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FROM ONE-BEAD ONE-COMPOUND COMBINATORIAL LIBRARIES

303

ACKNOWLEDGEMENTS

The authors would like to thank Amanda Enstrom for the assistance with the manuscript. This work was supported by NSF Grant MCB9728399, NIH Grants R33CA-86364, R33CA89706, and R01CA-098116. Ruiwu Liu is supported in part by the University of California System wide Biotechnology Research Program, grant number: 2001–07.

ABBREVIATIONS

 

AFM

atomic force microscopy

ATP

adenosine-5’- tri phosphate

Bn

benzyl

Boc

tert-butoxycarbonyl

BSA

bovine serum albumin

t-But

tert-butyl

DIEA

N ,N -diisopropylethylamine

DNA

deoxyribonucleic acid

ESI

electrospray ionization

EVHI

enabled/vasodilator-stimulated phosphoprotein homology I

Fmoc

9-fluorenylmethoxycarbonyl

FRET

fluorescence resonance energy transfer

GC

gas chromatography

HF

hydrofluoric acid

HPLC

high performance liquid chromatography

HTS

high throughput screening

IR

infrared

MALDI-FTMS

matrix-assisted laser desorption/ionization-Fourier

 

transform mass spectrometry

MALDI-TOF MS

matrix-assisted laser desorption/ionization time-of-flight

 

mass spectrometry

MMP-2

matrix Metalloproteinasese-2

MTT

3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide

NMR

nuclear magnetic resonance

OBOC

one-bead one-compound

PEG

polyethyleneglycol

PNA

peptide nucleic acid

PVDF

polyvinylidene fluoride

SELDI

surface-enhanced laser desorption/ionization

SH2

the Src homology 2 domain

SH3

the Src homology 3 domain

SPR

surface plasmon resonance

TBTU

O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium

 

tetrafluoroborate tetrafluoroborate

UDP-galactose

uridine-5’-diphospho galactose

304

KIT S. LAM ET AL.

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II

Advanced Microfluidic Devices

and Human Genome Project

9

Plastic Microfluidic Devices for DNA and Protein Analyses

Z. Hugh Fan1 and Antonio J. Ricco2

1Department of Mechanical and Aerospace Engineering, Department of Biomedical Engineering, and McKnight Brain Institute, University of Florida, PO Box 116250, Gainesville, FL 32611-6250 2NASA Ames Research Center, Mountain View, CA 94035 and Dept. of Electrical Engineering, Stanford University, Stanford, CA 94305

9.1. INTRODUCTION

Microfluidics and integrated microsystems are the current focus of unusually intense interest and activity on the part of academia, industry, and governmental agencies, an assertion substantiated by the solid attendance at the 2003 International Conference on Micro Total Analysis Systems (µTAS) [45] and by the recent publication of various books on this topic [46], both at a time when the economy in general, and the technology sector in particular, are at relative low points. Significant advances have been realized since the concept of µTAS was developed more than a decade ago as a means to enhance versatility and functionality relative to discrete chemical sensor devices [41]. Functional examples of the µTAS concept include on-chip PCR (polymerase chain reaction) [28, 44, 72], DNA analysis and sequencing [14, 58, 76], immunoassays [10, 19, 57], protein separations [23, 48, 64], and intraand inter-cellular analysis [29, 53, 63]. Advantages of these µ-TAS over bench-top instruments include low reagent consumption, small sample volumes, high separation efficiencies, short reaction times, ease of automation, and potential for massproduction with low cost [41].

9.1.1. Detection

In general, miniaturization of analytical instrumentation requires that detection systems detect ever-decreasing numbers of molecules. A variety of detection methods have

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been incorporated or appended (“hyphenated”) to µTAS devices, including laser-induced fluorescence [18], ultraviolet (UV) absorbance [30], electrochemistry [68, 54], and mass spectrometry [9, 26]. Due to its sensitivity, laser-induced fluorescence (LIF) is most often employed in applications with challenging limits of detection. Using confocal detection, LIF now routinely enables detection of fluorescently labeled molecules at concentrations around 10 pM; with sub-nanoliter detection volumes, the number of molecules detected is in the hundreds to thousands ( , 1 zeptomol). This detection limit is acceptable for most applications that require high sensitivity, such as DNA sequencing and many immunoassays. Though less sensitive in absolute terms, electrochemical detection is low in cost and readily integrated onto fluidic chips: Girault and colleagues integrated carbon microband electrodes in the bottoms or sidewalls of rectangular microchannels in plastics, demonstrating a detection limit of 1 fmol of ferrocenecarboxylic acid [54].

9.1.2. Materials

Several types of materials have been used for making µTAS devices, including silicon [21, 72], glass [13, 25], and plastics [3, 51, 61]. The primary motivation for the construction of µTAS from plastics is cost. While microfabrication of silicon, glass, and similar materials can be accomplished cheaply when chip sizes are small (a few mm2 in area), fluidic devices occupying many cm2 are often dictated by applications (vide infra). For diagnostic devices and other contamination-sensitive applications, costs must often be low enough for singleuse disposability. In addition, the biocompatibility of various plastics is well documented, allowing plastic devices to be adapted to a wide range of applications, including DNA and protein analyses. For these reasons, this chapter focuses on plastic microfluidic systems.

9.2. ELECTROKINETIC PUMPING

Manipulation of fluids in a microfabricated device requires pumps that are compatible with the typical flow rates used in the microfluidic system. Pumps using electronic and mechanical means have been most often employed. Electronic pumps include electrokinetic (vide infra), electrohydrodynamic [37], and dielectrophoretic [17], while mechanical pumps include those using pneumatic pressure, syringe drive, bubble generation, thermal expansion, osmotic pressure, and other transducer-induced motions/forces. Other pumping mechanisms involve thermal gradients, magnetic force, and magnetohydrodynamic flow. In this chapter, we will center on electrokinetic means to move and separate analytes.

Using electrokinetic phenomena as a means to pump and separate analytes was a major catalyst for the rapid growth of µ-TAS during the 1990’s. Its utility was demonstrated by Manz and Harrison early in the 1990’s [20, 40]. However, this seminal achievement came more than a decade after the first realization of integrated components for miniaturized analytical instrumentation, namely a microfabricated gas chromatography system on a single silicon wafer [66]. The long time delay was due primarily to the lack of an appropriate pumping mechanism suited to micro-scale devices.

The use of electrokinetic pumping was accompanied by widespread acceptance of capillary electrophoresis (CE) as a chip-appropriate separation method. CE was largely developed using fused silica capillaries, their diameter being in the same range as the

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FIGURE 9.1. (a) Formation of the double-layer at a channel wall/solution interface and the generation of electroosmosis under an applied electric field; µeo is EO mobility. (b) The nearly flat electroosmotic flow profile. In addition to EO, both cations and anions experience electrophoretic flow; µep is electrophoretic mobility. (c) A generic electropherogram showing cations, neutral molecules, and anions.

microfabricated channels that are a principal feature of fluidic devices, making its adaptation to chip-based separations straightforward.

The fundamentals of CE, found in textbooks [3] and reviews [12], are discussed briefly here. When a glass channel or a fused silica capillary is filled with an appropriate solution, a phenomenon called electroosmosis (EO) occurs when an electric field is applied to the ends. The generation of EO is schematically illustrated in Figure 9.1a. The walls of the channel or capillary are negatively charged in an aqueous solution at pH > 3 due to the ionization of surface silanol groups [35]. The negative charges on the wall surface attract positive ions from the buffer solution, thus giving a typical ionic double-layer structure. The mobile positive ions in the diffuse layer carry several solvent molecules each and these solvated ions are attracted to the cathode (negative electrode) by the electric field, thus moving parallel to the channel or capillary walls. The movement of this sheath of solvated ions drags with it the solution in the rest of the channel, and the resulting electroosmosis has a unique feature: a nearly flat flow profile across the entire diameter of the capillary, as shown in Figure 9.1b.

While electroosmosis moves both solutes and solvents in the same direction and at the same speed, the separation of solutes results from electrophoresis, which occurs at the same time as EO and is caused by the difference in ionic mobilities in the applied electric field. Although electrophoresis simultaneously drives cations (positive ions) to the cathode and anions (negative ions) to the anode, for glass channels it is often the case that electroosmotic mobility is larger than electrophoretic mobility, hence both cations and anions exhibit net