CRC Press is an imprint of the Taylor & Francis Group, an informa business Boca Raton London New York Bio-MEMS Technologies and Applications EDITED BY Wanjun Wang • Steven A. Soper DK532X_C000.fm Page i Monday, November 13, 2006 7:24 AM © 2007 by Taylor & Francis Group, LLC CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2007 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3532-9 (Hardcover) International Standard Book Number-13: 978-0-8493-3532-7 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data BioMEMS : technologies and applications / edited by Wanjun Wang and Steven A. Soper. p. cm. Includes bibliographical references and index. ISBN 0-8493-3532-9 (alk. paper) 1. BioMEMS. I. Wang, Wanjun, 1958- II. Soper, Steven A. TP248.25.B54B56 2006 660.6 dc22 2006045665 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com DK532X_C000.fm Page ii Monday, November 13, 2006 7:24 AM copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) © 2007 by Taylor & Francis Group, LLC Table of Contents Preface v About the Editors vii Contributors ix 1 Introduction 1 Wanjun Wang and Steven A. Soper Part I Basic Bio-MEMS Fabrication Technologies 2 UV Lithography of Ultrathick SU-8 for Microfabrication of High-Aspect-Ratio Microstructures and Applications in Microfluidic and Optical Components 11 Ren Yang and Wanjun Wang 3 The LIGA Process: A Fabrication Process for High-Aspect-Ratio Microstructures in Polymers, Metals, and Ceramics 43 Jost Goettert 4 Nanoimprinting Technology for Biological Applications 93 Sunggook Park and Helmut Schift 5 Hot Embossing for Lab-on-a-Chip Applications 117 Ian Papautsky Part II Microfluidic Devices and Components for Bio-MEMS 6 Micropump Applications in Bio-MEMS 143 Jeffrey D. Zahn 7 Micromixers 177 Dimitris E. Nikitopoulos and A. Maha DK532X_C000.fm Page iii Monday, November 13, 2006 7:24 AM © 2007 by Taylor & Francis Group, LLC 8 Microfabricated Devices for Sample Extraction, Concentrations, and Related Sample Processing Technologies 213 Gang Chen and Yuehe Lin 9 Bio-MEMS Devices in Cell Manipulation: Microflow Cytometry and Applications 237 Choongho Yu and Li Shi Part III Sensing Technologies for Bio-MEMS Applications 10 Coupling Electrochemical Detection with Microchip Capillary Electrophoresis 265 Carlos D. García and Charles S. Henry 11 Culture-Based Biochip for Rapid Detection of Environmental Mycobacteria 299 Ian Papautsky and Daniel Oerther 12 MEMS for Drug Delivery 325 Kabseog Kim and Jeong-Bong Lee 13 Microchip Capillary Electrophoresis Systems for DNA Analysis 349 Ryan T. Kelly and Adam T. Woolley 14 Bio-MEMS Devices for Proteomics 363 Justin S. Mecomber, Wendy D. Dominick, Lianji Jin, and Patrick A. Limbach 15 Single-Cell and Single-Molecule Analyses Using Microfluidic Devices 391 Malgorzata A. Witek, Mateusz L. Hupert, and Steven A. Soper 16 Pharmaceutical Analysis Using Bio-MEMS 443 Celeste Frankenfeld and Susan Lunte DK532X_C000.fm Page iv Monday, November 13, 2006 7:24 AM © 2007 by Taylor & Francis Group, LLC that while enough topics on the cutting edge of bio-MEMS research are covered, the book is still easy to read. In addition to structurally organizing the book from basic materials to advanced topics, we have made sure that each chapter and subject area are covered beginning with basic principles and fundamentals. Because of the shortage of suitable textbooks in this area, this collection is designed to be reasonable for graduate education as well as working application engineers who are interested in getting into this exciting new field. DK532X_C000.fm Page vi Monday, November 13, 2006 7:24 AM © 2007 by Taylor & Francis Group, LLC Whitaker Foundation, American Chemical Society, Department of Energy, and the National Science Foundation. Steven has published over 160 manu- scripts in various research publications and is the author of three patents. In addition, Steven has given approximately 165 technical presentations at national/international meetings and universities since 1995. Steven is now the director of a major multi-disciplinary research center at LSU, which is funded through the NSF. Prof. Soper has received several awards for his research accomplishments while at LSU, including the Outstanding Untenured Researcher (Physical Sciences, Louisiana State University, 1995) presented by Phi Kappa Phi; Outstanding Researcher in the College of Basic Sciences (Louisiana State University, 1996); and Outstanding Science/Engineering Research in the state of Louisiana (2001). In 2006, Dr. Soper was awarded the Benedetti- Pichler Award in Microchemistry. Prof. Soper is also involved in various national activities, such as serving on review panels for the National Institutes of Health, the Department of Energy, and the National Science Foundation. In addition, he serves on the advisory board for several technical journals including Analytical Chemistry (A-page editorial board), Journal of Fluorescence , and The Analyst. DK532X_C000.fm Page viii Monday, November 13, 2006 7:24 AM © 2007 by Taylor & Francis Group, LLC A. Maha Mechanical Engineering Department, Louisiana State University, Baton Rouge, Louisiana Justin S. Mecomber Rieveschl Laboratories for Mass Spectrometry, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, U.S.A. Dimitris E. Nikitopoulos Professor, Mechanical Engineering Department, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Daniel Oerther Department of Civil and Environmental Engineering, University of Cincinnati, Cincinnati, Ohio, U.S.A. Ian Papautsky Department of Electrical and Computer Engineering, University of Cincinnati, Cincinnati, Ohio, U.S.A. Sunggook Park Mechanical Engineering Department, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Helmut Schift Laboratory for Micro- and Nanotechnology, Paul Scherrer Institut, Villigen, Switzerland Li Shi Mechanical Engineering Department, The University of Texas at Austin, Austin, Texas, U.S.A. Steven A. Soper Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Wanjun Wang Department of Mechanical Engineering, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Malgorzata. A. Witek Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Adam T. Woolley Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, U.S.A. Ren Yang Department of Mechanical Engineering, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Choongho Yu Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, U.S.A. Jeffrey D. Zahn Department of Bioengineering, Pennsylvania State University, University Park, Pennsylvania, U.S.A. DK532X_C000.fm Page x Monday, November 13, 2006 7:24 AM © 2007 by Taylor & Francis Group, LLC 2 Bio-MEMS: Technologies and Applications of such systems are the microvolumes of biological or biomedical samples that can be delivered and processed for testing and analysis in an integrated fashion, therefore dramatically reducing the required human involvement in many steps of sample handling and processing, and improving data quality and quantitative capabilities. This format also helps to reduce the overall cost and time of the measurement and at the same time improves the sensitivity and specificity of the analysis. Though it is believed that the long-term impact of MEMS technologies on our life will be similar to that made by the microelectronics industry, the market for MEMS products has grown at a much slower pace than many people had expected. In comparison with the market development history associated with the microelectronics and computer industries, the market for MEMS is much more diversified with highly specialized, individual catego- ries of products with specifically targeted applications. The research and development efforts are therefore very diversified, often requiring multidis- ciplinary teams to work collaboratively to build effectively operating sys- tems. In addition, it is often desired that the researchers and product development engineers also possess multidisciplinary backgrounds—a requirement that is often extremely hard to meet. This may be particularly true for the field of bio-MEMS. In comparison with other MEMS subareas, which typically involve only different engineering disciplines such as mechanical, electrical, and optical engineers, the development of bio-MEMS involves a truly interdisciplinary integration of basic sciences, medical sci- ences, material sciences, and engineering. Functioning in an interdisciplinary endeavor requires researchers to possess the ability to cross-communicate, work in a team-directed fashion, and compartmentalize research tasks. This is a primary reason why bio-MEMS science and engineering, as well as the systems they produce, are evolving at a relatively slow rate of development in comparison with electrical and mechanical sensing devices and systems, whose developments primarily depended upon a specific discipline. There have been many high-quality books published in the general areas of design and fabrication technologies of MEMS devices and systems. Most of these books have focused on silicon-based technologies, such as surface micromachining, and wet and dry etching technologies (RIE and DRIE pro- cesses). As bio-MEMS technologies develop and many educational institu- tions begin to offer courses on this subject matter, textbooks covering both the fundamental fabrication technologies in a variety of different substrates (Si, thermoplastics, ceramics, etc.), metrology, and device characterization as well as the latest technology applications are needed. While there are a number of seminal books covering conventional MEMS-based technologies, there are very few that focus on the design and fabrication of bio-MEMS devices and systems. There are several reasons for this phenomenon. The first is that bio-MEMS technology is still in a much earlier stage of develop- ment in comparison to other MEMS technologies. The second, and perhaps the most important one, is that the topics to be covered in a bio-MEMS DK532X_book.fm Page 2 Tuesday, November 14, 2006 10:41 AM © 2007 by Taylor & Francis Group, LLC Introduction 3 textbook are so widely diversified that it is virtually impossible for a single author to fully understand or become expert in all of the relevant areas of expertise required to build effective bio-MEMS devices and systems. This is also the main reason why an edited book that includes contributions on different subjects from specialized researchers who work on the frontiers of bio-MEMS from both the basic science and engineering realms is highly desirable. As editors, we were fortunate enough to have a group of well- recognized researchers and educators as contributors in their specific areas of expertise, and to cover both fundamental knowledge and the latest research progresses in various areas of importance to bio-MEMS. This book was prepared with the intent of targeting two main areas. First, we wanted to cover enough fundamental materials so that it could be used as a textbook for classes at either the graduate or senior undergraduate levels. This book may also be suitable for those people who are not currently in the bio-MEMS field and may need to learn the fundamentals in order to enter the field. Second, with enough application examples covered and the latest research progress presented, the book may also be used as a reference for scientists or engineers who work in the bio-MEMS field to provide a guide as to what has been accomplished in many related areas to date. Because the materials to be covered in a bio-MEMS book are so widely diversified, to be able to cover all the key contents in a limited space is definitely a challenge. Some compromises and balances were obviously needed in compiling the contents of this book in order to cover relevant areas in bio-MEMS, but also to make it manageable for the reader. In this book, topics on microfabrication technologies focus primarily on nonsilicon-based methods. There are two reasons for this decision. First, there are already numerous books available on silicon-based microfabrication technologies and interested readers can always refer to these books. Secondly, the current trends in bio-MEMS seem to be in the direction of using nonsilicon-based fabrication technologies and materials. Because biologists and chemists have long used nonsilicon materials, such as glasses and polymers (PMMA, poly- carbonate, etc.), various surface treatment technologies have been developed and processes are well understood. Micro- and nanoreplication using mold- ing, imprinting or hot-embossing technologies also help to reduce the batch fabrication cost, making these substrates very appealing for bio-MEMS- related application areas. Because the potential readers of this book may have various educational backgrounds, it was also necessary to balance the fundamental fabrication principles with the advanced contents, as well as the scientific and engi- neering materials. To be able to serve readers who are interested in learning the fundamentals of bio-MEMS technologies as well as researchers who work in the field and need a good reference book, efforts were made by the contributors of this book to balance fundamental knowledge with the latest advancements in related subject areas. In addition, the readers with engineering backgrounds may have difficulty in fully understanding the DK532X_book.fm Page 3 Tuesday, November 14, 2006 10:41 AM © 2007 by Taylor & Francis Group, LLC 4 Bio-MEMS: Technologies and Applications biological or biomedical aspects of the materials covered in these chapters. The same may hold true for readers with basic science or life science back- grounds when reading the engineering sections of this book. The authors of each chapter have tried to include some basic introduction references to allow readers to obtain relevant background materials to augment those that are presented herein. 1.1 Main Contents and Organization of the Book The contents in this book can be generally divided into three basic sections: 1. 2. 3. 1.1.1 Microfabrication Technologies In this section, we focused on nonsilicon-based micro- and nanofabrication technologies, such as LIGA—a combination of deep-etch x-ray lithography with synchrotron radiation (LI), electroforming (G = Galvanoformung [Ger- man]), and molding (A = Abformung [German]), or UV-LIGA (using ultra violet lithography instead of x-ray lithography), hot-embossing, nano- imprinting, and so forth. Because UV lithography of SU-8 has become a popular choice for a lot of researchers in recent years, this topic is covered in Chapter 2. In addition to the basic lithography processing steps and optimal processing conditions, example applications in microfluidic devices and micro-optic devices are also presented. Chapter 3 provides a very detailed presentation on the LIGA process. Applications of LIGA technol- ogies in fabricating polymer bio-MEMS are also introduced. Nanoimprint lithography (NIL) is a low cost and flexible patterning technique particularly suitable for fabrication of nanoscale components for biological applications. Its unique advantages are that both topological and chemical surface pat- terns can be generated at the micro- and nanometer scales. Chapter 4 pre- sents an overview of NIL technology with the focus on the compatibility of materials and processes used for biological applications. Examples are also presented to demonstrate how NIL technology can be employed to fabricate devices used to understand and manipulate biological events. Hot emboss- ing is another reasonably fast and moderately inexpensive technique used to replicate microfluidic elements in thermoplastics. In the hot-embossing process, polymer and the prefabricated master containing the prerequisite DK532X_book.fm Page 4 Tuesday, November 14, 2006 10:41 AM Basic Bio-MEMS Fabrication Technologies (Chapters 2, 3, 4, and 5); Microfluidic Devices and Components for Bio-MEMS (Chapters 6, 7, 8, and 9); Sensing Technologies and Bio-MEMS Applications (Chapters 10, 11, 12, 13, 14, 15, and 16). © 2007 by Taylor & Francis Group, LLC [...]... cytometry and a review of the state-of-the-art in this field 1. 1.3 Sensing Technologies and Bio-MEMS Applications (Chapters 10 , 11 , 12 , 13 , 14 , 15 , and 16 ) Because of the enormous variations in biological and biomedical samples, the processing and detection principles required for the analysis of targets are often completely different There have been numerous bio-MEMS either in commercial applications. .. of SU-8 as a function of the wavelength Transmission (%) 10 0 80 60 40 20 0 300 350 400 Wavelength (nm) 450 500 (a) Cured vs uncured refractive index vs wavelength 1. 6 Refractive index 1. 595 Cauchy coefficients (uncured) A = 1. 510 00 B = 0.04440 C = –0.0 019 0 Uncured 1. 59 1. 585 Cured 1. 58 1. 575 1. 57 550 650 750 850 950 10 50 11 50 12 50 13 50 14 50 15 50 16 50 Wavelength (nm) (b) FIGURE 2 .1 Properties of SU-8 resist:... e–0.0031x 0.4 Expon (365 nm) Expon (405 nm) R2 = 0.99 51 0.2 0 0 500 10 00 15 00 Thickness (µm) 2000 Light intensity (normalized to 1) FIGURE 2.3 Measured transmissions for both the i-line and h-line for different thicknesses of SU-8 Ideal light intensity distribution (0 µm thick SU-8) 1 0.8 10 0 µm thick SU-8 0.6 200 µm thick SU-8 0.4 500 µm thick SU-8 0.2 10 00 µm thick SU-8 0 –20 10 0 Position (µm) 10 20... area Chapter 12 provides a complete review of bio-MEMS technologies for drug delivery Chapter 16 presents studies on pharmaceutical analyses using bio-MEMS Chapter 14 discusses © 2007 by Taylor & Francis Group, LLC DK532X_book.fm Page 7 Tuesday, November 14 , 2006 10 : 41 AM Introduction 7 the recent advances of bio-MEMS applications in assay development, improved separation performance, and enhanced... LLC DK532X_book.fm Page 12 Tuesday, November 14 , 2006 10 : 41 AM 12 Bio-MEMS: Technologies and Applications 2.6 Conclusions 40 References 40 2 .1 Introduction Ultraviolet (UV) lithography of ultrathick photoresist with high-aspectratio, high sidewall quality, and good dimensional control is very important for microelectromechanical systems (MEMS) and micro-optoelectromechanical... Filtered Light Source and Air Gap Compensation for Diffraction To demonstrate the superiority of the proposed optimal lithography of a filtered light source and gap compensation, we will show three different © 2007 by Taylor & Francis Group, LLC DK532X_book.fm Page 22 Tuesday, November 14 , 2006 10 : 41 AM 22 Bio-MEMS: Technologies and Applications i-line h-line g-line 10 0 80 3000 60 2000 40 10 00 0 300 20 Transmission... Page 16 Tuesday, November 14 , 2006 10 : 41 AM 16 Bio-MEMS: Technologies and Applications denote the angles between the vectors and the normal to the surface of integration, and ds represents the integration on the surface of the aperture For a rectangular pattern on the mask, the diffraction distribution at an arbitrary plane z will be: U p ( x , y , z) = e ikz iλz where u = and v = u2 ∫ e iπu2 2 v1 ∫... diffraction caused by the air gap, and the diffraction compensation effects using an optical liquid, such as glycerin In the simulations, the gaps between the mask and resist surface were assumed to be 50 µm, and the slot was assumed © 2007 by Taylor & Francis Group, LLC DK532X_book.fm Page 18 Tuesday, November 14 , 2006 10 : 41 AM 18 Bio-MEMS: Technologies and Applications 1 Transmission (%) y = e–0.0005x... 25 µm thickness [14 ] Ling et al obtained 360 µm–thick structures with a 14 µm feature size [15 ] With the help of a well-collimated proximity ultraviolet source, Dentinger et al obtained aspect ratios exceeding 20 :1 for film thicknesses of 200 to approximately 700 µm [19 ] Williams and Wang obtained a 65 :1 high-aspect-ratio structure up to 1 µm high with a Quntel aligner [20] Yang and Wang reported a work... (normalized to 1) 1. 5 Ideal light intensity distribution (0 µm thick SU-8) 10 0 µm thick SU-8 1 200 µm thick SU-8 500 µm thick SU-8 0.5 10 00 µm thick SU-8 0 –20 10 0 Position (µm) 10 20 (b) FIGURE 2.4 (a) Fresnel diffraction pattern in the bottom of the resist layer as projected by the i-line light source (b) Fresnel diffraction pattern in the bottom of the resist layer as projected by the h-line light . field. 1. 1.3 Sensing Technologies and Bio-MEMS Applications (Chapters 10 , 11 , 12 , 13 , 14 , 15 , and 16 ) Because of the enormous variations in biological and biomedical samples, the processing and. wavelength 1. 57 1. 575 1. 58 1. 585 1. 59 1. 595 1. 6 550 650 750 850 950 10 50 11 50 12 50 13 50 14 50 15 50 16 50 Wavelength (nm) Refractive index Cauchy coefficients (uncured) A = 1. 510 00 B = 0.04440 C = –0.0 019 0 Uncured Cured (b) (a) 10 0 80 60 40 20 300. States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number -1 0 : 0-8 49 3-3 53 2-9 (Hardcover) International Standard Book Number -1 3 : 97 8-0 -8 49 3-3 53 2-7 (Hardcover) This