mems for biomedical applications

OH, University at Buffalo, The State University of New York SUNY, USA Part III MEMS for tissue engineering and clinical applications 173 7 Fabrication of cell culture microdevices for

Implantable sensor systems for medical applications

(ISBN 978-1-84569-987-1)

Intelligent sensor systems for medical applications can greatly improve quality of life and medical care This book discusses the core technologies needed for these sophisticated devices and their current and potential applications Chapters in Part

I review a wide range of core technologies that are fundamental to intelligent cal sensor systems Part II reviews considerations for intelligent medical sensor sys- tems and the fi nal part discusses the various applications areas of intelligent sensor systems

Biomedical imaging: Applications and advances

(ISBN 978-0-85709-127-7)

The development of imaging techniques is of great importance for the monitoring of medical implants, diagnosis of disease, and for strategies of personalized medicine Signifi cant advances are being made in this technology and this book discusses the latest advances and developments in this increasingly important fi eld Chapters in Part I provide readers with a wide ranging review of medical applications whilst the second set of chapters discusses biomaterials and processes

Biosensors for medical applications

(ISBN 978-1-84569-935-2)

Biomedical sensors play an important role in the detection and monitoring of a range

of critical medical conditions This publication provides readers with a sive review of established, cutting edge, and future trends in biomedical sensors and their applications Chapters in Part I discuss principles and transduction approaches

comprehen-to biosensors Part II reviews a wide range of applications

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MEMS for biomedical

applications

Edited by Shekhar Bhansali and Abhay Vasudev

Oxford Cambridge Philadelphia New Delhi

80 High Street, Sawston, Cambridge CB22 3HJ, UK

First published 2012, Woodhead Publishing Limited

© Woodhead Publishing Limited, 2012

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ISBN 978-0-85709-129-1 (print)

ISBN 978-0-85709-627-2 (online)

ISSN 2049-9485 Woodhead Publishing Series in Biomaterials (print)

ISSN 2049-9493 Woodhead Publishing Series in Biomaterials (online)

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Woodhead Publishing Series in Biomaterials xv

Part I Fundamentals of MEMS for biomedical applications 1

P REZAI, W-I WU and P R SELVAGANAPATHY,

McMaster University, Canada

2 Review of sensor and actuator mechanisms

for bioMEMS 46

P K SEKHAR and V UWIZEYE, Washington State

University Vancouver, USA

Part II MEMS for biomedical sensing and

diagnostic applications 79

S ARAVAMUDHAN, North Carolina

A&T State University, USA

4 MEMS and electrical impedance spectroscopy (EIS)

for non-invasive measurement of cells 97

D T PRICE, University of South Florida, USA

4.1 Importance of MEMS in cellular assays 97

4.4 Bioimpedance before MEMS: patch clamp measurements 102

5.2 Modeling and design of capacitive micromachined

6 Lab-on-chip (LOC) devices and microfl uidics for

biomedical applications 150

K W OH, University at Buffalo, The State University

of New York (SUNY), USA

Part III MEMS for tissue engineering and clinical applications 173

7 Fabrication of cell culture microdevices for tissue

engineering applications 175

J D CUIFFI, Draper Laboratory, USA

7.1 Introduction: cell culture microdevices 175

7.2 Motivation for microdevice development 175

7.3 Design and fabrication concepts for cell culture 179

7.4 Applications of cell culture microdevices 185

8.3 Tissue scaffold fabrication using MEMS approaches 198

8.4 Applications of MEMS-fabricated tissue scaffold 210

9 BioMEMS for drug delivery applications 218

L KULINSKY and M J MADOU, University of California,

10 Applications of MEMS technologies for

minimally invasive medical procedures 269

K R OLDHAM, University of Michigan, USA

11 Smart microgrippers for bioMEMS applications 291

Y Q FU, University of the West of Scotland, UK,

J K LUO, University of Bolton, UK and A J FLEWITT

and W I MILNE, University of Cambridge, UK

12 Microfl uidic techniques for the detection,

manipulation and isolation of rare cells 337

M B SANO and R V DAVALOS, Virginia Tech – Wake

Forest School of Biomedical Engineering, USA

Part IV Emerging biomedical applications of MEMS 359

A V GOVINDARAJAN and M JE, Institute of Microelectronics,

Singapore, W-T PARK, Seoul National University of Science

and Technology, Korea and A K H ACHYUTA, The Charles

Stark Draper Laboratory Inc., USA

13.1 Introduction – neuronal communication 361

13.2 MEMS-based neuronal intervention devices 363

13.3 Tissue response against implanted neural microelectrode

13.4 Implantable wireless recording integrated circuit (IC)

W LI, Michigan State University, USA

14.2 Implantable MEMS for glaucoma therapy 397

14.3 Integrated microsystems for artifi cial retinal implants 408

15.4 MEMS technologies for microinjection 437

16 Hybrid MEMS: Integrating inorganic structures

into live organisms 449

A J SHUM and B.A PARVIZ, University of Washington, USA

16.2 Hybrid integration 450 16.3 Vacuum microfabrication on Drosophila 459

Index 475

Praveen Kumar Sekhar*

Assistant Professor, Electrical Engineering

School of Engineering and Computer Science Washington State University Vancouver

VECS 201W

14204 NE Salmon Creek Avenue Vancouver, WA 98686-9600 USA

E-mail: praveen.sekhar@vancouver.wsu.edu

Vianney Uwizeye Undergraduate Student School of Engineering and Computer Science Washington State University Vancouver

VECS 201W

14204 NE Salmon Creek Avenue Vancouver, WA 98686-9600 USA

E-mail: uwizey@hotmail.com

University of South Florida

4202 East Fowler Avenue

University of South Florida

4202 E Fowler Ave ENB 118

Engineering University at Buffalo, The State University of New York (SUNY) 113C Bonner Hall

Buffalo, NY 14260 USA

E-mail: kwangoh@buffalo.edu

Chapter 7

Joseph D Cuiffi Draper Laboratory - Bioengineering Center

3802 Spectrum Boulevard Suite 201

Tampa

FL 33612-9220 USA

E-mail: jcuiffi @draper.com

Chapter 8

Ching-Wen Li and Gou-Jen Wang Department of Mechanical Engineering, Graduate Institute

of Biomedical Engineering National Chung-Hsing University Taichung 40227

Taiwan E-mail: gjwang@dragon.nchu.edu.tw

Thin Film Centre

Scottish University Physics Alliance

E-mail: davalos@vt.edu; sano@vt.edu

Chapter 13

Anupama V Govindarajan and Minkyu Je

Institute of Microelectronics A-STAR

Singapore Science Park II Singapore

Woo-Tae Park*

Seoul National University of Science and TechnologyDepartment of Mechanical and Automotive Engineering

172 Gongreung-2 dong, Nowon-guSeoul 139-743

Republic of Korea E-mail: wtpark@seoultech.ac.kr

Anil Kumar H Achyuta

The Charles Stark Draper

GLOBALFOUNDRIES U.S Inc

Research and Development

2070 Route 52, Mail Zip A10

Box 352500 University of Washington Seattle, WA 98195-2500 USA

E-mail: babak.parviz@gmail.com

1 Sterilisation of tissues using ionising radiations

Edited by J F Kennedy, G O Phillips and P A Williams

2 Surfaces and interfaces for biomaterials

Edited by P Vadgama

3 Molecular interfacial phenomena of polymers and biopolymers

Edited by C Chen

4 Biomaterials, artifi cial organs and tissue engineering

Edited by L Hench and J Jones

8 Tissue engineering using ceramics and polymers

Edited by A R Boccaccini and J Gough

9 Bioceramics and their clinical applications

Edited by T Kokubo

10 Dental biomaterials

Edited by R V Curtis and T F Watson

11 Joint replacement technology

15 Shape memory alloys for biomedical applications

Edited by T Yoneyama and S Miyazaki

16 Cellular response to biomaterials

Edited by L Di Silvio

17 Biomaterials for treating skin loss

Edited by D P Orgill and C Blanco

18 Biomaterials and tissue engineering in urology

Edited by J Denstedt and A Atala

19 Materials science for dentistry

B W Darvell

20 Bone repair biomaterials

Edited by J A Planell et al

24 Regenerative medicine and biomaterials for the repair of connective tissues

Edited by C Archer and J Ralphs

25 Metals for biomedical devices

Edited by M Ninomi

26 Biointegration of medical implant materials: science and design

Edited by C P Sharma

27 Biomaterials and devices for the circulatory system

Edited by T Gourlay and R Black

28 Surface modifi cation of biomaterials: methods analysis and applications

Edited by R Williams

29 Biomaterials for artifi cial organs

Edited by M Lysaght and T Webster

30 Injectable biomaterials: science and applications

Edited by J Ferri and E Hunziker

33 Bioactive materials in medicine: design and applications

Edited by X Zhao, J M Courtney and H Qian

34 Advanced wound repair therapies

Edited by D Farrar

35 Electrospinning for tissue regeneration

Edited by L Bosworth and S Downes

36 Bioactive glasses: materials, properties and applications

39 Biomaterials for spinal surgery

Edited by L Ambrosio and E Tanner

40 Minimized cardiopulmonary bypass techniques and technologies

Edited by T Gourlay and S Gunaydin

41 Wear of orthopaedic implants and artifi cial joints

Edited by S Affatato

42 Biomaterials in plastic surgery: breast implants

Edited by W Peters, H Brandon, K L Jerina, C Wolf and V L Young

43 MEMS for biomedical applications

Edited by S Bhansali and A Vasudev

44 Durability and reliability of medical polymers

Edited by M Jenkins and A Stamboulis

45 Biosensors for medical applications

Edited by S Higson

46 Sterilisation of biomaterials and medical devices

Edited by S Lerouge and A Simmons

47 The hip resurfacing handbook: a practical guide for the use and management

of modern hip resurfacings

Edited by K De Smet, P Campbell and C Van Der Straeten

48 Developments in tissue engineered and regenerative medicine products

J Basu and J W Ludlow

49 Nanomedicine: technologies and applications

52 Implantable sensor systems for medical applications

Edited by A Inmann and D Hodgins

53 Non-metallic biomaterials for tooth repair and replacement

Edited by P Vallittu

54 Joining and assembly of medical materials and devices

Edited by Y N Zhou and M D Breyen

55 Diamond based materials for biomedical applications

Edited by R Narayan

56 Nanomaterials in tissue engineering: characherization, fabrication and applications

Edited by A K Gaharwar, S Sant, M J Hancock and S A Hacking

57 Biomimetic biomaterials: structure and applications

61 Microfl uidics for biomedical applications

Edited by X-J J Li and Y Zhou

62 Decontamination in hospitals and healthcare

S BHANSALI, Florida International University, USA

MEMS, initially an acronym for microelectromechanical systems, was

a descriptor for developing both passive (sensors) and active chanical systems It is now considered a generic acronym The foundation of MEMS was based on the fundamental idea that a reduced form factor can provide signifi cant improvement in performance even in non-CMOS pro-cesses The fi rst proof of this idea was demonstrated by Nathanson (1967) who demonstrated a cantilever-based resonant gate transistor Nathansons’ out of plane cantilever and Bean’s (1978) anisotropic etching of Si created the foundations of MEMS These works coupled with Petersens’ seminal

electrome-1982 paper, ‘Silicon as a mechanical material’ provided a framework for the explosion of MEMS technologies The 1980s saw major advances in the development of MEMS actuators based on different driving principles A synergistic development in the fabrication of these devices was qualifi cation

of different processes and their acceptance into mainstream processes The 1990s saw the maturation of MEMS technologies with the advent of the fi rst generation of complex devices (beyond the pressure sensor) – com-mercial accelerometers, gyroscopes, and microphones Electromechanical devices or MEMS moved beyond electromechanics

The 1990s also saw major efforts in the use of MEMS technologies for the development of control components and readouts for sensors, and micro-

fl uidics with the development of chemical sensors, lab-on-chip systems and complex actuators for extremely fi ne measurements and manipulations These technologies provided the building blocks for MEMS devices for bio-medical applications The last decade has seen a signifi cant maturation of MEMS for biomedical applications, as biomedical applications provide the perfect platform for integrating complex design and fabrication of articu-lation, recording and assistive systems with integrated control and signal processing and custom packaging This era also saw MEMS being used as an acronym to describe the miniature systems

The fundamental drivers for MEMS for biomedical applications have been the following: improved sensitivities and signal-to-noise ratios, minimal

trauma/scar tissue formation in in vivo applications and high-throughput

systems for biomedical applications (polymerase chain reactions (PCRs) and DNA probes to drug discovery platforms)

As MEMS applications have evolved, so has the range of materials being used to develop these MEMS Materials such as polymers and glass, con-sidered as dirty materials or packaging materials in IC processing, became

structural and functional components of MEMS devices While numerous new processing technologies are being explored to fabricate these devices, microfabrication, which involves sequential patterning of a substrate such

as silicon, glass, polymer or ceramic using techniques such as phy, thin fi lm deposition and etching, remains the mainstay of the technol-ogy MEMS processing technology, along with the use of novel materials, has allowed the integration of mechanical, electrical, thermal, optical and

photolithogra-fl uidic structures into a single system This has signifi cantly broadened the applications for MEMS sensors and actuators

For biomedical applications, MEMS technology has found success largely

in the sensing domain Along with the reduced form factor, scaling laws also enhance sensor performance through increased sensitivity, selectivity, reli-ability, repeatability and shelf life MEMS sensors are used as implantable devices for continuous monitoring of a physiological variable, as continuous feedback sensors in surgical instruments, in miniaturized microphones in hearing aids and as sensors in disposable diagnostic devices that can be used

at home

MEMS actuators have been used for providing electrical stimulation in neural probes, cardiac pacemakers and defi brillators They have also been used as implantable and transdermal drug delivery systems, and in biome-chanics as prosthetic devices

Some of the inherent features of MEMS technology and the functional and structural materials used in MEMS device processing provide critical advantages in its use as biomedical systems Silicon, the basic material used

in MEMS devices, is a proven biocompatible material The use of polymer materials in MEMS devices allows for easy interaction with very small vol-umes of fl uids for use as lab-on-chip devices Low power consumption and reduced form factor allows for easy implantation and long-term usage The extensive development and characterization of the microfabrication tech-niques translates into high reproducibility, reliability and low cost

This book provides the reader with fundamental concepts (beyond ditional microfabrication, which is covered by multiple books) and applica-tions in developing diverse biomedical devices The fi rst section of the book introduces the reader to the basics of MEMS technology with a focus on polymers, since polymers are extensively used in biomedical microdevices

tra-A review of polymers and microfabrication techniques used to process polymers to create bioMEMS devices is presented in Chapter 2 This is fol-lowed by a review of sensing and actuation mechanisms of MEMS devices

as applied to biomedical applications (Chapter 3) These chapters provide a comprehensive background to understand the different biomedical applica-tions developed using MEMS

The second section of the book presents examples of biomedical cations of MEMS, and is focused at diagnostic applications and means to

appli-achieve high-throughput, point-of-care microsystems Use of MEMS

sen-sors for implantable applications, which provide vital advantages such as

minimally invasive procedures and continuous monitoring, is presented in

Chapter 3 An application example for the incorporation of

electrochem-ical impedance spectroscopy (EIS), a high-sensitivity measurement

tech-nique, and MEMS processing technology for non-invasive measurement

of cellular functions is presented in Chapter 4 Development of ultrasonic

transducers using MEMS technology and its contribution toward

creat-ing high-resolution imagcreat-ing tools for biomedical applications is detailed

in Chapter 5 A comprehensive review on microfl uidics and lab-on-chip,

a subspecialization of MEMS technology that deals with development of

miniaturized fl uidic systems for point-of-care diagnostic applications, is

presented in Chapter 6

The third segment of the book presents clinical applications accomplished

using microdevices machined using MEMS technology Tissue engineering

is a promising regenerative medicine technology that uses a combination of

cells, engineered scaffolds and growth factors to create tissue constructs that

can replace or replenish tissues for specifi c biological operations Chapter

7 provides an application example for the development of a MEMS device

for culturing cells for tissue engineering applications The MEMS

process-ing technology, which has the capabilities to create 3D constructs, can be

applied for the fabrication of scaffolding designs for tissue engineering The

various MEMS manufacturing techniques used for fabrication of tissue

scaffolds are presented in Chapter 8

Another central application of MEMS in the biomedical fi eld is in drug

delivery Micro- and nanofabricated platforms such as microneedles

pro-vide key advantages in drug delivery such as painless injections, timed drug

release and targeted drug delivery Chapter 9 articulates the

micro/nano-fabrication of microneedle-based drug delivery systems along with a brief

overview of other drug delivery systems such as drug eluding stents and

biodegradable drug reservoirs

MEMS technology also fi nds applications in surgical tools such as

micro-manipulators that provide guidance to surgeons during minimally invasive

procedures In Chapter 10, a survey of MEMS applications to minimally

invasive procedures is presented, exploring proposed uses of micromachined

mechanisms in primarily short-term tests or interventions Microgrippers

or microtweezers are critical surgical tools in biomedical applications that

require manipulations of cells and tissues with a high degree of precision,

resolution and reliability Chapter 11 presents a design review of

MEMS-based microgrippers along with an illustration of a microgripping system

based on bimorph structures

Chapter 12 describes the development of a microfl uidic platform that

uses the surface properties as well as volumetric, mechanical, magnetic and

electrical properties of cells to manipulate them in the microfl uidic system

to achieve rare cell enrichment, sorting and detection

The last section of the book presents the emerging applications of MEMS

in the biomedical fi eld While still nascent, these emerging applications show promise in improving the state-of-the-art in these fi elds through the use of miniaturized systems based on MEMS technology Chapter 13 pres-ents the micromachining of electrodes using MEMS technology for appli-cation as neural probes for stimulation and recording of the activities in the brain Chapter 14 presents the use of MEMS technology to develop ocular implants for intraocular pressure monitoring and glaucoma therapy

A review on the use of MEMS technology to create a platform for injection of discrete cells for therapeutic and research applications using microneedles and microfl uidics is presented in Chapter 15 The last chap-ter (Chapter 16) in the book presents a novel concept termed as Hybrid MEMS, which explores the integration of living organisms such as bacteria

micro-and Caenorhabditis elegans into MEMS devices, in which the living

organ-isms act as the functional feature of the device Various novel concepts such

as worm-on-chip and electronically controlled insects are discussed as well After reading this book, the reader would have an appreciation of the history, the state-of-the-art and the potential of MEMS for biomedical applications

References

Bean, K E (1978) ‘Anisotropic etching of silicon’ IEEE Transactions on Electron

Devices, 25(10), 1185–1193.

Nathonson, H C., Newell, W E., Wickstrom, R A and Davis J R Jr (1967) ‘The

reso-nant gate transistor’ IEEE Transactions on Electron Devices, 14(3), 117–133 Petersen, K E (1982) ‘Silicon as a mechanical material’ Proceedings of the IEEE, 70(5),

420–457.

Part I

Fundamentals of MEMS for biomedical applications

1

Microfabrication of polymers for bioMEMS

P REZAI, W-I WU and P R SELVAGANAPATHY,

McMaster University, Canada

Abstract: Use of microfabrication methods derived from the

semiconductor industry have been adapted to new materials in the recent past to produce electromechanical and fl uidic systems in the microscale Polymers are one such class of new materials as they are considered more suited for biomedical applications due to low cost, abundance, and availability of a wide range of functionality in addition to properties such

as low protein adsorption, chemical resistance, and low electrical and thermal conductivities This chapter describes in detail the properties, microfabrication methods and applications associated with most of the widely used polymers such as polydimethylsiloxane, parylene, SU-8, hydrogels, biodegradable materials and thermoplastics

Key words: polymers, microfabrication, polydimethylsiloxane (PDMS),

parylene, SU-8, hydrogels, porous monoliths, biodegradable polymers, paraffi n, thermoplastic polymers

BioMEMS and lab-on-chip-based automation and miniaturization of analytical assays have signifi cantly improved their performance, through-put, and the cost associated with them in areas as diverse as medical diag-nostics, drug delivery, drug discovery, analytical chemistry, and molecular diagnosis (Dittrich and Manz, 2006) Use of microfabrication methods

to produce lots of precisely replicable devices has led to repeatable and reliable performances Automation eliminates the human interfering fac-

tors and increases the confi dence in the analysis (Selvaganapathy et al ,

2003)

Polymers have been widely used in bioMEMS devices primarily due their low cost, chemical inertness, low electrical and thermal conductivi-ties, ease of surface modifi cation, and their biocompatibility Since poly-mers cost less, they are ideally suited for disposable bioMEMS devices where cross contamination is an issue The low cost of polymeric materi-als and their processing technique is one of the biggest advantages that provide impetus for development of novel processing technologies for microfabrication of polymeric MEMS/microfl uidic systems This chapter

describes some of the widely used polymers in MEMS, their properties, and fabrication methods

1.1.1 Polymers and their classifi cation

Polymers have high molecular masses (>1000 Da, having more than 100 repeat units) They are macromolecules polymerized from smaller mol-ecules called monomers through a series of chemical reactions Depending

on the position of the reacting groups in the monomer and the cross-linker, these chemical reactions can produce linear or cross-linked (large three-dimensional (3D) network) polymers The process of polymerization is statistically dependent resulting in the development of a range of polymer chain lengths, causing a nondefi ned melting temperature point, rather soft-ening over a temperature range called the melt interval Polymers are clas-sifi ed according to their structure and behavior (Nicholson, 1997)

Polymers are mostly classifi ed according to their response to thermal treatment One of the most important characteristic properties in this clas-

sifi cation is the glass transition temperature ( T g ) above which the polymers melt and hence can be molded into specifi c shapes After cooling below T g ,

polymers can regain their solidity while taking the shape of the mold insert Linear or branched polymers such as thermoplastics (e.g., polyethylene (PE) and polystyrene (PS)) are not polymerized by cross-linking and hence have a reversible thermal behavior (they undergo the same phase transition without hysterisis) They melt into plastic forms upon heating above their glass transition temperature and solidify upon cooling This property is ideal

in plastic molding applications Elastomers (such as polydimethylsiloxane, PDMS) are weakly cross-linked polymers that have small elastic modulus with high ranges of deformability Due to their cross-linked nature, they decompose by excessive heating rather than melting Finally, thermosetting polymers (e.g., bakelite and vulcanized rubber) are heavily cross-linked polymers, mostly in a rigid and brittle nature with a low range of elasticity and a high resistance against heat

Lithography-based microfabrication was originally developed for grated circuit (IC) fabrication in the semiconductor industry It involves thin-fi lm deposition and etching techniques combined with photolithogra-phy to defi ne specifi c patterns to produce micro/nanoscale structures in the order of 0.1–5 µm thickness on planar substrates These techniques were adapted in the 1970s to create high aspect ratio structures (20–200 µm) that could be used for construction of micromechanical components Known as

inte-surface and bulk micromachining, these techniques allowed the traditional materials used in microfabrication such as silicon and glass to be structured microscopically Surface micromachining was developed in the late 1980s

to create micro- and nanostructures for MEMS and microfl uidic devices

In this process, alternative layers of structural (that will be retained in the end) and sacrifi cial (that will be removed in the end) materials are depos-ited, lithographically defi ned, and then etched to create a 3D structure This allowed extending the range of materials that can be used to include oxides and nitrides of various elements as well as some polymeric materials With the advent of chemical and biological sensing and processing appli-

cations of MEMS (Manz et al , 1990), bulk and surface micromachining were

initially adapted to produce fl uidic devices in silicon and glass (Harrison

et al , 1993; Liang et al , 1996) Nevertheless, these lithography-based

micro-fabrication processes have certain disadvantages The range of materials that could be used was restricted Functional materials such as hydrogels, porous materials, and polymers with specifi c properties could not be incorporated into these devices The cost of lithographic fabrication was substantially higher compared to other methods and became an important consideration since many of the biological and chemical sensing devices were designed to

be disposable Polymers as functional materials are considered more suited for chemical and biomedical applications as they are abundantly available

at low cost and can be produced with a wide range of functionality while providing properties such as low protein adsorption, chemical resistance, and low electrical and thermal conductivities Many standard laboratory tools (cell culture plates, catheter, feeding tubes, pipette tips, etc.) have been made

of various polymers and the protocols developed have included the surface chemistry associated with these polymers in the biochemical reaction Most importantly, fabrication of polymer macrostructures is a well-established and low-cost process, which is ideally suited for disposable devices These factors provided a signifi cant impetus to the adoption of polymeric materials as sub-strate and functional materials in fl uidic MEMS devices as well as spurred the development of alternate microfabrication processes in the 1990s for polymeric materials adapted for their large-scale manufacturing processes Several manufacturing techniques such as hot embossing, injection mold-ing, and casting allow polymeric materials to be microstructured by repli-cation from a master mold The replication can be performed in ambient while still retaining similar resolution to photolithography Several reviews

of these polymer-based microfabrication techniques have been recently published (Xia and Whitesides, 1998; Heckele and Schomburg, 2004; Giboz

et al , 2007; Becker and Gärtner, 2008) Various techniques for

structur-ing 3D objects in the microscale have been developed in the past A brief description on the techniques relevant for MEMS and microfl uidics is given

in the following text

1.2.1 Injection molding

The injection molding process involves melting (above glass transition perature) and injecting thermoplastic polymers into a mold cavity that has preexisting features that need to be replicated The injected plastic solidifi es

tem-in the mold upon cooltem-ing and can be released subsequently The next cycle

of production can begin immediately once the part is cooled and ejected, which makes it one of the most ideal methods for mass production Its pro-cess fl ow is shown in Fig 1.1 a

Injection molding technique has been widely used for manufacturing CDs, DVDs, and large auto parts such as car panels and seats It has been adapted

to fabricate microparts, MEMS, and microfl uidic devices since the 1990s Various microfabrication techniques that include silicon micromachining, LIGA process, SU-8 photolithography, and electrical discharge machining have been used to create the mold inserts Feature sizes from 10 to 1000 µm and aspect ratio <10 have been obtained

1.2.2 Hot embossing

Hot embossing is a process of stamping a pattern into a softened plastic fi lm The process is depicted in Fig 1.1 b The stamp (mold insert) can be made by similar techniques mentioned above Thermoplastics such as polycarbonate (PC) and polymethylmethacrylate (PMMA) have been hot embossed successfully with features in the micrometer scale The stamp and thermoplastic fi lm are fi rst heated above its glass tran-sition temperature Subsequently, they are pressed together at certain embossing pressure thus the pattern on the stamp is transferred to the

thermo-Injection molding

Molds fabricated by

conventional micromachining

High pressure injection

of molten plastic into hot die

High pressure embossing and local heating for melting

Polymerization by heat or UV application

Molded part release

Molds fabricated by conventional micromachining

Low viscosity, low surface energy prepolymer melting and casting

1.1 Various polymeric microfabrication techniques, (a) microinjection

molding, (b) hot embossing, (c) casting, and (d) stereolithography

fi lm While other processes occur in a molten or liquid-phase polymer, hot embossing process occurs in a semisoftened polymer that is still in its solid phase Therefore, it can be done at a lower temperature, subse-quently reducing the shrinkage during cooling Moreover, parts made from hot embossing have lower stress as the modifi cation only occurs at the surface and not in the bulk Thus, high aspect ratio structures (>10) can be replicated easily in thin fi lms with the thickness of 1–100 µm

A variation termed nanoimprint lithography is used to replicate a tern on photoresist fi lms from stamps, and the imprinted photoresist is then cured by heat or UV light

1.2.3 Casting

Similar to injection molding, the material is introduced into a mold in its uid state and then is solidifi ed in the mold However, instead of being forced through a nozzle, it is poured or casted onto the mold This technique has also been adapted for microfabrication and evolved as reaction casting The process involves mixing two components of low molecular mass reactants and casting them into the mold With the low viscosity, the mixture can fl ow and wet the entire surface of the mold The viscosity of the casted mixture

liq-is then increased by thermal or UV light-based cross-linking Thliq-is results

in a solid high molecular mass replica that can be removed from the mold Typically, thermosetting plastics (polyurethane (PU)), epoxies, and elasto-mers (PDMS) are the common materials for casting and features in the scale of nanometers can be replicated easily The process is illustrated in Fig 1.1 c

1.2.4 Stereolithography

Stereolithography was developed as an additive manufacturing process for rapid prototyping in 1980s A vat of liquid-phase photopolymer that is UV-curable and a UV light source are used to build parts from a series of 2D exposures along the z-stack layers as shown in Fig 1.1 d The laser beam induces the polymerization at the focusing region of the liquid-phase pho-topolymer As the laser traces the cross-section patterns layer by layer, com-plete 3D parts are formed Optic apparatus positioning and diffusion in the photopolymer are the key factors to the resolution, which is around 150 µm

along XYZ axes The maximum thickness of part is determined by the laser

penetration capability Alternatively, digital micromirror devices have been used to generate complex patterns instead of a single point by focused laser

beam that eliminates the movements in XY plane and thus increases the

throughput

1.2.5 Inkjet printing

Inkjet printer creates images or texts by propelling ink droplets onto paper

or overhead transparencies The concept of inkjet printing originated in the early 1980s and has then been adapted for printing of liquid-phase poly-mers other than inks Much effort has been made in accurate deposition of tiny quantities of polymers to turn it into a versatile tool for manufactur-ing processes The criterion here is the viscosity of the liquid-phase poly-mer that has to be low enough (<20 mPas) so that the energy exerted to the fl uid from the (piezoelectric) actuator cannot be dissipated viscously Typically, the liquid-phase polymer could be melted waxes or colloidal gels that become solidifi ed on contact with the substrate The control of the size and the positioning of the drops have been demonstrated in an accuracy

of micrometer scale This method can be extended to biopolymers such as proteins, DNA, and biological cells Since proteins are sensitive to temper-ature and various solvents, care needs to be taken in order to maintain the viability For example, specifi c reagents have been delivered to individual locations through inkjet printing on a slide to synthesize different DNA sequences

1.2.6 Micromilling

Traditionally, milling refers to the turning-based production machining that involves cutting, shaping, and fi nishing Micromilling is used to create microscale features on the surface of various materials including metals, plastics, and ceramics A high-precision positioning system and a high-speed spindle that moves the cutting tool in a precise 3D path produce the req-uisite 3D features on the substrate Similar to other mechanical machining processes, the tool abrasion is the main issue for micromilling of metals but

is not an issue with polymers Alternatively, laser micromilling uses laser pulses to ablate a small amount of material from the surface The desired feature can be determined by the scanning laser across the surface and the depth can be controlled by the number of pulse at each position It can often

be a more cost-effective alternative to micromilling

A wide variety of polymers have been used in fabrication of microsystems for biomedical applications They include thermoplastic materials such as polymethylmethacylate, polycarbonate, polyvinylidenefl uoride, polysul-fone, polystyrene, polyvinylchloride, polypropylene, polyetheretherketone, polyoxymethylene, and polyamide (Heckele and Schomburg, 2004) as well

as cross-linked materials such as PDMS, paraxylylene (parylene), SU-8, hydrogels, porous polymers, biodegradable polymers, polyesters, polyimide (PI), and paraffi n Since many biomedical applications require the MEMS

or microfl uidic device to be disposable and hence low-cost, polymeric rials are an ideal choice Furthermore, many of the biochemical reactions have been characterized in polymeric materials and will function similarly

mate-in microdevices made of the same material This section describes mate-in detail the properties, fabrication methods, and applications associated with such polymers

1.3.1 Polydimethylsiloxane (PDMS)

PDMS is the most widely used polymer for rapid prototyping in microfl ics and bioMEMS It has a repeating Si–O backbone connected to two side organic groups (CH 3 ) via Si–C bonds One of the main advantages associ-ated with this material is its versatility in different rheological forms such

uid-as fl uids, emulsions, lubricants, resins, eluid-astomers, and rubbers (Brook, 2000) that depends on the number of repeating backbones and the degree of cross-linking in the polymeric chain PDMS is mechanically strong (Young’s

modulus of 360–868 kPa (Armani et al , 1999)), optically transparent, ble, biocompatible (Chang et al , 2007), and gas permeable; all these features

dura-make it suitable for biology and life science applications

Polymerization

Siloxane polymers exist in forms of fl uid, gel, elastomer, and resin Fluids consist of linear chains of PDMS terminated with a trimethylsilyl group Gels are 3D matrices of partially cross-linked PDMS chains (introduced either through a trifunctional silane – such as CH 3 SiCl 3 giving a branched silicone structure – or through a chemical reaction between a Si-vinyl group on one polymer chain and a hydrogen-bonded silicon in another (Noll, 1968)) Elastomers have a completely cross-linked form that is ideal for microfl uidic and bioMEMS applications The polymerization of linear PDMS polymers into a cross-linked elastomer is done through an organo-metallic cross-linking reaction

PDMS elastomer is formed through a cross-linking reaction of a two-part mixture consisting of long-chain PDMS polymer (base) with short-chain cross-linkers The siloxane base oligomers (prepolymer) contain vinyl-ter-minated end groups (CH 2 =CH–) The base solution also contains platinum-based catalyst and silica fi ller The cross-linker typically contains oligomers such as dimethyl methylhydrogen siloxane, tetrakis(dimethylsiloxy) silane (TDS) (HSi(CH 3 ) 2 O) 4 Si), and an inhibitor (tetramethyl tetravinyl cyclotet-rasiloxane) The platinum-based catalyst catalyzes the addition of the Si–H

bond across the vinyl groups, forming Si–CH 2 –CH 2 –Si linkages (Fu et al ,

2003) Multiple reaction sites on both the monomer and cross-linking chain enhance 3D cross-linking that can also be accelerated through heat appli-cation No waste product such as water is generated during such reactions Increasing the ratio of the curing agent to the base will result in a higher rate

of cross-linking and hence a harder elastomer

Microstructure fabrication for MEMS and microfl uidic devices

PDMS microchannels are one of the most widely prototyped polymeric devices primarily due to their low cost and simple fabrication methods

( Fig 1.2 ) (Effenhauser et al , 1997) These devices are less expensive than the ones fabricated from silicon and glass materials (Harrison et al , 1993; Liang et al , 1996) Figure 1.3 shows a replicated microchannel in

PDMS

PDMS is microfabricated by a casting-based approach A micromold master is made with the features to be negatively replicated ( Fig 1.2 a) The PDMS prepolymer consisting of a base (linear PDMS chains) and a cross-linker (short PDMS cross-linking chain with an initiator) is cast on the mas-ter and let to settle and assume the shape of the mold ( Fig 1.2 b) Then the mixture is cross-linked using heat, and the elastomer is formed This trans-forms the fl uid prepolymer into a solid cross-linked elastomer, which is then peeled off ( Fig 1.2 c) (Kumar and Whitesides, 1993) Subsequently, the rep-licated elastomeric substrate is punctured for liquid access ports ( Fig 1.2 d) and bonded to another PDMS elastomer or glass to form a sealed MEMS and microfl uidic device ( Fig 1.2 e)

Master molds have been fabricated using different methods such as bulk

micromachining (lithographic patterning and etching (Effenhauser et al ,

1997)) of silicon (expensive) or additive surface micromachining (thick

photoresist lithography) on a silicon wafer (Qin et al , 1996; Duffy et al ,

1998a; Xia and Whitesides, 1998) The cost of the later method can be reduced (10–50 times) by utilizing transparency photomasks instead of the chrome ones (∼500-nm resolution) during the photolithography process

(Duffy et al , 1998a), albeit with reduced resolution due to resolution of the

photoprinter The PDMS prepolymer can be mixed in different base:agent ratios (usually 10:1) and casted over the master mold Heat is used (usually 65°C for a few hours) to facilitate the process of polymerization; however, PDMS can also be cured at room temperature but over longer time To facilitate the peeling process, the surface of the mold can be treated with

various chemicals (i.e., silanized in 3% ( v / v ) dimethyloctadecylchlorosilane

in toluene for 2 h) to lower the surface tension between PDMS and the mold After peeling the PDMS (containing a negative replica) off the mold,

it can be cut into individual devices and punched for fl uidic interconnect

installations ( Fig 1.2 d and 1.2e) Different bonding methods have been developed for PDMS that are more comprehensively described in the next section Two PDMS slabs of same chemical composition can form a reversible (advantageous for post-process cleaning) weak bond (no exter-nal force required) if brought together after peeling off the master mold

(Effenhauser et al , 1997), which were able to withstand pressures of 1 bar

Capillary electrophoresis separation of φX-174/HaeIII DNA was

demon-strated in this kind of devices (Effenhauser et al , 1997).To create stronger

bonds between PDMS slabs to operate on higher pressures, plasma tion of PDMS surface has been very effective in making irreversible bonds, which are addressed later

oxida-Master mold with patterned photoresist (a)

Cured PDMS peeled off

Access ports punctured

Bonding to a secondary substrate

1.2 Soft lithography technique for PDMS microstructures replication, (a)

master mold made lithographically, (b) PDMS prepolymer casted over the master mold, (c) cured (heat treated) PDMS peeled off the master mold, (d) fl uidic access ports punctured, and (e) PDMS layer bonded to

a secondary layer (glass, PDMS, parylene, etc.) for device enclosure

PDMS bonding

Different applications require bonding of PDMS to various polymers, PDMS, glass, or metallic substrates to generate embedded devices The most common methods used and materials bonded to PDMS are summarized

in Table 1.1 along with the bond strengths that were achieved PDMS was

initially bonded to itself (Duffy et al , 1998a) by plasma oxidation of its

sur-faces The methyl groups existing on the surface of the PDMS make it inert and hydrophobic Plasma oxidation opens hydroxyl radicals (hydrophilic)

on the surface of the PDMS Two oxidized surfaces brought in conformal

contact will then generate irreversible Si–O–Si covalent bonds (Duffy et al ,

1998b) between the surfaces This method has been used to bond PDMS to

PDMS, glass, and Si (Bhattacharya et al , 2005) as well as PDMS to

passi-vated layers on Si, that is, phosphosilicate glass (PSG), undoped silicate glass (USG), Si 3 N 4 , and SiO 2 (Tang et al , 2006) This bond has been studied exten-

sively to evaluate the effect of plasma parameters (different gasses, chamber pressure, plasma power, and time) on the quality of bonding Bhattacharya

et al (2005) studied the effect of various plasma parameters (time: 5–60 s,

power: 5–150 W, pressure: 20–1000 mTorr) on the quality of bonding in PDMS–PDMS and PDMS–glass interfaces Intermediate exposure time (20 s), high pressure (>700 mTorr), and low power (20 W) were more effec-tive in bonding quality enhancement with a maximum PDMS–glass and PDMS–PDMS bond strength of 74 and 58 psi, respectively, measured using

a blister leak test method Longer exposure times (>30 s) can result in the growth of thin oxidized layers on the surfaces that can eventually crack and

1.3 A replicated microchannel structure in PDMS using the soft

lithog-raphy technique ( Source : Effenhauser et al , 1997.)

a urethane functionality on the surface

weaken bonding An important factor that can cause recovery of the surface from hydrophilic to hydrophobic after oxidization is aging in ambient Low-molecular-weight PDMS molecules can migrate to the surface and induce

this recovery (Hillborg et al , 2000) The hydrophobic surface of PDMS can

also be rendered hydrophilic using other methods such as chemical

treat-ment (Jo et al , 2000) using sodium silicate (low-temperature adhesive for glass-bonding applications (Wang et al , 1997b; Ito et al , 2002)), sol–gel tech- niques (Roman et al , 2005), silanization (Papra et al , 2001), chemical vapor deposition (Lahann et al , 2003), atom transfer radical polymerization (Xiao

et al , 2002), and polyelectrolyte multilayers (Liu et al , 2000) Cross-linking

of polyelectrolyte multilayers have also been used to provide greater

stabil-ity of the surface layer (Makamba et al , 2005)

Tang et al (2006) also studied the oxygen plasma effect (20–140 W power,

30–500 mTorr pressure, and 10–40 s time) on bonding PDMS to PSG, USG,

Si 3 N 4 , and SiO 2 deposited on a silicon wafer A postbonding oven-based thermal treatment at either 150°C or 100°C for 2 h with an applied pressure

on the sample was included in the bonding process Shear and peel tests showed that low pressures (30 mTorr) and moderate powers (60 W) can both improve the bond quality of PDMS to PSG, USG, and Si 3 N 4 The bond strength of PDMS to SiO 2 surface was, however, not improved considerably Thermal treatment had no effect on the bond strength of PDMS

Eddings et al (2008) also studied the quality of bonding (using air leakage

method) between two PDMS layers bonded using different methods such

as partial PDMS curing, varying base:agent mixing ratio, uncured PDMS adhesive, oxygen plasma, and corona discharge with approximate average bond strengths of 650, 470 with optimum base:agent ratio of 15:1, 670, 300, and 290 kPa, respectively

PDMS has also been bonded to other plastic materials While utilizing these materials would reduce the gas permeability and evaporation rates through the device, deformable PDMS structures would still provide the benefi ts of valve and pump microcomponents Using a 1-min plasma expo-sure of 1:2 argon:oxygen gas fl ow rate ratio followed by overnight heat

treatment (60°C) and pressure, Mehta et al (2009) investigated the bond

between polyethylene terephthalate glycol (PETG), cyclic olefi n mer (COC), and PS to PDMS and PU layers Burst pressures of bonded interfaces were more than 120 kPa for PETG–PU bonds that decreased

copoly-to ∼20 kPa after storing for 168 h in humidifi ed condition at 37°C Oxygen plasma, chemical grafting, UV polymerization, and thermal bonding did not provide signifi cant improvement in bonding for these combinations of materials

PDMS–PMMA (Ko et al , 2003) and PMMA–PMMA (with intermediate PDMS layers) (Chow et al , 2006) bonding have been accomplished using

low temperatures and pressures without a need for plasma oxidization

However, a low bonding strength of 15 kPa was reported between PMMA and PMMA

PDMS bonding to PDMS or PMMA was also acquired by a chemical face modifi cation approach The surfaces were coated (either by immersing

sur-or by spinning) with a thin layer of diluted silane solution (5% ltriethoxysilane in water), plasma oxidized, and physically attached together

3-aminopropy-(Vlachopoulou et al , 2009) Tensile bond strengths of approximately 1100 and 400 kPa were realized for PDMS – PMMA and PDMS – PDMS interfaces,

respectively This method was also used to form PMMA–Si or PMMA–glass bonds A similar but more elaborate chemical gluing method (Tang and Lee, 2010) was used to bond PDMS to PMMA, PC, PET, U-PET (primed with a urethane functionality on the surface of PET), and PI The bond strengths are listed in Table 1.1

PDMS elastomers have also been bonded to parylene using a plasma

enhancement method (Rezai et al , 2011) The parts were fabricated

sepa-rately and a microcontact printing process on PDMS prepolymer and ment was used to form a weak seal (∼400 kPa tensile strength) between them The assembly was then exposed to plasma of different gases (SF 6 , O 2 , and N 2 ) The effects of gas fl ow rates, plasma power, time, and chamber pres-sure were investigated It was reported that higher fl ow rates of SF 6 and N 2 gases and high plasma power and time were required for an effective bond-ing Oxygen had a deterrent effect in the bond and the chamber vacuum pressure was almost neutral PDMS–parylene bonds as strong as 1.6 MPa (tensile) were reported

Multichannel structures

Unger et al (2000) developed a practical technique (‘multilayer soft

lithog-raphy’) to produce multiple stack layers of microfl uidic features and bond them together in a 3D format The technique is very similar to soft lithog-raphy Each layer of PDMS is casted and cured over its own master mold However, each layer contains an excess amount of either the PDMS base or the agent component After curing each layer, they can be aligned and her-metically bonded to each other ( Fig 1.4 ) Due to the existence of reactive molecules, gradual bonding will happen at the interface resulting in a mon-olithic 3D patterned structure composed entirely of elastomer Additional layers can always be added to the stack simply by making a PDMS slab of opposing chemical polarity at each layer

1.3.2 Parylene

Parylene is another important polymer after PDMS with a para-xylylene backbone used in bioMEMS, microfl uidic, electronic packaging, and even

cosmetic product industries This material can be vapor deposited in a very conformal format (Gorham, 1966) Parylene exists in three forms as N,

C, and D ( Fig 1.5 ) The basic parylene N (poly-para-xylylene) is a linear and highly crystalline material Commercial parylene products are differ-ent in their benzene ring atoms’ composition (Fig 1.5) Parylene C and

D have one and two chlorine atoms replaced in their backbone, tively Parylene applications include fabrication of microchannels (Man

et al , 1997; Webster and Mastrangelo, 1997), microvalves (Rich and Wise, 1999; Wang et al , 1999; Carlen and Mastrangelo, 2002), membrane fi lters (Yang et al , 1998), and other micromachined devices as well as encapsu-

lation for microelectronic circuits (Olson, 1989; Lin and Wong, 1992) and

biological samples (Nosal et al , 2009), as interlayer dielectrics (Selbrede

and Zucker, 1997) and for strengthening wire bonds (Flaherty, 1995) in microchip packaging

Polymerization

Parylene’s molecular weight is relatively high (∼500 000 Da) that results

in high melting temperatures and crystallization characteristics This is the reason why parylene cannot be polymerized and molded in a similar man-ner as PDMS for microdevices fabrication However, this material can be deposited ( Fig 1.6 ) using thermal sublimation at 140–160°C (furnace), vapor division into monomers at 680°C (pyrolysis chamber), and conformal deposition (Lee and Cho, 2005) and polymerization on the surfaces under vacuum at room temperature (deposition chamber) while forming uniform thin fi lms

+

+ +

+ +

+

+ + +

+ +

1.4 A digital microfl uidic device developed by the multilayer soft

litho-graphy technique, (a) general purpose microfl uidic device schematic, (b) the storage cells photomicrograph; channels are fi lled with food color-

ings for clarity ( Source : Urbanski et al , 2006 Reproduced by permission

of The Royal Society of Chemistry http://dx.doi.org/10.1039/b510127a.)