus non-polar groups are left with no other choice but to
stick to each other. They are not attracted; but they are rather “bullied” into
“hugging” each other by the surrounding water network of protons and
hydronium ions. (e.g., Self-assembly of lipid bilayer)

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Physisorption vs. Chemisorption

 Adsorption: Phenomenon that molecules adhere to a surface
 If the adsorption is mediated purely by physical forces, it is called
physisorption. If a chemical bond forms between the molecule and
surface, then it is called chemisorption.
 Physisorption is relatively simple and does not require special equipment.
For example, glass slides or petri dishes used for cell culture.
 On the other hand, chemisorption requires a specialized substrate that
allows for a chemical linkage between the biomolecules and the surface.
Chemisorption often requires the expertise of a chemist.
 Many biomolecules can also physisorb atop each other; thus, ensuring a
chemical linkage between the bottom layer and the surface does not
necessarily ensure a stable coverage either.
 Cell attachment: Cell adhesion is mediated by cell membrane-bound
整合素 receptors, in particular known as integrins. It is a family of transmembrane
proteins that are linked to the cytoskeleton on the cytoplasmic side of the
membrane, and recognize specific peptide sequence present in the cell-
secreted fibrillar meshwork known as extracellular metrix (ECM).
EECS 509 BioMEMS 27

细胞粘附是由细胞膜结合介导的
受体，特别是称为整合素。它是跨膜家族
与细胞骨架上的细胞骨架相连的蛋白质
膜，并识别存在于细胞外的纤维状网状结构中的特定肽序列，称为细胞外子宫

Surface Engineering
 Traditionally, glass has been the substrate of choice for surface chemical
immobilization of biomolecules.
 SAM (Self-Assembled Monolayer): The SAM molecules react (i.e.,
chemisorb) with a surface from solution. They minimize the free energy of
the surface by spontaneously forming a densely packed, crystalline-like
layer (“self-assembly”) of single-molecule thickness.

CH3

12nm Au
(transparent)

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Alkylsilanes on Glass
硅烷类  Silanes 烷基硅烷
 Substrate: glass, anything terminated in –OH
 Reaction widely used in immobilization of biomolecules
 Synthesis is ~ difficult
氯硅烷  Chlorosilanes:

EECS 509 BioMEMS 29

BSA on Polystyrene (PS) for Selective Cell

Attachment

牛血清蛋白  BSA (bovine serum albumin) readily sticks to surfaces and to other
molecules, so it effectively blocks binding sites. Also, BSA does not contain
any known integrin-binding sequences, so it is suited for deterring cell
attachment.
细胞分泌的蛋白酶会
消化其迁移轨迹中的  Cells secrete proteinases that digest proteins in their migration tracks, so
蛋白质 the selectivity does not last permanently.
Prof. Albert Folch, University of Washington (Langmuir, 2002)
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Nonadhesive Surface – PEG Coating

非粘性表面：醋酸纤维素，
琼脂糖，PEG，氟康康  Nonadhesive surfaces: cellulose acetate, agarose, PEG, fluocarcon
聚合物，聚乙烯醇 polymers, poly (vinyl alcohol)
 PEG – poly (ethylene glycol) 聚乙二醇
Ethylene: C2H4 or H2C=CH2 ; Glycol: HO-CH2-CH2-CH2-OH
 Direct immobilization of PEG on silicon or glass

Functionalized PEG with

SiCl3 can react with
hydroxyl groups on glass 羟基
to form a multilayer of
PEG film.

Thin flims of co-polymer

PEG and acrylic acid
support no cell adhesion.

EECS 509 BioMEMS 31

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Micropattern of
SAM and Proteins
Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

SAM Micropatterning
烷硫醇  Micropatterning biomolecules by engineering the adhesiveness of the
surface by SAM.

First micropattern of SAM using Gold microelectrode pattern on

photoresist as a physical barrier glass; Derivatized with an
(Philip Hockgerber group at AT&T alkanethiol SAM leaving the
Bell labs) glass intact
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Microcontact Printing of SAM

 Microfabricated elastomer stamp is used to contact-transfer
SAM precursor molecules onto the selective region of surface.
- Hexadecanethiol molecules (CH3-(CH2)15-SH in ethanol) onto gold.
- Alkylsiloxanes onto Si or SiO2
- Alkanephosphonic acids on aluminum oxide

 Typically, inking with

alkanethiols in ethanol
works well because the
ethanol quickly evaporates
and is absorbed into the
PDMS, leaving a
homogeneously thin oily
film on the stamp.

EECS 509 BioMEMS 3

Selective Removal of SAM

 Formation of SAM over the whole substrate surface and then local
modification or removal of the SAM in the selected areas.
- Ablation using laser or ion beam
- Degradation using an electron beam
- Electrochemical desorption using STM tips
- Mechanical Shear using AFM tips
- Oxygen plasma using shadow mask

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Micropattern of Proteins Using Aminosilane

SAM on Alkylsilane SAM Background
 Immunoassay applications; cell biology & tissue engineering applications.
 Photolithography is not suited to directly micropattern proteins because the
developer severely denature proteins. Solvents repel the water that the
proteins need to stabilize their structure. HRP (horseradish peroxidase)
Rhodamine isothiocyanate (RITC)
BHK (Baby hamster kidney)

EECS 509 BioMEMS Biotechnol Prog. 8, 155, 1992

5

印章蛋白的步骤
Patterning Proteins Using Photobleaching-
Induced Adsorption
 Start coating the surface with BSA (bovine serum albumin), acting as sticky
光漂白 surface for photobleachable molecules.
 Biotin-4-fluorescein: photobleachable molecule in blue light.
 Alexa 594-lableled anti-dinitrophenyl IgG: photobleachable in yellow/green

Costantino Group,
Lab Chip, 2009

 Mutliprotein patterning is possible using

different fluorophores at different wavelengths.
 Submicrometer resolution
EECS 509 BioMEMS 6

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Microstamping Proteins
 Stamping requires drying, and dried proteins form crystals, irreversibly
losing their 3D structures. Then, how does microstamping of protein work?
 Surprisingly, PDMS stamp with 300nm-deep features transfers
fluorescently-tagged IgG antibodies to glass with more than 99%.

Biebuyck Group, IBM, Langmuir, 1998

EECS 509 BioMEMS 7

Protein Transfer by Stamping

蛋白转移需要  Microstamping of proteins is sensitive to the choice of substrate, ambient
印章是疏水的 humidity, and surface condition.
关键是印章和
 Hydrophobicity of both stamp and the stamped surfaces are critical.
印章表面的
 The key parameter is the differential of wettability between the stamp and 润湿性不同
the surface. (Carboxylic acid termination (-COOH) makes more hydrophilic.) 但是总体都还是
- When the PDMS stamp is derivatized with hydrophobic functionality (-CF3, or 必须是疏水的，
methyl group), then proteins are transferred to moderately hydrophilic surface. 只是程度不同
- When the PDMS stamp is derivatized with hydrophilic functionality (-NH2 , or
amine group), then surface
must be strong hydrophilic
蛋白的走向取决于 to ensure efficient transfer.
哪一方的亲水性更 - Unfortunately, PDMS deriva-
强，蛋白朝向亲水 tization is still a non-
性强的一边。 quantitative science. It is
laboratory-specific and can
change with time and curing
condition.
EECS 509 BioMEMS Tan et al, Langmuir, 18, 1998 8

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Microcontact Printing of Protein on Mixed

Self-Assembled Monolayer
 Patterned SAM surfaces consisting of COOH-terminated SAM (hydrophilic)
localized in 5 m diameter islands and separated from neighboring islands
by 10 m by CH3-terminated (hydrophobic) SAM.
 Upon CP on the patterned SAM substrates using a flat, unpatterned
stamp, a pattern mimicking the COOH SAM regions of the substrate
emerged.
 The transfer of protein ended sharply and smoothly at the boundary
between high and low wettability regions.

Tan et al, Langmuir, 18, 1998

EECS 509 BioMEMS 9

Stamping with Agarose Gel Micropatterns

 Can we stamp proteins multiple times without re-inking?
 We can do this by keeping the proteins in hydrated state using a hydrogel.
 Agarose stamps allow repetitive stamping without re-inking up to 100 times
at resolution down to 2 m.

Prof. George Whitesides, Proteomics, 2004

EECS 509 BioMEMS 10

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Microfluidic Patterning
免疫球蛋白
 Two different immunoglobulin solutions are delivered to two adjacent
PDMS microchannels filled by capillary.
 Microchannels are then removed before application of antitbodies against
the proteins to show the successful delivery and coating of proteins.
 Extremely simple! You do not have to worry about wettability, dry, etc. as
you do in stamping.

Dr. Biehuyck Group, Science, 1997

EECS 509 BioMEMS 11

Capillary vs. Pressure-Driven Flow in

Microfluidic Patterning of Proteins
 One of the issues related with patterning proteins using microfluidic devices
蛋白转移在体积比表 is protein loss to the walls. This becomes significant especially in capillary
面积高的地方损失比 filling where the surface-to-volume ratio is very high.
较严重
 If the resolution and reagent cost are not a serious consideration, pressure-
driven flow can be used in wider and deeper channels.

Prof. Alber Folch, Biotechnol Prog, 1998

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“Mosaic” Immunoassays 镶嵌免疫

测定
 Orthogonal binding approach – First, deliver antigens (different antigens or
different dilutions of the same antigen) with the microfluidic device and then
remove it. Second, add different antibodies to the orthogonal direction by
rotating the microfluidic device.

Anal Chem, 73, 8, 2001

EECS 509 BioMEMS 13

Particle Lithography
 If the mask aligner is available, is there any easy way to define an array of
submicron regular protein patterns?
Using self-assembly of beads from short-range
attractive force

Prof. Shmidtke Group, Langmuir, 2009

EECS 509 BioMEMS 14

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Micropattern of Cells

Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Cellular Micropatterning
 Micropatterns of cells on non-biomolecular templates
 Cells on micropatterns of metals or oxides
 Cell adherence: Acetate < Palladium (Pd) < Polystyrene;
 Glass < Gold (But after 24 hours of culture, no difference)
 Cells on SAM micropatterns
 Cells on polymer micropatterns

 Micropatterns of cells on biomolecular templates

 Micropatterns of physisorption-repellent background
 Micropatterning cell-substrate adhesiveness
 Cells on chemisorbed patterns of specific peptide sequences
 Other cell patterning strategies

EECS 509 BioMEMS 2

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细胞是需要依托于
Aminosilanes Cells on SAM Micropattern
 Alkylsilane/Aminosilane SAM micropatterns by photolithography
 Cells attach & grow selectively on the aminosilanes
- Alkylsilanes (are hydrophobic and) deter cells from attaching to them
- Aminosilanes enhance attachment (1) by integrin binding to physisorbed ECM
from serum; (2) by electrostatic force between the positive charges present on
amine-terminal SAM and the negative charges present at the cell surface.
Clean Si or
Quartz Derivatize with alkyl-
Spin-coat with tricholorosilane
photoresist

Expose through
mask Strip
photoresist

Derivatize with
Develop amino-trihydroxysilane
photoresist

Lithographically Chemically defined

defined surface surface
EECS 509 BioMEMS 3

Cells on Polymer Micropattern

 Paraffin: no adhesion of hamster fibroblasts
 Poly(N-isopropylacrylamide) or poly-NIPAM: Cells can be cultured only on
poly-NIPAM; then detached by lowing the incubation time below LCST
(lower critical solution temperature, 32oC)
 Photoreactive copolymer containing phenylazide-conjugated monomers.

Endothelial cells are attached only on hydrophobic surface.

EECS 509 BioMEMS 4

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Cellular Micropatterning
 Micropatterns of cells on non-biomolecular templates
 Cells on micropatterns of metals or oxides
 Cell adherence: Acetate < Palladium (Pd) < Polystyrene;
 Glass < Gold
 Cells on SAM micropatterns
 Cells on polymer micropatterns

 Micropatterns of cells on biomolecular templates

 Micropatterns of physisorption-repellent background
 Micropatterning cell-substrate adhesiveness
 Cells on chemisorbed patterns of specific peptide sequences
 Other cell patterning strategies

EECS 509 BioMEMS

Cell Adhesion/Barriers
 Using natural bio-recognition interactions between molecules present in the
cell membrane and molecules present on the adhesive substrate.
 Biological adhesiveness
- Passive: ECM proteins or peptide sequence recognized by integrins in the cell
membrane
- Active: Antibody recognizing molecules on the cell membrane
 Physisorption barriers
- Physical barriers: stencil
- Chemical barriers: SAM which repels protein absorption
 Cells can adhere to a micropattern by their specificity to biomolecules.

- Neurons grow along

collagen (polyornithine)
coatings, not along
palladium.
- UV-irradiated laminin repels
cell growth.
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HEG-Thiol SAM as Physisorption-Repellent

Background
 Methyl-terminated alkanethiol SAM on gold surface patterned by stamp.
 Then, fill the background with alkanethiols terminated in hexa(ethylene
glycol) (HEG) group.
 When exposed to ECM protein solutions, proteins physisorb onto the
methyl-terminated areas only.

Implication: Cell
function can be
tailored by
modifying its
shape.

Prof.
George Whitesides,
Sience, 1997

EECS 509 BioMEMS 7

PEG as Repelling Cell Layer

 Thin film of “interpenetrating” polymer network (IPN) of PEG can be
patterned to confine cell attachment and growth.
 Stability and durability of PEG-IPN is superior to thiol-based SAMs.
 But not easily patterned by simple microstamping as SAMs can be.

PEG-IPN

Cells constrained to attach to a small island (< 900 mm2) cannot

form cytoskeleton, whereas long-term cytoskeleton organization is
observed for larger islands.
Kevin Healy Group, J. Biomech. Eng, 1999
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Pluronic Copolymer for Blocking Cell

Adhesion & Migration
 By exposing the surface to a phosphate-buffer solution of surfactant
Pluronic F68 or F108 and ECM proteins, adsorption of Pluronic copolymer
can be selectively adsorbed onto the hydrophobic areas only.

Flow
Migration Direction
Blocking
Patterns

Cell
Capture
Site
Selective coating of Pluronic copolymer F108 only on hydrophobic SU8
pattern, not on a hydrophilic glass substrate. Cultured PC3 cells for 4days.
Cell migration was effectively blocked by selective coating of triblock
pluronic copolymer on the SU8 wall.
Prof. Euisik Yoon, Biomicrofluidics, 2014
EECS 509 BioMEMS 9

Agarose Hydrogel for Cell-Repellent Material

 Create micropatterns of hydrogel (agarose), which is known to deter protein
physisorption and cell attachment.
 When the PDMS/agarose textured surface is incubated in a fibronectin
solution, fibronectin physisorbs only onto the bare PDMS areas.

PDMS

Dr. Mehmet Toner, Biotechnol. Prog., 1998

EECS 509 BioMEMS 10

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SH-PVS Hydrogel on Gold

 Thiolated poly(vinyl alcohol) (SH-PVA) hydrogel can be selectively
immobilized on gold in aqueous solution.

T. Matsuda,
Langmuir., 1998

EECS 509 BioMEMS 11

Collagen Patterning by Photoresist Lift-Off

 Chemisorbing collagen by lift-off and then filling the background of the pattern by
physisorbing albumin.
 Hypatocytes cells selectively
attach on collagen in serum
free condition, not on
albumin.
 However, fibroblast cells
attach onto albumin surface
No serum because they seeded in a
In serum serum containing medium
that contains a lot of other
proteins that promote cell
adhesion, even though
albumin does not.
 Would solvent denaturize
collagen during lift-off?

Dr. Mehmet Toner, J. Biomater. Sci. Polym., 1998

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How Is It Possible?
 During the lift-off process, collagen is denatured by a strong solvent. But
cells do not really attach to the whole collagen molecules – only to a small
sequence of peptides that has not been altered.
 The conventional protocol (chemisorbed to an aminosilane SAM via a
glutaraldehyde linkage; See the lecture Slide #5-5 in Micropattern of SAM
and Proteins.) can be skipped if denaturization of proteins is tolerated for
cell adhesion.
 Would it be working if you use polystyrene (Petri dish material) as
substrate? No, polystyrene will be attacked by organic solvents and must
be ruled out as the substrate.
 Proteins undergo partial denaturization when exposed to most solvents.
However, cells can attach, spread, grow, and function on denaturized ECM
proteins as long as the degree of denaturization does not damage integrin
binding to the ECM peptide fragments.
 This method cannot be combined with other biomolecules such as
antibodies that are irreversibly damaged by the solvent.

EECS 509 BioMEMS 13

How About Fiberblasts?

 Fiberblasts can attach to the albumin surface because they are seeded in a
serum-containing medium that contains a log of other proteins that promote
cell adhesion, even though albumin does not.

EECS 509 BioMEMS 14

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PDMS Stencil to Pattern Collagen

 Why do we bother to pattern photoresist and worry about denaturization
during the lift-off? Why don’t we use a removable mask (stencil) to pattern
the protein on the surface?
 A micromolded PDMS stencil (~50 – 100 m) can be nondistructively
applied onto a surface and protect the area from collagen coating. Cells are
seeded on the surface and then the stencil is peeled off after cell
attachment.

PDMS stencil can be applied

onto any surface.

Prof. David Beebe & Dr. Mehmet Toner,

J. Biomed. Mater., 2000

EECS 509 BioMEMS 15

Collagen Pattern Using Microfluidic Channel

 Use of microfluidics to create ECM protein templates for selective cell
attachment.
 Variety of biocompatible substrates have been investigated including
polystyrene, PDMS, polycarbonate, and PMMA.

Prof. Albert Folch & Dr. Mehmet Toner, Biotechnol. Prog., 1998
EECS 509 BioMEMS 16

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Inkjet Printing
 Can we selectively attach the cells in any desired locations?
 Custom-built inkjet printer to deposit protein droplets in the smallest island
of ~65 m with a gap of ~8 m.

How about
Nano-ink or
Microfluidic
fountain-pen?
(See lecture
slide #2-18.)

Prof. Sawyer Fuller, MIT, J. Neurosci. Methods., 2004

EECS 509 BioMEMS 17

Direct Cell Patterning Using Microfluidic

Channel
 Why do we bother to define the pattern of proteins that cell may attach
onto? We can simply inject the cell suspension media inside the
microfluidic channels and induce cell attachment in no-flow condition. (We
may need to provide perfusion culture later.)
 Cell attachment is a highly metabolic, oxygen-dependent process, special
schemes may be needed for different cell types.

Prof. Albert Folch & Dr. Mehmet Toner, J. Biomech.Eng., 1999

EECS 509 BioMEMS 18

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Hydrodynamic Cell Seeding Inside

Microfluidic Channels
 Sandwiched porous
membrane between the top
and bottom channels for
trapping cells within
microfluidic channels.
 Cells self-aggregate and form
a spheroid after long-term
culture.

Prof. Shu Takayama,

Lab Chip, 2007

EECS 509 BioMEMS 19

Chemisorbed Micropattern of Adhesion

Receptor
 Glass surface is derivatized with an aminosilane SAM; then the SAM is
selectively photoablated using a high-radiance (~10J/cm2) deuterium lamp.
 Cysteine-labeled peptide is coupled to the aminosilane using the hetero-
bifunctional crosslinker, which reacts with amine groups on the SAM and
the thiol groups on the cysteine.

Dr. Wolfgang Knoll Group,

J. Neurosci. Methods,
1996

Neuronal micropatterns
using cell-adhesion
peptides.

EECS 509 BioMEMS 20

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Microfluidic Delivery of Cell-Adhesion Peptides

Attach PLA-PEG-
biotin surface is
prepared on PEG
substrate.

Flow avidin
selectively inside
the microfludic
channels

Microfluidic
channels are
flushed and
removed, and apply
biotinylated
peptides are
introduced
Prof. Kevin Shakesheff, FASEB, 1998
EECS 509 BioMEMS 21

Selective Cell Capture

 Immnocapture: When the substrate (either glass or plastic plate) is coated
with antibodies against proteins present on the membrane of a certain cell
type, then the plate will selectively capture a preferential type of cells. And
the rest can be rinsed away.
 DNA barcode cell patterning: You can decorate cells with DNA strands
and use the pattern of complementary DNA immobilized on the surface to
capture cells in selected location.

Prof. Mathies & Francis, Lab Chip, 2007

EECS 509 BioMEMS 22

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Basic Microfluidics

Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Micro-Fluidic Channel

 Microfluidics: Dimension < 1 mm

 Nanofluidics: Dimension < 1 m
 Newtonian fluid (applying Navier-Stokes Equation)
- Coefficient of viscosity is constant over all shear stress
- Incompressible, Steady (time-invariant) flow
- Fully developed flow
 Laminar flow due to low Reynolds number
- No turbulence  Mixing becomes difficult
灌注气泡  Priming bubbles very difficult
- Surface tension > buoyant force
 Capillary and viscous forces become dominant.
 Electrophoretic, Electroosmotic flows more easily handled
than pressure driven flow.

EECS 509 BioMEMS 2

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Types of Fluid Flow

 Reynolds’ experiment
- Turbulent flow : unsteady flow
- Laminar flow : steady flow

Dye Dye

Glass pipe Glass pipe

Laminar flow Turbulent flow

EECS 509 BioMEMS 3

Reynolds Number

 Ratio of the inertial force to the viscous force

vD Q
Re     A D
h
 h
 : density
Q: volumatric flow rate
A: cross -sectional area of channel
D : hydraulic diameter (4A/perimeter)
h
 : viscosity(g/seccm)

 Transitional value (Re): 2,000~3,000

EECS 509 BioMEMS 4

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Mechanism of Mixing

 Mixing was produced by mechanical and molecular

physical process
 Macro-scale: Dominated by mechanical process
- Turbulence, stirring
 Micro-scale: Dominated by molecular process
- Laminar, diffusion

EECS 509 BioMEMS 5

Parabolic Flow Profile

 Pressure-driven fully-developed Newtonian flow

EECS 509 BioMEMS 6

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Force Profile Across the Channel

 Force acting on the cells as a function of position across the channel

Velocity

EECS 509 BioMEMS 7

微流控管道材料选择
Fabrication of Microfluidic Channels
 Silicon and Glass
- Conventional micromachining, bonding, etching
- Expensive
 Plastics
- Injection molding using thermoplastic materials such as polystyrene,
polypropylene, etc.
- Inexpensive
 PDMS
- Good research material but not amenable to inexpensive mass
production for commercial devices.
 Hydrogels
- Highly porous polymeric matrices: collagen, Matriegel, agarose, PED,
etc.; Easily molded from a PDMS mold for 3D cell culture.
 Paper
- Extremely inexpensive, natural embedded capillary pump
EECS 509 BioMEMS 8

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Bulk Micromachined Silicon Microchannels

Chen and Wise,

Transducers 1995

Tjerkstra, et al., MEMS 1997

EECS 509 BioMEMS 9

Surface Micromachined Microchannels

Dielectric
channels
(Lin, et al.,
Trans. ’93)

Polymer
channels
(Man, et al.,
MEMS ’97)

EECS 509 BioMEMS 10

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Polystyrene Microfluidic Channels 热塑性材料，聚

 Thermoplastic materials 苯乙烯。
(polystyrene) can be molded into
devices with extremely small
features from shrinking.
 Injection molding can be avoided
but still very inexpensive.
 Low-cost “Shrinky-dinks”

$6.42
At Amazon

Prof. Luke Lee at Berkeley, Lab Chip 2008

EECS 509 BioMEMS 11

ECM Hydrogel Microchannel

嵌入胶原蛋白中的基质  Selectively remove matrigel microstructure embedded in collagen
 Use dispase, an enzyme, to digest matrigel selectively through porous
collagen membrane.
使用分散酶（一种
酶）通过多孔选择性
消化基质胶胶原膜。

Prof. Joe Tien, Boston U., Adv. Mater. 2004

EECS 509 BioMEMS 12

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Paper Microfluidics

 Paper is impregnated with 纸浸有

photoresist and then 光刻胶，然后
patterned by 仿制
photolithography. 光刻
 The remained photoresist in
the paper after development
will form hydrophobic wall
for the fluids.
 Paper is inexpensive and
biodegradable.
 Applicable for resource-poor
countries and settings.

Prof. George Whitesides,

Anal. Chem, 2008
EECS 509 BioMEMS 13

Laminar Flow in Paper Microchannels

 Paper supports flow at speeds that are fast enough that mixing between
adjacent streams is negligible.
 Heterogenous-flow assay can be implemented in paper. (Prof. Paul Yager,
U. of Washington)

Prof. Albert Folh,

U. of Washington
EECS 509 BioMEMS 14

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Room-Temperature Bonding PDMS to Plastic

Substrate Using Silanes
 Bonding between
PDMS and plastics
(PMMA,
polycarbonate,
polyimide, and PET)
using simple, silane-
based room
temperature
process.

Prof. Nae Yoon Lee,

Lab Chip, 2010
EECS 509 BioMEMS 15

Modular Microfluidics
 How to connect each microfluidic channels and components?
 Can we make a microfluidic breadboard or PCB?
 Plug-and-play, LEGO-like modularity

Prof. Mark Burns, University of Michigan, Lab Chip 2008

EECS 509 BioMEMS 16

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Tubeless Microfluidics by Embedding

Microchannels on 96-Well Plates
 Hybrid integration of microfluidic
channels inside the 96-well plate.
 Channels run under the well
through an aperture.
 Introduction/withdrawal of reagents
to each well through the flow
channels.
 Total 11 analytes can be supplied
to the plates.

Prof. Brian Cunningham, UIUC, Lab Chip 2007

EECS 509 BioMEMS 17

Chip-to-Chip Nanoliter Dispenser

 Why do we bother to integrate microfluidic channels on the 96-well plate?
 Why don’t we just make a microfluidic dispenser?

Prof. Yanyi Huang,

Peking U.,
Lab Chip, 2009

EECS 509 BioMEMS 18

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Actuation of Fluids
Electro-osmosis, Electrophoresis,
Dielectrophoresis
Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Electrokinetics and Microfluidics

 Using electric fields to facilitate microfluidic/nanofluidic
actuation and manipulation provides a variety of advantages
including simplicity, efficiency, and miniaturizability.
 Many applications have been demonstrated such as DNA
separations, enzyme assays, immunoassays, cell patterning,
flow cytometry, integrated PCR amplification, and etc.

EECS 509 BioMEMS 2

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Ionic Double Layers

 The chemical equilibrium between the electrolyte and
insulating solid surface leads to:
- Net fixed electrical charge at the interface
- Layer of mobile ions forming in the region near the interface
 Glass and silica surfaces acquires a negative charge when
immersed in water.

EECS 509 BioMEMS 3

Electrophoretic vs. Electroosmotic

+V -V

+ +

- 2+

+
-2
+ +

介电泳可以束缚住负电荷
Electrophoretic Electroosmotic
Immobilized negative surface charge
(channel: Glass, SiO2)

EECS 509 BioMEMS 4

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Electro-Osmosis Flow (EOF)

 When an electric field is applied along the microfluidic channel,
the net charge in the electrical double layer is induced to move
by the resulting Coulomb force.

C. H. Liu group (NTHU), Lab Chip, 2008

EECS 509 BioMEMS 5

What Is Really Happening in EOF?

• Function of pH and ion concentration
Net mobility
+V -V net= eo+ E

No movement
- - - - - - -
Double + +
+
+ +
High concentration
- +
Layer + + + of positive ion
+
Net movement
-
+
Mobile -
Layer - +
+
+ +

- -
+ + + +
+ + + +
- - - - - - - -
+

Electrophoretic force
Immobilized surface charge

EECS 509 BioMEMS 6

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Advantages of Electro-Osmosis Flow

 Plug flow profile (approximately planar)
 No moving parts
 Easy fabrication
 Large-scale integration

EOF Pressure
driven
J. G. Santiago group (Stanford), Micro- and Nano-Scale Diagnostic Techniques, 2002
EECS 509 BioMEMS 7

Velocity Profile of Different Fluidic Driving

• External pressure driving

Velocity

• Electroosmotic force

Velocity

EECS 509 BioMEMS 8

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Cascaded Electro-Osmotic Pump

 The pressure output of a pump cannot be increased by simply
connecting several of them in series. However, this barrier can
be eliminated by simply assembling several Electro-Osmotic
pumps in serial.

Capillaries
coated
with
positively
charged
polymer Capillaries
coated with
negatively
charged
polymer S. Liu group (OU), Anal. Chem., 2012
EECS 509 BioMEMS 9

Potential Problems of EOF

电解
 DC voltage drive causes electrolysis Problem:
and bubbles.
 Needs high voltages over long
distances (> 1000V)
 Potential pressure driven back flow

Solution:
 Use highly resistive porous plug with
closely spaced electrodes.
 Use AC current drive with zero net
charge transfer or other driving
methods.

Slides from Dr. Senol Mutu, EECS, Univ. of Michigan

EECS 509 BioMEMS 10

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AC Driven EOF

Y. B. Gianchandani group (UM), MEMS conference, 2004

EECS 509 BioMEMS 11

Electrophoresis
 A particle in solution can be charged or obtain charge due the
dissociation of its ionic compounds on its surface
 Electropheresis describes the motion of this kind of particles
relative to the fluid, under the influence of a spatially uniform
electrical field.
Electrophoresis of ion Electrophoresis of particle

J. G. Santiago Group (Stanford), Micro- and Nano-Scale Diagnostic Techniques, 2002

EECS 509 BioMEMS 12

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Macro-scale Gel Electrophoresis

 DNA has 3D helical
structure and it is
negatively charged.

 Shorter molecules
migrate more easily
(faster) through the
pores of the gel

 It is tedious,
subjective and
subject to potential
variations from one
lab to the others.
https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2011/03/genetic-testing/
EECS 509 BioMEMS 13

Microfluidic Electrophoresis
 Step1: samples move through microchannels from loaded well
 Step2: every sample is inserted in the separating channel
 Step3: samples are separated through electrophoretic gradient
 Step4: results are read according to the fluorescence, which
generates an image identical to gel electrophoresis

http://www.agilent.com/chem/labonachip
EECS 509 BioMEMS 14

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Microfluidic Electrophoresis (video)

http://www.youtube.com/watch?v=8fXk7-aWBpY
EECS 509 BioMEMS 15

EOF & Electrophoresis, Again

 Electrophoresis and
EOF might compete
each other.
 Electrophoresis
speed is usually
much smaller than
EOF.
 Electrophoresis is
superimposed on
EOF (fluid is
transported by EOF
while particles are
separated by
electrophoresis).
Slides from Prof. K. W. Oh, EE, UB
EECS 509 BioMEMS 16

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Dielectrophoresis (DEP)
 Dielectrophoresis (DEP) is the force generated on a dielectric
particle when it is exposed to a non-uniform electric field.
 The strength and direction of DEP force depends on a variety
of factors including particle’s permittivity, liquid’s permittivity,
particle’s shape and size, frequency of electric field.

EECS 509 BioMEMS 17

DEP and Electrical Field

EECS 509 BioMEMS 18

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Electrodes design (1)

K. Kalantar-zadeh group (RMIT Univ. Australia), Anal Bioanal Chem, 2009

EECS 509 BioMEMS 19

Electrodes design (2)

K. Kalantar-zadeh group (RMIT Univ. Australia), Anal Bioanal Chem, 2009

EECS 509 BioMEMS 20

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DEP Actuation (video)

• One of the most widely used techniques to manipulate
micro or nano-scale particles.
• Interaction of between polarizable particles and the
media in non-uniform electric fields

EECS 509 BioMEMS

DEP Patterning (video)

http://www.youtube.com/watch?v=YVtOyeb7Ji8
EECS 509 BioMEMS 22

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DEP cell patterning

PDEP (HepG2 cell) NDEP (3T3 cells)

C. H. Liu Group (NTHU), MicroTAS, 2011
EECS 509 BioMEMS 23

DEP Dell Sorting

 The negative DC-DEP force
acting on the cells is
proportional to the cells’ size.

J. E. Eid Group (Vandy), Biomed, 2008

EECS 509 BioMEMS 24

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Operation Mechanism(1)
 DC electric field
- DEP particle separation and electrokinetic particle transportation

DC-DEP force equation

We consider that σp = 0.
Cell membrane blocks DC current.
Cells behave like an insulator.

Negative DEP Distribution of E-field and

force analysis
EECS 509 BioMEMS 25

Operation Mechanism (2)

 Control the flow stream and particle motion

- By changing voltage at electrode A
- Particles move following the streamlines without the block corner
regions

A
Effects of branch voltage VA on the separation of 5.7μm and 15.7μm
EECS 509 BioMEMS 26

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Results
 Separation by particle size
- The magnitude of the particle trajectory deviation is proportional to the
DEP force.

Separation of 5.7μm and 15.7μm particles

Comparison of the simulation
and experimental results
EECS 509 BioMEMS 27

DEP Cell Sorting (video)

http://www.youtube.com/watch?v=WBj3sBHumGw
EECS 509 BioMEMS 28

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DEP Cell Transportation

K. Kalantar-zadeh Group (RMIT Univ. Australia), Anal Bioanal Chem, 2009

EECS 509 BioMEMS 29

DEP Cell Transportation (video)

K. Youcef-Toumi Group (MIT), Anal. Chem., 2007

EECS 509 BioMEMS 30

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Active Capturing of Single Cells

 Operation Principle: DEP
• Capture in micro-well • Branch channel
Electrode for DEP Outlet 1

Electrode 1 Electrode 2
A B F for DEP for DEP D
Inlet C Outlet
B C
A
D E F
Inlet
G
Micro capture site
for cell/bead E
Outlet 2
Drain

Electrode ON : A  B  C  D  E Electrode1 ON : A  B  C  D
Electrode OFF : A  B  F Electrode2 ON : A  E  F  G

EECS 509 BioMEMS

Single Cell Positioning Microfluidic Chip

 Fabricated PDMS channel structure

100μm

 Fabricated Single cell control chip

Pads for DEP Electrodes Electrodes for DEP

Outlet 1
Outlet port
Micro wells
Inlet port Inlet Drain
Drain port Outlet 2
10mm 100m

Prof. Euisik Yoon, MEMS, 2005

EECS 509 BioMEMS

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Active Microbead Capturing (Video)

• Microbead : 15μm polystyrene bead

• Solution : PBS buffer
• Supply voltage : 10Vpp at 1MHz Prof. Euisik Yoon, MEMS, 2005
EECS 509 BioMEMS 33

Capturing of Microbeads: Any Numbers

 Capture results of single microbead

per each micro-well

 Microbeads capture results

at various numbers
Prof. Euisik Yoon, MEMS, 2005
EECS 509 BioMEMS

17
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Microvalves

Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Types of Microvalves
 Microvalve is a microfluidic component used to turn on/off or
otherwise modify the flow of a fluid passing through it.
 In terms of whether requiring external actuation power:
- Passive valves
- Active valves
 In terms of operation mode:
- Normally open valves
- Normally close valves
 Based on actuation mechanisms:
- Magnetic, Electrostatic, Piezoelectric, Thermal, Electrochemical, Phase
change, Pneumatic, etc.
 Microvalves are essential for:
- On/Off control of fluids
- Integrated microfluidic logics

EECS 509 BioMEMS 2

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Basic Mechanical Valve Types

Valve seat

Cantilever type Cantilever type (with

valve seat)
Micro
sphere

Disc type Ball type

K.-S. Yun and E. Yoon, “Micropump Systems Techniques and Applications in MEMS,” in
MEMS/NEMS HANDBOOK: TECHNIQUES AND APPLICATIONS, Springer 2006.
EECS 509 BioMEMS 3

Valve Specification
 An ideal valve should have:
- Zero leakage
- Zero dead volume
- Low power consumption
- Large differential pressure capability
- Fast response time
- Insensitive to environment such as temperature
- Reliable
- Biocompatible
- Ability to work with different liquids/gases
- Scaling down capability
- Convenient fabrication and operation
- …
 In practice, we usually compromise performance requirements
for different applications.
EECS 509 BioMEMS 4

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Check Valves (Passive Valves)

 Passive valves are mostly used as check valves, allowing flow
only in one direction. In this respect, it is analogous to a diode
in electrical circuits.

G. M. Whitesides Group (Harvard), Biomed Microdevices, 2002

EECS 509 BioMEMS 5

Other Types of Passive Valves

 Hydrophobic valves:
- Liquid enters into the narrow channel only after applying a pressure
higher than the critical value.

Minoru Seki group (University of Tokyo, Japan), Anal. Chem., 2004

 The nonstick polymer piston valve:

J. E. Rehm Group (SNL), Anal. Chem., 2002

EECS 509 BioMEMS 6

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Self-Regulating Floating-Disk Microvalve

Y. C. Tai (Caltech), MEMS Conference, 2008

EECS 509 BioMEMS 7

Pneumatic Microvalve
 Push-down valve

 Push-up valve

 Normally-closed
valve

S. R. Quake Group (Stanford), Annu Rev Biophys Biomol Struct., 2007

EECS 509 BioMEMS 8

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Pneumatic Microvalve Fabrication

S. R. Quake Group (Caltech), SCIENCE, 2000

EECS 509 BioMEMS

Pneumatic Actuation
Valve Operation Pump Operation

EECS 509 BioMEMS

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Microfluidic Multiplexor

EECS 509 BioMEMS

Microfluidic Memory Storage Device

20 X 40 chambers
250pL

Prof. S. R. Quake (CalTech)

EECS 509 BioMEMS

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Memory Operation

Purging Mechanism

(i) Pressurized Fluid is introduced in the purge buffer input

(ii) The row multiplexor directs the Fluid to the lower channel of the selected row
(iii) The column multiplexor releases the vertical valves of the chamber
Prof. S. R. Quake (CalTech)
EECS 509 BioMEMS

Microfluidic Comparator chip

Prof. S. R. Quake (CalTech)

EECS 509 BioMEMS

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Large scale integration of pneumatic valve

6.4mm
S. R. Quake Group (Stanford), Annu Rev Biophys Biomol Struct., 2007
EECS 509 BioMEMS 15

Microfluidic Perfusion with Microvalves (video)

http://www.youtube.com/watch?v=Al4kZzg825g
EECS 509 BioMEMS 16

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Microfluidic Mixing with Valve Actuation (video)

http://www.youtube.com/watch?v=b7MB3rjadng
EECS 509 BioMEMS 17

Electrostatic Microvalve
Valve open

Valve closed

A A’

Y. C. Tai (Caltech), MEMS Conference, 2003

EECS 509 BioMEMS 18

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压电
Piezoelectric Microvalve
 Piezoelectric valve utilizes the ability of piezoelectric actuation
to produce mechanical stress or stretching with an applied
electric field, resulting in on/off swtiching of valve operation.

T. George Group (JPL), JMEMS, 2004

EECS 509 BioMEMS 19

Thermally Pneumatic Microvalves

 Thermopneumatic microvalves are operated by volumetric
thermal expansion coupled to membrane deflection:

Y. K. Kim Group (SNU, Korea), Microelectronic Engineering, 2004

EECS 509 BioMEMS 20

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Bi-Metallic Microvalves
 Bi-metallic valves consist of two elements of different materials
(aluminum and silicon here). By varying the heat generation at
the resistors, displacement of the central boss can be controlled

Hal Jerman (IC Sensors), Transducers Conference, 1991

EECS 509 BioMEMS 21

Phase-Change Microvalves
 Phase-change utilizes material’s phase change for valve
actuation.
石蜡  Paraffin below actuates a latchable valve from its phase
change. The valve closes under a pneumatic pressure and
opens by the membrane’s elastic force. However, both
closuring and opening operations require paraffin to be melted
by the microheater.

Q. Lin group (Columbia University), JMEMS, 2009

EECS 509 BioMEMS 22

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Shape Memory Alloy (SMA) valve

 The shape memory effect can be utilized to actuate valves.
 In this example, bent nitinol wires experience compression on
their inner perimeter and tension on their outer perimeter.
When heated by electric current the outer perimeter contracts
and reset the wire to its original straight, annealed shape.
Nitinol is a metal alloy of nickel and titanium,
which has shape memory and superelasticity.

B. Towe Group (ASU), Sensors & Actuators A-Phys, 2006

EECS 509 BioMEMS 23

Hydrogel Microvalve
 Hydrogel valves utilize hydrogels that undergo reversible
volume change with environment conditions.
 Hydrogels can respond to a variety of inputs such as pH,
temperature, electric fields, light, carbohydrates, antigens, etc.

In situ hydrogel
photopolymerization

D. J. Beebe (UW-Madison), Adv. Drug Deliv. Rev., 2004

EECS 509 BioMEMS 24

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Micropumps

Euisik Yoon

University of Michigan
1301 Beal Avenue
Ann Arbor, Michigan 48109-2122
Tel: (734) 615-4469, FAX: (734) 763-9324
e-mail: [email protected]
EECS 509 BioMEMS 1

Introduction
 Microvalves are of special interest due to their miniaturized
size, lower cost, and improved dosing accuracy, when
integrated in microfluidic chips.
 Micropumps can be miniturized from the macroscale
analogues such as:
- Check valve pumps
- Peristaltic pumps
- Rotary pumps
 Micropumps can be also realized using special microscale
effects such as:
- Electrohydrodynamic pumps
- Elctrokinetic pumps
 Micropumps are having lots of overlap with microvalves (in the
previous lecture) in terms of driving mechanism and design
structures. And both of them are essential in integrated
microsystems including LOCs.
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Micropump Parameters
 Maximum flow rate:
- Also called pump capacity
- Qmax: Volume of liquid per unit time delivered at zero back pressure.
 Maximum back pressure (Pback,max):
- Maximum pressure the pump can work against.
 Pump efficiency
- Ƞ= Ppump/Pactuator
- Ppump: Power of the pump
- Pactuator: Input power of the actuator
 Size
 Frequency
 Also some others like:
- Qmax/Ap(μl/min mm2), P/Q(W min/ml), V/Q(V min/ml)
B. D. Iverson (Purdue), Microfluid Nanofluid, 2008
EECS 509 BioMEMS 3

Micropump Classification

D. J. Laser (Stanford), JMM, 2004

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Micropump

 Critical component that exerts a pressure on liquids to

transport reagents or control liquids.

Micropump

Indirectly-Driven Micropumps Directly-Driven Micropumps

Reciprocating Membrane Micropumps Electrohydrodynamic Micropumps

Peristaltic Micropumps Electroosmotic Micropumps
Syringe Micropumps Magnetohydrodynamic Micropumps
Rotary Micropumps Surface Wave-Induced Micropumps
Bubble-Driven Micropumps

Pressure-driven liquid actuation Direct force on liquid molecule

Ref: K.-S. Yun and Euisik Yoon, Chapter 5. Micropump Systems
Techniques and Applications, MEMS, MEMS/NEMS HANDBOOK:
TECHNIQUES AND APPLICATIONS Volume 4, Springer 2006.

EECS 509 BioMEMS 5

Indirectly-Driven Micropump

Valve
Inlet Outlet

Membrane Chamber
Actuator
Actuator

Step I Step II

 Most indirectly-driven micropumps have a similar structure

but with different actuation mechanisms.

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Also Called as Reciprocating Micropumps

往复式微型泵  A reciprocating micropump usually uses a moving boundary
driving working fluid in a periodic manner.
 Reciprocating micropumps with a wide range of driving
mechanism and structure design have been reported.

D. J. Laser (Stanford), JMM, 2004

EECS 509 BioMEMS 7

Pneumatic Reciprocating Micropump

D. J. Laser (Stanford), JMM, 2004

L. G. Griffith group (MIT), JMM, 2007

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Various Actuation Mechanisms

Actuation Response Operation Power

Pressure Displacement
Type time voltage consumption
Piezoelectric
very large very small fast very large small
(Stack type)

Electrostatic small very small very fast very large small

Thermo -
large medium medium medium large
pneumatic
Electro -
small large fast small large
magnetic
Bimetallic large small medium large medium

SMA large - - - large

EECS 509 BioMEMS

PZT Actuation
Piezoelectric
material V

•Disk Type
Electrical energy

Piezoelectric
material
Mechanical energy •Cantilever Type V

悬臂

Stack type
piezoelectric V
material

•Stack Type

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PZT-Driven Micropump

-Flow rate : 365 l/min (25 Hz)

-Membrane size : d=5 mm, t=11 m
-Back pressure : 0.238 mH2O (25Hz,100V)
NiFe t=7m
-Chamber size : d=5 mm, t=370 m
-Operation voltage :100V

Wang,Tsinghua Univ. (China), Int.Symp.Micromechatronics & Human Sci., 1998

EECS 509 BioMEMS 11

Thick-Film Piezoelectric Actuation

-Membrane size : 8 X 4 mm, t=70 m -Flow rate : 120 l/min(200 Hz,600V)

-Back pressure : 0.2 mH2O (200 Hz,600V)
-Displacement : 1 m (100V)

Koch, Univ. Southamptom, Transducer’97, p.353

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Piezoelectric Reciprocating Micropump

D. J. Laser (Stanford), JMM, 2004

Q. M. Zhang group (PSU), Sensor Actuat A-Phys, 2006

EECS 509 BioMEMS 13

Valveless Diffuser/Nozzle Pumping

 During the expansion stroke, inlet acts as a diffuser and outlet
acts as a nozzle.
 During the compression, inlet acts as a nozzle and outlet acts
as a diffuser.
 More liquid passing through a nozzle than a diffuser.
 A net flow is generated from the inlet to the outlet.

Overall flow direction

Erik Stemme(KTH, Sweden), Electronics cooling, 1996
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Electrostatic Reciprocating Micropump

D. J. Laser (Stanford), JMM, 2004

A. Machauf (Technion, Israel), JMM, 2005

EECS 509 BioMEMS 15

Membrane Pump with Electrostatic Actuation

-Membrane size : 4 X 4 mm, t=25 m -Flow rate : 70 l/min (25 Hz,170V)

gap = 5 m -Back pressure : 0.25mH2O (170V)

-Operation voltage :170V

Zengerle (Fraunhoff), MEMS, 1992

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Thermo-Pneumatic Actuation

-Flow rate : 220 l/min (~20Hz, ~15V)

-Back pressure : 1 mH2O - Operation voltage :15V

Schomburg (German), MEMS,1997

EECS 509 BioMEMS 17

Thermal Reciprocating Micropump

D. J. Laser (Stanford), JMM, 2004

Y. S. Kim Group (Myongji Univ., Korea), Current Applied Physics, 2007

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Bidirectional Magnetic Actuated Micropump

Valve Pump Valve

Permalloy

Inlet Membrane Spiral coils Outlet

-Flow rate : 20 l/min (5 Hz)

-Membrane size : 8 X 8 mm, t=30 m
NiFe t=7 m -power consumption :300 mA,3 V,0.9 W

Prof. C. Ahn (U. of Cincinnati), Solid-State Sensor & Act. Workshop,1996

EECS 509 BioMEMS 19

Magnetic Reciprocating Micropump

Prof. B. Ziaie group (UMN), JMM, 2005

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Surface Tension in Micro World

From Movie “Ants”

EECS 509 BioMEMS 21

Micropump Driven by Surface Tension

Electric Potential Surface Tension Motion of

Gradient Variation Liquid Drop
V

Electrode Electrolyte
x

Hg
Motion

High surface tension Low surface tension

Prof. K. S. Yun (Sogang U., Korea), JMEMS 2002

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Design and Operation of Micropump

Inlet Outlet

Si Si
Si Si
SU-8 Hg SU-8 Hg

Glass Glass

Step 1 Step 2

Alternating motion Net flow from

of mercury drop inlet to outlet
Prof. K. S. Yun (Sogang U., Korea), JMEMS 2002
EECS 509 BioMEMS 23

Fabricated Device
Surface Tension Driven Actuation

往复运动 Hg drop
增大频率运动加速

Pt

2mm

Prof. K. S. Yun (Sogang U., Korea), JMEMS 2002

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Experimental Results
Vapp = 2.3 V
Vapp = 2.0 V
at 2.3 V, 25 Hz
80 Vapp = 1.7 V
70
70 measurement
Flow rate (L/min)

Flow rate (L/min)

60 linear fit
60
50
50
40
40
30 30

20 20

10 10
0 0
0 10 20 30 40 50 0 100 200 300 400 500 600 700 800

Frequency (Hz) Backpressure (Pa)

• Operating voltage : 2.3 V
• Power consumption : 170W
• Maximum flow rate : 70 l/min
Prof. K. S. Yun (Sogang U., Korea), JMEMS 2002
EECS 509 BioMEMS 25

Peristaltic Pump (Piezoelectric actuation)

PZT Membrane
Inlet Outlet

-Flow rate : 100 l/min (100V)

-Back pressure : 0.6mH2O (100V)

Smits, Boston University, Sensors & Actuators, 1990

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Peristaltic Thermopneumatic Micropump

-Membrane size : 10 x 3 mm, -Flow rate : ~5 l/min (4 Hz)

t=120 m (si rubber) -Back pressure : 0.36 mH2O

Y-C Tai (CalTech), Transducer, 1999

EECS 509 BioMEMS 27

Peristaltic Pneumatic Micropump

 A peristaltic pump uses in serial positive displacements
pumping a variety of fluids/gases.

Phase I

Phase II Phase III

S. Konishi group (Ritsumeikan Univ. Japan), Sensor Actuat A-Phys, 2007

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Peristaltic Pump Driving

 Similar with reciprocating pumps, peristaltic pumps can be
driven by different mechanisms.

B. Ziaie group (UMN), EMBS conference, 2004

H. H. Liao group (NTU, Taiwan), JMM, 2009 D. Snakenborg group (DTU. Denmark), Lab Chip, 2009
EECS 509 BioMEMS 29

Rotary Micropumps
 Rotary pumps are especially suitable for viscous liquids.

E. D. Fabrizio group (INF Italy), Microelectron. Eng., 2006

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Rotary Micropump
 Electromagnetic force
Inlet
reservoir
Inlet Outle Pumping chamber
t

Outlet

Coil
Rotation direction Permalloy

•5000 rpm, 24 L/min

C. H. Ahn and M. G. Allen, Proc. 8th IEEE Int. Conf. on Micro Electro
Mechanical Systems, 1995, p. 408-412.

EECS 509 BioMEMS 31

Other Rotary Micropump Designs

B. D. Iverson (Purdue), Microfluid Nanofluid, 2008

B. K. Gale group (UOU), IMECE conference, 2004

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Syringe Micropump

 Electrochemical Actuation (Electrolysis)

Nozzle

Electrode

Electrolysis
voltage

J. Xie, Q. He, Y.-C. Tai, J. Liu and T. Lee, Proc. 16th IEEE Int. Conf. on Micro
Electro Mechanical Systems, 2003, p. 443-446.

EECS 509 BioMEMS 33

Bubble-Actuated Micropumps
 Bubble pumps utilize volume changes to displace fluid for
pumping

Cooling Heating Push-out phase

end end

Valve close phase

Bubble pump based on phase change Bubble pump based on electrolysis
Prof. C.-J. Kim (UCLA), J. Appl. Phys. 83, 5658 (1998). W. Wang group (LSU), Proc. Of SPIE, 2007
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EHD Micropump
(Directly-Driven Micropump)

 Electrohydrodynamic Micropump
- Electrical generation of charged molecule (ion, dipole…)
- Electrical field push/drag the charged molecule
 Charge Generation
- Injection: on electrode surface
- Induction: when the electrical field is applied at the
interface where the conductivity or permittivity changes

EECS 509 BioMEMS 35

EHD Injection Micropump

Emitter Collector
V

•Flow rate: 14 mL/min

•Pumping pressure: 2.48 kPa at an applied voltage of 700 V

A. Richter, A. Plettner, K. A. Hofmann and H. Sandmaier, Sen. Actuators

A-Phys. 29, 159-168 (1991)

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Electrohydrodynamic micropumps
 Electrohydrodynamic pumps utilize electrostatic forces on dielectric liquids
to generate flow.
 Several types of EHD pumps have been reported, as we are talking about in
the other lecture (Electrowetting & Digital Microfluidic Logics).

D. J. Laser (Stanford), JMM, 2004

https://engineering.purdue.edu
EECS 509 BioMEMS 37

Electroosmotic Micropump

 Electroosmotic Micropump (Electrokinetic Micropump)

+ + + + + + +

+ - + - +
+ - + - + –
+ + + + + + +

Capillary length
Permittivity Zeta potential
 8 
v   eo E  eo   P  EL
 a2

Velocity Electric field Viscosity Capillary radius

Mobility

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Principle of Magnohydrodynamic Pumping

 Magnetohydrodynamic Micropump
- Lorentz force

y
V
x
z

N F I S

EECS 509 BioMEMS 39

Magnetohydrodynamic Micropumps
 In magnetichydrodynamic pumping, current-carrying ions in
aqueous solutions are subjected to a magnetic field to import a
Lorentz force and induce flow.

D. J. Laser (Stanford), JMM, 2004

A. P. Lee group (UCI), Sensor Actuat B-Chem, 2000

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Ferrofluid Micropumps
 Ferrofluids are colloidal liquids made
of nanoscale ferromagnetic, or
ferrimagnetic, particles suspended in
a carrier fluid.
 The ferrofluid can be actuated by the
motion of an external permanent
magnet.

M. A. M. Gijs group (EPFL Switzerland), JMEMS, 2005

EECS 509 BioMEMS 41

Other Pumping Methods for Microfluidics

 Integrated micropumps are not the only choice for
microfluidics. A lot of other liquid driving methods are available
especially for larger instruments or prototype tests.

Gravity flow

Centrifugal chip

Surface tension
Capillary driven flow
Syringe pump
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