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About the Author
Jeong-Yeol Yoon received his B.S., M.S., and Ph.D. degrees in Chemical
Engineering from Yonsei University, Seoul (South Korea) in 1992, 1994, and
1999, respectively, under the guidance of Dr. Woo-Sik Kim, in collaboration with
Dr. Jung-Hyun Kim, where he worked primarily on polymer colloids. He received
his second Ph.D. degree in Biomedical Engineering from the University of
California, Los Angeles in 2004, working on lab-on-a-chip and biomaterials,
under the guidance of Dr. Robin L. Garrell. He joined the Agr icultural &
Biosystems Engineering (ABE) faculty in August 2004 and holds joint appointment
in the Department of Biomedical Engineering at the University of Arizona. He is
also a faculty member in the Biomedical Engineering Graduate Interdisciplinary
Program (BME GIDP), Microbiology Graduate Program, and BIO5 Institute at the
University of Arizona. Dr. Yoon is currently an Associate Professor and is directing
the Biosensors Lab (http://biosensors.abe.arizona.edu). He is a member of the
Institute of Biological Engineering (IBE) , American Society of Agricultural and
Biological Engineers (ASABE) and SPIE—The International Society for Optics
and Photonics. He currently serves as Associate Editor and Editorial Board
Members for numerous journals, including Transactions of the ASABE, Biological
Engineering Transactions, Journal of Biological Engineering, and Resource
Magazine. Dr. Yoon has published ~50 articles in peer-reviewed journals.
vii
Contents
1 Introduction 1
1.1 Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Transducers . 2
1.3 Biosensors . . 4
1.4 Bioreceptors 5
1.5 Transducers for Biosensors . . . . 11
1.6 Overview of this Textbook . . 12
Bibliography 14
2 Resistors 15
2.1 Electric Circuit . . 15
2.2 Current and Voltage . 15
2.3 Resistance and Ohm’s Law . . . 17
2.4 Resistors in Series, or Voltag e Divider 18
2.5 Potentiometer, or Pot 19
2.6 Resistors in Parallel, or Curre nt Divider . . . . . . . . . . . . . . . . . . . 20
2.7 Laboratory: Resistors . . 22
2.7.1 Reading Resistor Values . . . . . . . . . . . . . . . . . . . . . . . . 22
2.7.2 Breadboards 24
2.7.3 Connecting to a Power Supply . . . . . . . . . . . . . . . . . . . . 25
2.7.4 Resistance Measurements 27
2.7.5 Task 1: Resistors in series 28
2.7.6 Task 2: Resistors in parallel . . . . . . . . . . . . . . . . . . . . . . 30
2.7.7 Task 3: “Droop” 31
2.7.8 Potentiometer (Pot) 33
2.8 Further Study: The
´
venin’s theorem . . . . . . . . . . . . . . . . . . . . . . 35
Bibliography 37
3 Diodes and Transistors 39
3.1 Semiconductors . . . . 39
3.2 Diodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
ix
3.3 Zener Diode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.4 Transistors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.5 Laboratory: Diodes and Transistors 49
3.5.1 Operational Amplifier 49
3.5.2 Task 1: LED 50
3.5.3 Task 2: Zener Diode 53
3.5.4 Task 3: Transistor 55
Bibliography 57
4 Temperature Sensors 59
4.1 Thermocouple 59
4.2 Thermistor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.3 Diode Temperature Sensor 62
4.4 Transistor Temperature Sensor . . . 64
4.5 Laboratory: Temperature Sensors . . . . . . . . . . . . . . . . . . . . . . . 65
4.5.1 Task 1: Thermistor 65
4.5.2 Task 2: Zener Diode Temperature Sensor 66
4.5.3 Task 3: Transistor Temperature Sensor 69
Bibliography 73
5 Wheatstone Bridge 75
5.1 Wheatstone Bridge . 75
5.2 Strain Gauge 77
5.3 Cantilever Biosensor 78
5.4 Laboratory: Wheatstone Bridge . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.4.1 Task 1: Wheatstone Bridge 79
5.4.2 Task 2: Wheatstone Bridge for a Thermistor . . . . . . . . . . 81
5.4.3 Task 3: Wheatstone Bridge for a Strain Gauge . . . 84
Bibliography 85
6 Op-amp 87
6.1 Op-amp 87
6.2 Basics of Op-amp . . . . . . 89
6.3 Voltage Follower or Buffer Op-amp . . . . . 90
6.4 Non-inverting Op-amp . . . 91
6.5 Inverting Op-amp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
6.6 Summing Op-amp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
6.7 Differential Op-amp 94
6.8 Laboratory: Op-amp . . . 95
6.8.1 Task 1: Non-inverting Op-amp Operation . . . . . . . . 95
6.8.2 Task 2: Signal Conditioning
for Temperature Sensor 98
Bibliography 101
x Contents
7 Light Sensors 103
7.1 Light 103
7.2 Photoresistor . 104
7.3 Photodiode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
7.4 Phototransistor 108
7.5 Light Emitting Diode 109
7.6 Laser Diode . . . 111
7.7 Laboratory: Photodiode 113
7.7.1 Task 1: Photoconductive Operation . 113
7.7.2 Task 2: Photovoltaic Operation 116
Bibliography 119
8 Spectrophotometry and Optical Biosensor 121
8.1 Spectrophotometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8.2 Miniature Spectrophotometer . . . . . . . . . . . . . . . . . . . . . . . . . 124
8.3 Optical Glucose Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
8.4 Laboratory: Glucose Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . 128
8.4.1 Task 1: Glucose Assay Kit
with a Spectrophotometer . . . . . . . . . . . . . . . . . . . . . . . 129
8.4.2 Task 2: Glucose Assay Kit with
LED/PD Circuit 134
8.5 Further Study: Pulse Oximeter 137
Bibliography 138
9 Fluorescence and Optical Fiber 141
9.1 Fluorescence . . 142
9.2 Fluorescent Dyes . 144
9.3 Optical Fibers 147
9.4 Laboratory: Optical Fiber Spectrometer . 150
9.4.1 Reflection Probe . . . 151
9.4.2 SpectraSuite™ Software . . . . . . . . . . . . . . . . . . . . . . . 152
9.4.3 Task 1: Fluorescent Lamp Measurement 153
9.4.4 Task 2: Fluorescent Excitation and Emission
Measurement 155
Bibliography 160
10 Electrochemical Sensors 161
10.1 Electrolytic and Electrochemical Cells . . . 161
10.2 Ion-Selective Electrodes (Potentiometric) . 166
10.3 pH Electrode (Potentiometric) 167
10.4 Electrochemical Glucose Sensor (Amperometric) . . 168
10.5 Conductometric Biosensors . . 170
10.6 Laboratory: pH Meter and Glucose Meter 171
10.6.1 Buffer 171
10.6.2 Task 1: Buffer Preparations
and Their pH Measurements . . . 172
Contents xi
10.6.3 Task 2: pH Meter Circuit . . . . . . . . . . . . . . . . . . . . 175
10.6.4 Task 3: Commercial Electrochemical
Glucose Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
11 Piezoelectric Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
11.1 Piezoelectricity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
11.2 Pressure Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
11.3 Crystal Oscillators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
11.4 Quartz Crystal Microbalance . . . . . . . . . . . . . . . . . . . . . . . . . 184
11.5 Viscoelasticity Consideration in QCM . . . . . . . . . . . . . . . . . . 187
11.6 Flow-Cell QCM as Biosensor . . . . . . . . . . . . . . . . . . . . . . . . 189
11.7 Laboratory: Quartz Crystal Microbalance . . . . . . . . . . . . . . . . 190
11.7.1 Task 1: Quantifying BSA Adsorption
on QCM Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
12 Immunosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
12.1 Enzyme-Linked Immunosorbent Assay . . . . . . . . . . . . . . . . . 199
12.2 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
12.3 Antibody Fragments and Aptamers . . . . . . . . . . . . . . . . . . . . 203
12.4 Lateral-Flow Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
12.5 Optical Immunosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
12.6 Surface Plasmon Resonance Immunosensor . . . . . . . . . . . . . . 209
12.7 Electrochemical Immunosensors . . . . . . . . . . . . . . . . . . . . . . 210
12.8 Impedance Immunosensors: Interdigitated
Microelectrode Immunosensor . . . . . . . . . . . . . . . . . . . . . . . . 212
12.9 Piezoelectric Immunosensors: QCM Immunosensor . . . . . . . . 213
12.10 Immunosensing Kits Versus Handheld Immunosensors . . . . . . 214
12.11 Laboratory: ELISA kit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
12.11.1 Task 1: Insulin ELISA Kit . . . . . . . . . . . . . . . . . . . 215
12.11.2 Task 2: Insulin ELISA Kit with Optical
Fiber Spectrometer . . . . . . . . . . . . . . . . . . . . . . . . . 217
12.11.3 Task 3: Insulin ELISA Kit with
Cell Phone Camera . . . . . . . . . . . . . . . . . . . . . . . . . 219
12.12 Further Study: DNA Sensors . . . . . . . . . . . . . . . . . . . . . . . . . 221
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
13 Lab-on-a-Chip Biosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
13.1 What Is Lab-on-a-Chip . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
13.2 How to Make an LOC: Photolithography
and Soft Lithography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
13.3 Early LOC: Capillary Electrophoresis . . . . . . . . . . . . . . . . . . 231
13.4 LOC for Point-of-Care Testing . . . . . . . . . . . . . . . . . . . . . . . 232
13.5 Use of Optical Fibers in LOC . . . . . . . . . . . . . . . . . . . . . . . . 235
13.6 Sample/Reagent Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 236
xii Contents
13.7 Mixing in LOC . . . . . . 238
13.8 LOC with Cell Phone Camera . . . . . . . . . . . . . . . . . . . . . . . . 239
13.9 Other Applications of LOC . . . . . . . . . . . . . . . . . . . . . . . . . . 239
13.10 Laboratory: Lab-on-a-Chip . . . . . . . . . . . . . . . . 240
13.10.1 Task 1: LOC Fabrication . . . . . . . . . . . . . . . . . . . . 241
13.10.2 Task 2: Mixing Experiment . 243
13.11 Further Study: Latex Immunoagglutination
AssayinLOC 245
13.12 Further Study: Polymerase Chain Reaction in LOC . . 247
Bibliography 252
Index 257
Contents xiii
Chapter 1
Introduction
1.1 Sensors
As implied in the title of this textbook, Biosensors: From Electric Circuits to
Immunosensors, we are going to learn both electric circuitry (in relation to conven-
tional sensors such as temperature sensors) and biosensors (such as antibody-based
immunosensors), with equal emphasis on both. The overarching aim is to build an
antibody-based immunosensor from scratch. Before we begin this textbook, let us
define two important terms: sensors and biosensors. Let’ s start with senso rs.
Literally, a sensor is a device used to sense a physical variable, which includes,
but is not limited to: temperature, strain, humidity, pressure, mass, light, and
voltage. To sense these variables, we need to convert them into a universal and
easily accessible signal—usually a voltage. This voltage signal changes continu-
ously with time, and is directly proportional to a corresponding physical variable.
A component responsible for this conversion is a transducer. The resu lting voltage
signal is usually an analog signal.
The analog voltage signal is usually transferred to a computer or a microproces-
sor, which recognizes digita l signals only. An analog signal is converted into a
series of high and low voltages (i.e., binary numbers), such that a small fluctuation
in the analog signal (i.e., noise) does not affect the overall digital signal. An analog-
to-digital converter (A/D converter) performs this conversion. Today, all-in-one
type sensors have become very popular. They incorporate a transducer, an A/D
converter, a microprocessor, and a small liquid crystal display (LCD) panel.
The signal can also be sent to a computer’s universal serial bus (USB) from an
A/D converter.
J Y. Yoon, Introduction to Biosensors: From Electric Circuits to Immunosensors,
DOI 10.1007/978-1-4419-6022-1_1,
#
Springer Science+Business Media New York 2013
1
1.2 Transducers
The most common transducers for physical sensors are thos e used to measure
temperature, strain, pressure, and light; however, the other variables listed in
Fig. 1.1 can also be measured from these four basic transducers: for example,
humidity from a set of temperature transducers or mass from a strain transducer
(electronic balance). Voltage measurements require no transducers.
Let us begin with temperatu re transducers. The oldest and simplest temperature
transducer is a thermocouple. Details will be discusse d later in Chap. 4. Thermo-
couples can be made by simply connecting two different types of metal wires and
then attaching them to a voltmeter (a device that measures voltage). We normally
use a digital multimeter (DMM) that can measure not only voltage, but current and
resistance as well (Fig. 1.2).
Semiconductors, including a resistor,adiode or a transistor can also be used to
measure temperature, as the semiconductors’ current–voltage responses are affected
by ambient temperature. A resistor-type temperature transducer is specifically called
a thermistor. Semiconductor transducers generally provide more accurate tempera-
ture information and are smaller in size than a thermocouple. This book includes a
lab procedure (Chap. 4) for all three types of semiconductor temperature
transducers: a therm istor, a diode temperature transducer, and a transistor tempera-
ture transducer.
The strain transducer obviously measures strain, the deformation of a body.
Figure 1.3 shows a typical setup of a strain gauge, which is attached to a body. As
the body elongates horizontally, the physical width of a metal coil decreases and the
Fig. 1.1 A typical sensor
Fig. 1.2 A thermocouple
2 1 Introduction
resistance changes accordingly. This resistance change is very small and generally
requires a circuit layout known as a Wheatstone bridge. A lab procedure is available
in this book for a strain gauge (Chap. 5), used as part of a Wheatstone bridge
experiment. The strain gauge is widely used in civil and mec hanical engineering
applications. It is also used widely in an electronic balance.
Pressure transducers measure pressure, a force applied to a unit area of surface.
In the field applications, pressure is generally measured with a capacitor. A capacitor
comprises two metal plates (conductors), separated by a dielectric (electrical insula-
tor). Air or vacuum is commonly used as a dielectric. Once voltage is applied to a
capacitor, electrons accumulate on the plates. The amount of electrons is determined
by (1) the distance between the two plates, (2) the dielectric constant, and (3) the
voltage applied to it. A pressure transducer is basically a special type of capacitor,
where one plate is replaced with a diaphragm.AsshowninFig.1.4, this diaphragm
can be deformed depending on the outside pressure, causing a change in the distance
between the two plates and a subsequent change in the capacitance of the pressure
transducer. We do not have a lab procedure for pressure sensors, since they are rarely
used in biosensor applications.
Light transducers sense light, which is a wave of photons. Like temperature
transducers, three major types of semiconductors can be used as light transducers,
namely the photoresistor, the photodiode, and the phototransistor. The photodiode
(PD) is proba bly the most popular. Similar to a diode-type temperature transducer,
the current–voltage response from a PD is affected by photons. A PD is usually
combined with a light emitting diode (LED) or a laser diode as the light transducer
requires a light source. There are lab procedures for the LED and PD in this book
(Chaps. 7 and 8) (Fig. 1.5).
Fig. 1.3 A strain gauge
Fig. 1.4 A pressure
transducer
1.2 Transducers 3