Hughes M.P., Hoettges K.F. (Eds.) Microengineering in Biotechnology

ETHODS IN

OLECULAR

IOLOGY

Series Editor

John M. Walker

School of Life Sciences

University of Hertfordshire

Hatfield, Hertfordshire, AL10 9AB, UK

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Microengineering in Biotechnology

Edited by

Michael P. Hughes and Kai F. Hoettges

University of Surrey, Guildford, UK

Editors

Michael P. Hughes

University of Surrey

Centre for Biomedical

Engineering

Guildford

Duke of Kent Building

United Kingdom GU2 7TE

m.hughes@surrey.ac.uk

Kai F. Hoettges

University of Surrey

Centre for Biomedical

Engineering

Guildford

Duke of Kent Building

United Kingdom GU2 7TE

k.hoettges@surrey.ac.uk

ISSN 1064-3745 e-ISSN 1940-6029

ISBN 978-1-58829-381-7 e-ISBN 978-1-60327-106-6

DOI 10.1007/978-1-60327-106-6

Library of Congress Control Number: 2009933982

# Humana Press, a part of Springer ScienceþBusiness Media, LLC 2010

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Preface

Just as the twentieth century witnessed developments both in electronic engineering

and molecular biology which have revolutionized the way we live, so the twenty-first

century has been predicted to see the ever-increasing blurring of the line between them.

Since so many biochemical procedures occur at the molecular level, microelectronic

engineering offers the opportunity to reduce the way in which such procedures are

performed to the same level. The advantages of miniaturized analysis are manifold;

reducing the sample volume increases reaction speed and detector sensitivity whilst

reducing sample and reagent requirements and device cost. Some of the world’s largest

technology companies are already involved in the development of so-called laboratories

on a chip, and the field is set for rapid expansion in the next decades. The market is vast –

having potential to provide, for example, bench-top versions of large and expensive

equipment that could make analyses like flow cytometry as commonly available as gel

electrophoresis is now.

The aim of this book is to provide biochemists, molecular biologists, pharmacolo-

gists and others with a working understanding of the methods underlying microengi-

neering and the means by which such methods can be used for a range of analytical

techniques. It describes the methods by which microengineered devices can be built to

perform a number of applications and considers how the field may progress by examin-

ing some more complex lab on a chip devices which have great potential in the

advancement of the way in which molecular biology is performed. We also hope that

this book will be of use to microengineers, both as a reference guide for practical

microengineering techniques and as a route into the development of new devices for

biological applications. The union of molecular biology and microelectronics offers

huge promise but one which will be all the stronger wherein both sides understand the

needs of the other.

Guildford, UK

Michael P. Hughes

27 April 2009

Kai F. Hoettges

Contents

Preface ............................................................ v

Contributors........................................................ ix

1. Microfabrication Techniques for Biologists: A Primer on

Building Micromachines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Douglas Chinn

2. The Application of Microfluidics in Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

David Holmes and Shady Gawad

3. Rapid Prototyping of Microstructures by Soft Lithography

for Biotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Daniel B. Wolfe, Dong Qin, and George M. Whitesides

4. Chemical Synthesis in Microreactors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Paul Watts and Stephen J. Haswell

5. The Electroosmotic Flow (EOF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Gary W. Slater, Fre´de´ric Tessier, and Katerina Kopecka

6. Microengineered Neural Probes for In Vivo Recording . . . . . . . . . . . . . . . . . . . . . 135

Karla D. Bustamante Valles

7. Impedance Spectroscopy and Optical Analysis of Single Biological Cells

and Organisms in Microsystems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Shady Gawad, David Holmes, Giuseppe Benazzi, Philippe Renaud,

and Hywel Morgan

8. Dielectrophoresis as a Cell Characterisation Tool . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Kai F. Hoettges

9. AC-Electrokinetic Applications in a Biological Setting . . . . . . . . . . . . . . . . . . . . . . 199

Fatima H. Labeed

10. Wireless Endoscopy: Technology and Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

David R. S. Cumming, Paul A. Hammond, and Lei Wang

Subject Index .......................................................... 247

vii

Contributors

GIUSEPPE BENAZZI

•

School of Electronics and Computer Science, University of

Southampton, Highfield, Southampton, UK

ARLA D. BUSTAMANTE VALLES

•

Orthopaedic & Rehabilitation Engineering Center,

The Medical College of Wisconsin & Marquette University, Milwaukee, WI, USA

OUGLAS CHINN

•

Sandia National Laboratories, Albuquerque, NM, USA

AVID R. S. CUMMING

•

Department of Electronic and Electrical Engineering,

University of Glasgow, Glasgow, UK

HADY GAWAD

•

Swiss Federal Institute of Technology, Lausanne, Switzerland

AUL A. HAMMOND

•

Department of Electronic and Electrical Engineering, University

of Glasgow, Glasgow, UK

TEPHEN J. HASWELL

•

Department of Chemistry, University of Hull, Hull, UK

AI F. HOETTGES

•

Centre for Biomedical Engineering, University of Surrey, Guildford,

Surrey, UK

AVID HOLMES

•

School of Electronics and Computer Science, University of Southampton,

Highfield, Southampton, UK

ATERINA KOPECKA

•

Department of Physics, University of Ottawa, Ottawa, ON,

Canada

ATIMA H. LABEED

•

University of Surrey, Guildford, Surrey, UK

YWEL MORGAN

•

School of Electronics and Computer Science, University of Southamp-

ton, Highfield, Southampton, UK

ONG QIN

•

University of Washington, Seattle, WA, USA

HILIPPE RENAUD

•

Swiss Federal Institute of Technology, Lausanne, Switzerland

ARY W. SLATER

•

Department of Physics, University of Ottawa, Ottawa, ON, Canada

RIC TESSIER

•

Department of Physics, University of Ottawa, Ottawa, ON, Canada

EI WANG

•

Department of Electronic and Electrical Engineering, University of Glas-

gow, Glasgow, UK

AUL WATTS

•

Department of Chemistry, University of Hull, Hull, UK

EORGE M. WHITESIDES

•

Department of Chemistry and Chemical Biology, Harvard

University, Cambridge, MA, USA

ANIEL B. WOLFE

•

Department of Chemistry and Chemical Biology, Harvard

University, Cambridge, MA, USA

Chapter 1

Microfabrication Techniques for Biologists: A Primer on

Building Micromachines

Douglas Chinn

Abstract

In this chapter we review the fundamental techniques and processes underlying the fabrication of devices

on the micron scale (referred to as ‘‘microfabrication’’). Principles laid down in the 1950s now form the

basis of the semiconductor manufacturing industry; these principles are easily adaptable to the production

of devices for biotechnological processing and analysis.

Key words: Fabrication, photolithography, photomask, etching, thin films.

1. Introduction

Fabrication of electronic devices on a micron scale was developed

by the integrated circuit industry, beginning with the invention of

the integrated circuit (IC) simultaneously by Jack Kilby of Texas

Instruments and Robert Noyce of Fairchild in 1958. Microma-

chining began with the challenge issued by Professor Feynman in

1959 to build a tiny motor. In 1965, Gordon Moore of Intel

postulated what is now known as Moore’s Law, where the data

density of integrated circuits doubles every 18 months. Today,

2006, the largest companies are fabricating complex state-of-the-

art chips with over 40 photomask layers, including 10 metal layers,

and are approaching 10

transistors in an area the size of a postage

stamp. Lateral dimensions are below 100 nm and shrinking all the

time. Vertical dimensions for the thinnest oxides are a few mono-

layers, with films of metal and dielectrics on the order of a few

nanometers (nm) to a micrometer (micron, mm). A modern silicon

integrated circuit fabrication facility costs over $2 billion to build

M.P. Hughes, K.F. Hoettges (eds.), Microengineering in Biotechnology, Methods in Molecular Biology 583,

DOI 10.1007/978-1-60327-106-6_1, ª Humana Press, a part of Springer Science+Business Media, LLC 2010

and equip. The new MESA micromachine laboratory at Sandia

National Laboratories costs almost $500 million. Only large cor-

porations and governments can make this kind of capital invest-

ment. Chips must be made in huge quantities with exceptional

quality control to achieve an adequate return on investment.

Because chip-making processes advance so quickly, process equip-

ment is typically depreciated after 2 years.

An integrated circuit is fabricated using only four steps: film

growth and deposition, patterning, etching, and annealing. A

typical process begins by depositing a film, spinning photoresist,

patterning and developing the resist, etching the thin film, and

finally stripping the resist. By repeating these steps over and over,

the most complex devices can be made. This is a gross oversimpli-

fication but it demonstrates how a number of simple steps can be

combined to make very complex devices. In industry, complex

processing tools such as etchers and thin film deposition systems

are dedicated to a single process. Engineers in semiconductor and

micromachine factories devote entire careers to reducing variabil-

ity by characterizing processes and equipment and thus improving

device yield. Even so, scrap rates run up to 50% of all material

started in the line, depending on the maturity of the process.

Mature lines with well-characterized processes will skip testing in

wafer form and package every device made, rejecting the defective

parts at that stage, indicating that well over 99% of all wafers were

processed correctly.

Most modern wafer processing machine tools are ‘‘cassette to

cassette,’’ where all wafers are carried around the facility in specially

designed wafer holders known as cassettes or boats. Humans never

handle wafers. Instead, cassettes are placed into ‘‘indexers’’ that

automatically move the wafers into the process chamber, afterward

returning them to a cassette when the process is finished. Since

humans make mistakes and add defects, they must be removed as

far as possible from the wafers.

Here we must distinguish between the terms ‘‘fab’’ and ‘‘lab.’’

Fab refers to a large, commercial factory set up to turn a profit,

which produces a small variety of integrated circuit devices that

have similar processes. Lab refers to a smaller facility, usually at a

university or government laboratory, set up to produce a wide

variety of electronic, optical, and mechanical devices with many

different processes. Machinery (machine tools or just tools) in a fab

is designed for high throughput (low cost) and must be designed

to minimize the number of particles and defects they add to wafers.

Uptime is a major consideration, and fabs will schedule routine

maintenance into the process. Although programmers who use

chips to create amazing programs get all the glory, the people who

design and build the machines that make the chips are the real

heroes because the semiconductor industry arguably has the high-

est technology machine tools in existence. Creating a 25-mm

2 Chinn

square chip with dozens of layers, thousands of process steps,

geometries below 0.25 mm, and one billion transistors with no

defects is not an easy task!

The emerging micromachine industry has benefited from all

the advances made by the semiconductor industry, but is several

Moore’s law generations behind it. In many micromachining

applications, lateral dimensions are above 1 mm, and vertical

dimensions are above 100 nm. Universities and other small labs

do not need the expensive dedicated cassette to cassette machines

designed for high throughput and quality control. This chapter is

written for the small lab, with contrasts to large production facil-

ities. We hope to give rules of thumb that help get devices fabri-

cated without the reader having to ‘‘re-invent the wheel’’ while

learning to build microdevices.

Why is this chapter called ‘‘Microfabrication for Biologists’’

when it has absolutely no reference to biology in it? Because most

commercially successful micromachines have biological applica-

tions and most of those are microfluidic devices that sense some

kind of biological agent. Since a market exists, biologists have been

driving micromachining away from silicon-based devices that

often have moving parts to devices that analyze fluids built on

glass and polymer substrates.

Many good books on the subject of microfabrication have

been written (see Suggested Reading List). These books list

some exotic and complex processes and the reader is referred to

these books and others for rigid analysis and mathematical detail.

Specific details can be found in the technical literature. A great deal

of information is also available on the Web. A person building their

first device needs practical information to get started on a project.

Here we attempt to supply the reader with a lot of practical knowl-

edge, gained from the author’s experience in building devices in

industry, university, and government laboratories. The approach

used in this chapter is to teach a novice engineer, scientist

or biologist how to design a device pattern using a CAD

(computer-aided design) program and how to develop a process

run sheet to get it fabricated with the help and assistance of

professionals who work in microdevice process labs every day.

We have avoided the use of trade names where possible. This

chapter is intended to be a practical guide to getting started in

the field, making no attempt to define the underlying physics and

chemistry. Since most biologically oriented micromachining

involves substrates that are not silicon or period II–VI or III–V

semiconductor compounds, this chapter is written with that in

mind.

Any device built by micromachine techniques has hundreds of

potential variables to control. Small changes in any one of these

can have a large impact on the final product. The keys to

successful microdevice fabrication are good process control in

Microfabrication Techniques for Biologists 3

Hughes M.P., Hoettges K.F. (Eds.) Microengineering in Biotechnology

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