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Nanobiosensors for Biomolecular Targeting
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Summary
Nanobiosensors for Bio-molecular Targeting presents the latest analytical methods for the detection of different substances in the range of small molecules to whole cells, exploring the advantages and disadvantages of each method. Biosensors combine the component of biological origin and physicochemical detector to show the presence of analytes in a given sample. The use of bionanotechnology has led to a significant advancement in the progression of nanobiosensors and has been effectively used for biomedical diagnosis.
Explains the detection techniques used by nanosensors, exploring the strengths and weaknesses of each for the detection of disease Shows how biosensors are used to detect various types of biomolecules Demonstrates how the use of nanomaterials makes biosensors both cheaper and more efficientPublisher: Elsevier ScienceReleased: Oct 16, 2018ISBN: 9780128139011Format: book
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Nanobiosensors for Biomolecular Targeting
Nanobiosensors for Biomolecular Targeting
First Edition
Subash C.B. Gopinath
Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar
School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Thangavel Lakshmipriya
Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Table of Contents
Cover image
Title page
Copyright
Contributors
Preface
1: An Introduction to Biosensors and Biomolecules
Abstract
1.1 Introduction
1.2 Biosensors
1.3 Detection of Biological Molecules
1.4 High-Performance Sensing
1.5 Validation of Biosensors by Enzyme-Linked Immunosorbent Assay
1.6 Conclusions
2: Physical Surface Modification on the Biosensing Surface
Abstract
Acknowledgments
2.1 Biosensors
2.2 Biomolecule Recognition Elements
2.3 Transducer
2.4 Requirements of Biosensors
2.5 Surface Modification
2.6 Concluding Remarks
3: Functionalization on Sensing Surfaces for Efficient Biomolecular Capturing
Abstract
Acknowledgments
3.1 Introduction
3.2 Nanotechnology in Functionalization
3.3 Polymers in Functionalization
3.4 Aptamers in Functionalization
3.5 Functionalization in Optical Sensing
3.6 Functionalization in Electrochemical Sensing
3.7 Functionalization in Physical Sensing
3.8 Carbon Materials in Functionalization
3.9 Functionalization of Silicon (Si) Surface
3.10 Trend and Future Scope of Functionalization
3.11 Conclusion
4: Nucleic Acid Complementation Analysis on Biosensors
Abstract
4.1 Introduction
4.2 Types of Biosensors
4.3 Applications of Biosensors
4.4 Experimental Procedure
4.5 Results and Discussion
4.6 Conclusions
5: Recognition of Bacterial DNA on SAW-Based Biosensors
Abstract
Acknowledgments
5.1 Introduction
5.2 Acoustic-Based Sensors
5.3 Methodology of Producing Nano Structure Waveguide SHSAW (Love Wave) Biosensor
5.4 Functionalization SiO2 Nanoparticles Thin Layer Waveguide Surface for DNA Detection
5.5 Analytical Performance of SiO2 Nanoparticles Waveguide Biosensor
5.6 Conclusion
6: A Disposable Biosensor Based on Antibody-Antigen Interaction for Tungro Disease Detection
Abstract
Acknowledgments
6.1 Introduction
6.2 Methodology
6.3 Development of Electrochemical System
6.4 Immobilization of Antibodies in Polypyrrole
6.5 Electrochemical Characterization of Screen Printed Carbon Electrode (SPCE)
6.6 Calibration Curve of Tungro Disease Immunosensor
6.7 Cross-Reactivity Study Using Different Antigen Parameters
6.8 Result and Discussion
6.9 Cross-Reactivity Studies
6.10 Conclusion
7: Antibody-Mediated Diagnosis of Biomolecules
Abstract
Acknowledgements
7.1 Introduction
7.2 Antibody
7.3 Material Substrate Use in Biosensing Applications
7.4 Metal Substrates for Biosensing
7.5 Polymeric Substrate for Biosensing
7.6 Hybrid Substrate for Biosensing
7.7 Miscellaneous Substrate for Biosensing
7.8 Conclusion
8: Biosensor Recognizes the Receptor Molecules
Abstract
8.1 Introduction
8.2 Why Use Nanotechnology?
8.3 Why Use Biosensors?
8.4 Bioreceptor Molecules
8.5 Nucleic Acid Biosensor-Based
8.6 Biosensor Development Considerations
8.7 Type of Transducers
8.8 Future Prospects of Biosensors
8.9 Conclusion
9: Nanoelectronics in Biosensing Applications
Abstract
9.1 Introduction
9.2 Neutralizer Displacement and Micro-Nuclear Magnetic Resonance
9.3 BioDVD Platform
9.4 Smartphone
9.5 Interdigitated Electrode (IDE) Sensor
9.6 Field Effect Transistor-Based Biosensor
9.7 Microfluidic-Delivery on Electronic Sensors
9.8 Enhancing the Performance of Nanoelectronic Sensors
9.9 Conclusions
10: Microtechnology and Nanotechnology Advancements Toward Bio-Molecular Targeting
Abstract
10.1 Zinc Oxides’ Thin Film Deposition and Growth Techniques
10.2 Gold Nanoparticles’ Properties and Application
10.3 Interdigitated Electrodes
10.4 Zinc Oxides for Nanobiosensors
10.5 DNA/Nucleic Acid Biosensor
10.6 Chapter Summary
11: Electrospun Nanofibers for Biosensing Applications
Abstract
Acknowledgments
11.1 Introduction
11.2 Electrospinning Mechanism
11.3 Electrospinning Parameters
11.4 Rationale of Using Nanofibers for Biosensing Applications
11.5 Conclusion
12: Carbon Dots as Optical Nanoprobes for Biosensors
Abstract
12.1 Introduction
12.2 CDs as Biosensor Receptors
12.3 Design and Modification of CDs for Biosensors
12.4 Typical Optical Sensing Mechanism
12.5 Practical Utilization of CDs in Biosensors
12.6 Summary and Outlook
13: Formaldehyde Biosensors in Foodstuffs Applying Nano Gold Entrapped in p-HEMA Deposited on Screen-Printed Carbon Electrodes: A Short Review
Abstract
13.1 Formaldehyde Biosensor
13.2 Nano Gold Particles in Biosensor
13.3 Screen-Printed Carbon Electrodes in Biosensor
13.4 Transducer Systems
13.5 Future Perspectives
Index
Copyright
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Contributors
Musa Ahmad Chemical Technology Program, Faculty of Science and Technology, Universiti Sains Islam Malaysia, Bandar Baru Nilai, Malaysia
Yarub Al-Douri
Nanotechnology and Catalysis Research Center (NANOCAT), University of Malaya, Kuala Lumpur, Malaysia
Physics Department, Faculty of Science, University of Sidi-Bel-Abbes, Sidi-Bel-Abbes, Algeria
Sagir Alva Mechanical Engineering Department, Faculty of Engineering, Mercu Buana University, West Jakarta, Indonesia
Sanjay B. Bari Department of Pharmaceutical Chemistry and Quality Assurance, H.R. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
Prashant K. Deshmukh Department of Pharmaceutics, H.R. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
S. Faridah Biotechnology Research Centre, MARDI Headquarters, Persiaran MARDI-UPM, Serdang, Malaysia
K.L. Foo Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, Malaysia
Subash C.B. Gopinath
Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar
School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
C.M. Hasfalina Department of Biological and Agricultural Engineering, Faculty of Engineering, Universiti Putra Malaysia, Serdang, Malaysia
U. Hashim
Institute of Nano Electronic Engineering
School of Microelectronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Lee Yook Heng School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia
A.S. Ibraheam Physics Department, College of Science, University of Anbar, Al Rumadi, Iraq
Zamir G. Khan Department of Pharmaceutical Chemistry and Quality Assurance, H.R. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
Thangavel Lakshmipriya Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
W.W. Liu Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, Malaysia
Mazidah Mat Rice and Industrial Crops Research Centre, MARDI Headquarters, Kuala Lumpur, Malaysia
M.K. Md Arshad
Institute of Nano Electronic Engineering
School of Microelectronic Engineering, Universiti Malaysia Perlis, Pauh Putra, Perlis, Malaysia
Norani Muti Mohamed
Centre of Innovative Nanostructures and Nanodevices (COINN)
Department of Fundamental and Applied Sciences, Universiti Teknologi PETRONAS, Seri Iskandar, Malaysia
Mahesh P. More Department of Pharmaceutics, H.R. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
Satisvar Sundera Murthe
Centre of Innovative Nanostructures and Nanodevices (COINN)
Department of Fundamental and Applied Sciences, Universiti Teknologi PETRONAS, Seri Iskandar, Malaysia
Sing Muk Ng
Faculty of Engineering, Computing, and Science
Research Centre for Sustainable Technologies, Swinburne University of Technology Sarawak Campus, Kuching, Malaysia
A.N. Nordin Department of Electrical and Computer Engineering, Engineering Faculty, International Islamic University Malaysia, Kuala Lumpur, Malaysia
M. Nuzaihan MN Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, Malaysia
N.A. Parmin Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Pravin O. Patil Department of Pharmaceutical Chemistry and Quality Assurance, H.R. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
Ashwini G. Patil Department of Biotechnology and Microbiology, R.C. Patel Arts, Commerce, Science College, Shirpur, India
Veeradasan Perumal
Centre of Innovative Nanostructures and Nanodevices (COINN)
Mechanical Engineering Department, Universiti Teknologi PETRONAS, Seri Iskandar, Malaysia
S.F.A. Rahman Institute of Advanced Technology, Universiti Putra Malaysia, Serdang, Malaysia
Mohamed Salleh Mohamed Saheed
Centre of Innovative Nanostructures and Nanodevices (COINN)
Department of Fundamental and Applied Sciences, Universiti Teknologi PETRONAS, Seri Iskandar, Malaysia
Mohamed Shuaib Mohamed Saheed
Centre of Innovative Nanostructures and Nanodevices (COINN)
Department of Fundamental and Applied Sciences, Universiti Teknologi PETRONAS, Seri Iskandar, Malaysia
Sung Ting Sam School of Bioprocess Engineering, Universiti Malaysia Perlis, Kangar, Malaysia
A.A. Samsuzanaa Department of Biological and Agricultural Engineering, Faculty of Engineering, Universiti Putra Malaysia, Serdang, Malaysia
Rita Sundari Mechanical Engineering Department, Faculty of Engineering, Mercu Buana University, West Jakarta, Indonesia
Rahul S. Tade Department of Pharmaceutical Chemistry and Quality Assurance, H.R. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
S.T. Ten Malaysian Agricultural Research and Development Institute, Serdang, Malaysia
Theivasanthi Thirugnanasambandan International Research Centre, Kalasalingam Academy of Research and Education (Deemed University), Krishnankoil, Tamilnadu, India
M.N.A. Uda School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Chun Hong Voon Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, Malaysia
Preface
Subash C.B. Gopinath, Universiti Malaysia Perlis (UniMAP), Kangar, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Thangavel Lakshmipriya, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
The field of nanotechnology has experienced great advancements that can be used to improve the diagnosis of biomolecules. Achievement in nanobiosensor developments has been driven by top-down and bottom-up approaches to interdisciplinary and multidisciplinary sciences. These two approaches are significant in the creation of nanostructures, which is attested to be a complete platform for research, which has formed a path from the laboratory to industry. Under laboratory conditions, self-assembly approaches involving nanofabrication by physical or chemical forces at the nanoscale level to transform basic units into complete nanoforms have been a great success. Nanoelectronics
is the term used in the field of nanotechnology to describe electronic components and research on the improvement of electronics, such as a display, size, and power consumption of devices for practical use. This also includes research on memory chips and surface physical modifications of the electronic devices. Nanoelectronics cover quantum mechanical properties of hybrid materials, semi-conductors, single-dimensional nanotubes, and nanowires. Well-developed nanoelectronics can be applied in different fields, and are especially useful in detecting disease-causing agents and disease biomarkers. Consequently, point-of-care detection became popularized due to the involvement of nanoelectronics.
Nanoelectronics are also involved in the generation of nanosensors in nano-sized dimensions for applications from home to field.
Nanoelectronics-based nanodevices are important in the development of high-performance analyses. Researchers are working toward the development of portable sensors for bed-side analyses and other point-of-care applications. A portable sensor is considered as effective if it is easy to use, accurate, and offers real-time display. Some nano-sized devices generated from nanoelectronics have already been commercialized. High-performance detection systems have been achieved because of two vital factors; one is generation of suitable, high-sensitivity sensors, and another is the material compatibility of the electronic devices.
This book is primarily designed to cover an overall view of the biosensors and biomolecules. Chapters were arranged from the basic introduction, to the potential applications. The chapters are also expanded on the topics of surface modification, nanohybrids, nanoelectronics, and nanostructures as mandatory elements for successfully integrating nanobiosensor technology into interdisciplinary sciences. The cutting-edge technologies discussed herein focus on the production of high-performance sensing, with special focus on a range of clinically important biomarkers. The chapters expand on the drug discovery process, and high-throughput screening for future sensing applications. Further, in regard to the commercialization, this book provides platform for research and industry. The motto of this book is Making roads from the laboratory to industry,
while bridging all disciplines, expanding and sharing knowledge, and forming a scientific hub.
1
An Introduction to Biosensors and Biomolecules
Thangavel Lakshmipriya⁎; Subash C.B. Gopinath⁎,† ⁎ Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
† School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Malaysia
Abstract
The development of sensors capable of characterizing and quantifying biomolecules is a significant contribution to the field of biology. In the past few decades, sensors have been routinely used in various sectors, especially in the field of medical diagnosis. In the fields of therapeutics and medicine, sensors have been used to fulfill the potential roles of clinically important biomarkers. Sensors used for diagnosing biomarkers or biomolecules are called biosensors.
For biosensing applications, two important biomolecules are, the probe and the analyte. The probe used to interact with the target is called the analyte
in the given test sample. The biosensor has the transducer, and physical elements to display the biomolecular interactions. In this chapter, the fundamentals of biosensors and biomolecules are overviewed.
Keywords
Biosensor; Biomolecule; Pathogen; Biomarker; Diagnosis
1.1 Introduction
Characteristics of desired analytes and ligands, which include proteins, enzymes, antibodies, glycans, and nucleic acids, are important elements to consider while generating the sensing systems (Fujimaki et al., 2010; Gopinath et al., 2006, 2007, 2012a, b; Kumarevel et al., 2004, 2008). Sensing systems have been implemented to diagnose diseases and monitor the environment; and have been used in therapeutics, drug discovery, and screening processes (Gopinath et al., 2008a, b; Kim et al., 2010; Lakshmipriya et al., 2013a, b, 2014). A high-performance sensing system needs the appropriate biomarkers to diagnose diseases (Anbu et al., 2006; Chen et al., 2015; Gopinath, 2007, 2008; Gopinath et al., 2003, 2007). A range of sensing systems in the past few decades has demonstrated a good performance (Gopinath et al., 2013a, b, c, d; Nomura et al., 2013; Perumal et al., 2015, 2016). Sensing systems such as the waveguide mode sensor (Gopinath et al., 2008a, b; Lakshmipriya et al., 2013b), surface plasmon resonance sensor (Gopinath et al., 2013a; Lakshmipriya et al., 2014), electrochemical sensor (Kang et al., 2010), and surface acoustic wave sensor (SAW sensor) (Thiele and Da Cunha, 2006) have displayed a high sensitivity in diagnosis of different pathogenic diseases. On the sensing surface, nanostructure-mediated enhancements with higher sensitivity were shown. These nanostructures include nanoparticles (Lakshmipriya et al., 2016), nanoflowers (Perumal et al., 2016), nanogaps (Gopinath et al., 2016), and nanowires (Haarindraprasad et al., 2015).
1.2 Biosensors
The very first biosensor was introduced in 1962 by Clark and Lyons, who attached glucose oxidase on an amperometric oxygen electrode surface in order to directly measure the glucose concentration. They described how to make electrochemical sensors (pH, polarographic, potentiometric, or conductometric) more intelligent
by adding enzyme transducers as membrane-enclosed sandwiches
(Wang, 2008). A biosensor is a self-integrated system, capable of providing specific quantitative or semiquantitative information using a biological recognition element (Arai et al., 2007; Koyun et al., 2012), in direct spatial connection with a transducer, as per the proposed IUPAC definition. Fundamentally, a biosensor is a compact analytical system with a biologically derived recognition element associated with the physiochemical transducer. The complete biosensor includes the biological recognition elements, a transducer to convert the bio-interactive process into a measurable signal, and a signal processing system to obtain a readable data (Yoo and Lee, 2010). Under this set-up, the reaction between probe and analyte reveal the chemical reaction (production of new chemical, the flow of charge, the release of heat, change of mass and pH). The signal processing system amplifies and displays the output in the right format (Fig. 1.1).
Fig. 1.1 Diagrammatic representation of the chemical sensor. The reaction between enzyme and substrate is shown.
Eventually, the signal output will be amplified and sent to a data processor. A measurable signal is produced; and then converted to a print-out, a digital display, or an optical change. The goal of this combination is to avail the high selectivity and sensitivity with biological sensing for analytical purposes to be applied in different fields.
Based on the transducing elements, biosensors have been classified as optical, electrochemical, thermal, and piezoelectric sensors. Electrochemical biosensors are also classified as amperometric, conductometric, and potentiometric sensors. The probes, such as antibodies, DNA, RNA, and aptamer peptides were used to detect the biomolecules (Gopinath, 2009; Gopinath et al., 2008a, b, 2011). The sensing surface optimization improves the biosensor applications (Gopinath, 2010; Gopinath et al., 2010a, b, 2011). The application of biosensors is used in diagnostics, medical and clinical applications, bioreactors, process control, agriculture and veterinary medicine, quality control, pathogenic diagnostics, drug production, mining, and control of the industrial wastewater and defense industries. Sensors have been generated to detect various types of biomolecules (Chen et al., 2015; Citartan et al., 2015; Gopinath et al., 2011, 2013a, b; Gopinath and Kumar, 2014; Nomura et al., 2013).
1.2.1 Electrochemical Sensor
Electrochemical biosensors commonly depend on the enzymatic catalysis reaction between the immobilized biomolecules and the targeted analyte that produces or consumes electrons or ions, which affects the electrical properties of the solution, such an electric potential or current (Monošík et al., 2012). There are three electrodes required for electrochemical sensing: a reference electrode, a working electrode, and a counter electrode. The working electrode is the combination of a biomolecular recognition system and the physiochemical transducer, which functions as the transduction element, known as the redox, or sensing, electrode. The reference electrode is made up of Ag/AgCl. Keeping the reference electrode at a distance from the reaction site maintains a stable potential. In the counter electrode, or auxiliary electrode, current can be passed to the working electrode by developing a connection to the electrolytic solution. Gold, platinum, carbon, and silicon compounds are commonly used electrodes, as they are conductive and chemically stable (Grieshaber et al., 2008). The electrochemical biosensor can be divided into amperometric, potentiometric, and conductometric transducers, which transform the reaction of bioreceptor molecules into the measurable signal (Leung et al., 2007).
Interdigitated electrode (IDE) biosensors are made with nanoscale terminal arrays coming under the electrochemical sensor. This biosensor has a good sensitivity compared with other impedimetric biosensors. A very tiny area of up to 200 nm on the surface of IDE is modified when a sample of the molecule is attached to the probes. Therefore, this type of biosensor demonstrates an enhanced responsiveness, compared with normal electrodes that range from 1 μm to the mm level. Furthermore, only a small volume of sample disease is required from patients for detection on the biosensor chip. Also, the cost of IDE chips reduces with size. The diagrammatic representation of an IDE chip is shown in Fig. 1.2.
Fig. 1.2 Electrochemical sensing system. An interdigitated electrode sensor is shown. This sensor has nanogaps and operates based on impedance.
Chronic diseases and other infections caused by pathogens can be determined by the binding of their DNA sequences to selective probes on an IDE. In addition to the binding of antigen to antibody, it can also be used for the determination of diseases and infections. When the analyte-containing sample of a particular disease is attached to the probe of an IDE, a direct electrical signal can be measured, using an instrument known as a dielectric impedance analyzer. Alteration in the impedance occurs as a result of the changes in electric features when an antigen binds to an antibody.
IDEs can be created in different ranges of measurement. The area between the interelectrode gaps can be utilized effectively, as the length-to-surface ratio is high. IDEs can be created abundantly from all types of metals with different surface properties. Properties on substrates such as silicon, silica, and glass are biologically compatible. Single molecule and minute objects can be micro-manipulated using IDE due to the electric charges on electrodes. IDEs can also be used to adjust the shape and expanse of nucleic acids in interelectrode gaps as a result of their bipolar structure.
One of the important applications of electrochemical impedance spectroscopy is to investigate the dielectric properties and the interaction of protein molecules. These include studying the protein-protein interactions on the surface of the electrode, as well as the antibody-antigen binding specificity. At low-frequency range, the interaction of these molecules produces a new layer, charged as a capacitance that is proportional to the double layer capacitance (Cdl), which therefore decreases the double layer capacitance and increases the impedance. This proves that a nano-interdigitated electrode is a good miniaturized immunosensor with high sensitivity.
1.2.2 Amperometric Sensor
The most widespread type of biosensor has been utilized to measure the current at a constant voltage (Higson, 2012). It generally has response times and dynamic ranges similar to the potentiometric biosensor, but is more sensitive and suited for mass production than the potentiometric one. The working electrode commonly used is the noble layer, covered by a biorecognition component. For the potential applied, conversion of electroactive species are formed in the enzyme layer at the electrode, and the resulting current is estimated (Mehrvar and Abdi, 2004).
1.2.3 Potentiometric Sensor
A potentiometric biosensor measures the potential difference between the reference electrode and the working electrode, or between two reference electrodes separated by a semipermeable membrane without any current flow (Korotkaya, 2014; Monošík et al., 2012). It is based on pH or pI of solution used during the measurement (Leung et al., 2007). The output signal possibly results from the ions deposited at the ion-selective membrane interface. Current flows through the electrode are equal to zero. The electrode follows in the occurrence of the monitored ion, resulting from the enzyme reaction (Pohanka and Republic, 2008). If the biosensor gives a change in pH with the analyte, a Nernst Equation can be used, as follows (Higson, 2012):
where E stands for the potential difference, E0 stands for the standard cell potential, R represents the universal gas constant, 8.3 J K− 1 mol− 1, T is for temperature, 298 K, F represents the Faraday's constant, 96,500 Cmol− 1, z is the valence of ion, co is the external concentration of ion, and ci is the internal concentration of ion.
1.2.4 Conductometric Sensor
The conductometric transducer measures the electrical conductivity of a series of biochemical reactions that occurred in a solution (Korotkaya, 2014). The overall conductivity, or resistivity of the solution, will be changed due to the production of ions or electrons during the reaction between biomolecules and analytes (Monošík et al., 2012). Separation of two metal electrodes at a certain distance and application of an AC potential across the electrodes will result in a current flow between the electrodes. An ohmmeter can be used to estimate the change in conductance during the biorecognition reaction. It is a less commonly used biosensor, especially when the recognition element is an enzyme (Korotkaya, 2014).
1.2.5 Optical Sensor
The optical biosensor was originally developed to measure the dissolved oxygen, carbon dioxide, and pH (Galindo, 2009). Light is the output transduced signal (Monošík et al., 2012). This biosensor is based on the methods, UV-vis absorption, fluorescence, chemiluminescence/bioluminescence, surface plasmon resonance, reflection spectroscopy, and laser light scattering (Korotkaya, 2014; Mello and Kubota, 2002). The two main areas of the development of optical biosensors are colorimetric (Fig. 1.3) for light, and photometric for light intensity (Fig. 1.4). Colorimetric involves the measurement of light absorption is changing between the reactants and products of a reaction, and the latter determines light output of the luminescent or fluorescent process by using a high voltage and expensive photomultiplier tube, or a low voltage and cheap photodiode system (O'Toole and Diamond, 2008). Colorimetric test strips are disposable cellulose pads impregnated with reagents and enzymes, a commonly availed technology for whole-blood monitoring of diabetes.
Fig. 1.3 Optical sensor. An optical system with the surface plasmon resonance is displayed. The upper figure is a basic system, and the lower one is displayed.
Fig. 1.4 Colorimetric detection. This strategy works with the protein attachment and detachment. The biofouling can be prevented using PEG-polymers.
Luminescence and reflection spectroscopy is very useful, especially in immunoassay (Galindo, 2009). A biosensor that involves luminescence uses firefly luciferase (Photinus-luciferin 4-monooxygenase) to identify the bacteria that presents in the samples.
1.2.6 Thermal Sensor
The thermal transducer type of biosensor is a rarely used analytic device to determine the amount of heat when a biochemical reaction occurs (Korotkaya, 2014). The total amount of heat absorbed or produced is proportional to the amount/concentration of target analyte and the molar enthalpy (Monošík et al., 2012). The thermal biosensor is basically a small calorimetric device equipped with a high sensitivity thermistor that is able to detect the temperature changes in the range of 0.0001–0.05°C. It can also detect the concentration of a target analyte as low as 10− 5 M (Galindo, 2009). ΔS (entropy) and ΔG (Gibbs free energy) for a reaction can be calculated by measuring ΔH, the enthalpy of reaction at different temperatures first, and hence collect the basic thermodynamic data (Leuing et al., 2007). The disadvantage of this biosensor is that it is not sensitive to optical and electrochemical properties of the sample. This technique is used for food, pharmaceutical, cosmetic, and other components’ analysis (Monošík et al., 2012).
1.2.7 Piezoelectric Sensor
A piezoelectric biosensor generates the electrical signal in response to the applied mechanical pressure. It constructs a biorecognition element with a piezoelectric component, usually a quartz crystal coated with a gold electrode, that shows the piezoelectric effect. Another type of material, such as tourmaline, lithium niobate, or aluminum nitride also exhibits the piezoelectric effect (Monošík et al., 2012). The piezoelectric effect is the capability of a certain component to produce an electric charge when stressed mechanically. When the coated crystal interacts with analytes, there will be a modification in the mass of crystal, and hence the vibration is made (Monošík et al., 2012). The oscillation frequency is depending on the mass of crystal and the coating (Galindo, 2009). Absorption of analytes on the surface of the crystal leads to the increase in mass, as well as changing the frequency of oscillation. The resulting change can be measured electrically, and utilized to identify the additional mass (positive or negative) of the crystal (Monošík et al., 2012). Immunosensors with the wave acoustics principle, which is considered the most sensitive sensor when compared with others, can be used to detect pathogens, gases, pesticides, hormones, and others (Korotkaya, 2014).
1.3 Detection of Biological Molecules
In the sensor, the target can be diagnosed by measuring the changes caused by the attached whole cell/target to the antiantibodies captured on the surface. The antibodies can be attached to the electrode by a proper linker. The changes across the electrodes in the electrochemical sensor were estimated after the series of the sample application. Captured antigens by the antibody change the flow between the electrodes, or on the other mode of measurements. The sensor signal changes over the background were proportional to the number of antigens. A sample with a high cell concentration tends to result in more antigens being attached to antibodies. A higher concentration of antigens generally increases the responses proportionally. Because the antigens attached to the surface act as resistors, a larger number of attached antigens increase the changes proportionally. When different sizes of gaps on the sensing surface are used, it shows that a larger area on the surface might be covered by antigen, and sensitivity of the biosensors is improved by the big changes on the surface. With the development of wide choices of the sensors, various biomolecules have been detected, from small molecules to whole cells. Biotin is one of the small molecules that are widely used in the sensing applications. It has higher affinity with the streptavidin. Basically, streptavidin has 4 sites that can interact with the biotins (Fig. 1.5). These molecules have affinity in the lower femtomolar ranges, and have been used to validate the sensor with the preliminary analysis (Lakshmipriya et al., 2014, 2016). Among several small molecular detections, glucose sensing is very popular, and has been used to detect diabetes.
Fig. 1.5 Interaction of streptavidin and biotin. Streptavidin has four sites to interact with the biotin at higher affinity. This biomolecular affinity is able to reach the femtomolar level.
1.3.1 Detection of Glucose
The first device of glucose enzyme electrodes was developed by Clark and Lyons of the Cincinnati Children's Hospital in 1962. The rate of oxygen consumed by the enzyme-catalyzed reaction was observed for the measurements. Clark used one or more enzymes to convert electrically inactive substrates to electrically active products. The interference effect was overcome by the usage of two electrodes. Later in 1975, the Yellow Spring Instrument Company modified Clark's technology to create the first glucose analyzer, the model 23 YSI analyzer. This principle was further developed by Updike and Hicks using two oxygen-working electrodes. Guilbault and Lubrano, in 1973, described the amperometric biosensor device for measurement of blood sugar (Guilbault and Lubrano, 1973). This biosensor produced good results. Oxygen co-substrate was used in the first generation of glucose biosensors to generate and detect hydrogen peroxide. This reaction reduces the Flavin group (FAD) into its reduced form (FADH2) when reacted with glucose.
1.3.2 Pathogenic Detection by Biosensor
Apart from the small molecular detections, most of the biosensors are widely used for the medical diagnosis of larger molecules or whole cells. Various diseases are prevalent nowadays and need to be prevented at the early stages. These diseases are caused by pathogens, mostly from viruses or bacteria. Diseases caused by pathogens can be detected by biosensors, which can help in efforts to cure them. Studies on different biomarkers that cause the disease are needed to focus on development of biosensors to detect the biomarker precisely, and at the earliest stage.
1.3.2.1 Viral Detections
1.3.2.1.1 Biomarkers for Human Papillomavirus
Human papillomavirus (HPV) is a DNA virus infecting humans, and there are more than 100 related viruses under the same group. HPVs are a group of nonenveloped DNA viruses, with an ~ 8000 bp, circular double-stranded DNA genome, encapsulated within the viral capsid (Kukimoto and Muramatsu, 2015). The genome is enclosed in an icosahedral capsid shell comprised of major and minor capsid proteins. This genome can be divided into an early region with 6 open reading frames (ORFs) E6, E7, E1, E2, E4, and E5; a late region with 2 ORFs, L1 (the major capsid protein) and L2 (the minor capsid protein); and a noncoding regulatory region (NCR) of ~ 1 kb (Fig. 1.6).
Fig. 1.6 Potential regions from human papillomavirus. These regions/sequences can be used as the biomarker in biosensor development.
The three regions are partitioned by early (AE) and late (AL) (Ruttkay-Nedecky et al., 2013). The E1 protein links to the origin of replication (Ustav et al., 1991). The E2 open reading frame encodes a protein, and acts as a transcriptional activator of HPV gene expression in keratinocytes. The E2 proteins bind to E1 and stimulate viral DNA replication. The E4 is expressed as a late gene, and plays a role in the productive infection. E5 protein stimulates the transforming activity of the epidermal growth factor receptor. The E6 protein of HPV-16 is a small polypeptide containing two zinc-binding domains. The HPV-16 E6 protein also activates telomerase, and E7 is a small protein of HPV-16 (Ruttkay-Nedecky et al., 2013). Other proteins are essential regulators of the cell growth (Dayyani et al., 2010). Both E6 and E7 proteins play a part in the cell transformation and immortalization (Dyson et al., 1989). The L1 and L2 late proteins form capsomers of the virus that encapsidate the viral DNA (Ruttkay-Nedecky et al., 2013). Genome changes with DNA are slower than those of RNA genomes (Bernard et al., 2006).
HPVs associated with cancers are high-risk HPVs, and those associated with benign anogenital are low-risk HPVs (Ajiro and Zheng, 2014). Among the common high-risk HPVs (HPV 16, 18, 31, 33, 45, and 58), HPV 16 is the most prevalent genotype (Ajiro and Zheng, 2014). HPVs 6 and 11 are examples of nononcogenic, or low-risk HPVs. HPV infection is determined by detection of DNA, not by the isolation of virus. Genital HPV infection is predominantly, but not exclusively, a sexually transmitted infection (Moscicki et al., 2006). Nonsexual routes are also may transmit genital HPV infection, but this appears to be uncommon (Matsumoto, 2010).
1.3.2.1.2 Biomarkers for Influenza Virus
Previously, researchers studied the virology of human influenza and the structure of the influenza virus. Researchers did a classification of influenza as a virus based on host-origin association. Herein, we present an overview on the influenza A virus, including the viral transmission, Influenza A subtypes, nomenclature of the influenza virus, prominent mutation of antigenic strains, and the relationship among influenza A subtypes as described before (Gopinath et al., 2006).
The most famous and lethal outbreak was the 1918 Spanish pandemic flu (H1N1), from 1918 to 1919, and 50 to 100 million people died. In 1957, Asian flu (H2N2), and in 1968, Hong Kong flu (H3N2), killed millions of people (Fig. 1.7). All known influenza A viruses can infect birds, except H17N10 and H18N11. Only 3 influenza A virus subtypes (H1N1, H2N2, H3N2) are in general, circulating among people.
Fig. 1.7 Evolution of influenza viruses. The emergence of different influenza subtypes that caused the epidemic and pandemic are displayed.
Influenza is commonly known as flu,
which is a viral infection that attacks your respiratory system. Human influenza viruses are members of the orthomyxoviridae family, which includes influenza virus A, B, and C (Gopinath et al., 2006). Influenza viruses A, B, and C are similar in overall structure. The size of the virus ranges from 80 to 120 nm. The influenza virus is simple in structure, and consists of the viral RNA genome, which is protected by a viral envelope composed of protein subunits. The viral RNA genome is complex, with viral enzymes such as protease and others viral proteins that package and protect the viral genome (Fig. 1.8). The size of the genome is about 13,588 base pairs, and segmented into eight parts, which allows the exchange of entire genes between the different viral strains, producing new viruses (Horimoto and Kawaoka, 1994). Viral RNA is negative sense, and it is transcribed into mRNA. The transcribed mRNA is translated into a viral protein by RNA-dependent RNA polymerase. The main viral proteins are: surface glycoproteins, hemagglutinin (HA), neuraminidase (NA), two matrix proteins (M1, M2), nucleoprotein (NP), three polymerase complex proteins (PB1, PB2, PA), and four nonstructural proteins (NS1, NS2, PA-X, PB1-F2) (Fig. 1.8).
Fig. 1.8 Structure of intact influenza virus. Different proteins that can be biomarkers to detect the influenza virus are shown.
NS1 interacts with a large number of host proteins, including several members of innate immune pathways, and hence contributes to virus growth, pathogenicity, and tropism. The active RNA-dependent-RNA is responsible for replication and transcription. M2 acts as an ion channel pump to lower or maintain the pH of the endosome. NS2, known as the nuclear export protein, mediates nucleus-to-cytoplasmic export of viral RNA by acting as an adaptor between viral NP-RNA and the nuclear export machinery of the cell. The role of the NA is to free the virus particles from the host cell receptor, to permit progeny virion to escape from the cell infected, and enable spread of the virus (Skehel and Wiley, 2000).
Influenza infection and replication is a multistep process. The infection process is initiated by the entry of the virus into the target cell. The influenza virus binds through HA onto sialic acid sugar on the surface of the target cell, especially in the noses, throats, and lungs of mammals; and the intestines of birds. Endosome is formed, which contains a center core. In the endosome, the viral envelope is fused with the vacuole's membrane, and then the M2 ion channel transports the protons through the viral envelope, and acidifies the virus's center core. This causes the core to disassemble, and releases the viral genome and viral protein into the cytoplasm. This viral genome is transported in complex through the nuclear pore into the nucleus. The mature virus buds off from the phospholipid membrane, acquiring HA and NA with this membrane coat. The membrane proteins of the influenza virus, hemagglutinin, are the first recognized by the human immune system. Therefore, the first method for the classification of the influenza virus is through immune response test. The numbering method is based on the recognition of HA and NA antibodies. For example, when a new NA was found in 1957 that was not recognized by the antibodies for N1, it was called N2, followed by N3, N4, and so forth. There is some cross-reaction between the antibodies, and some types of HA and NA, as the H7, that can be recognized by antibodies anti-H3; but this does not compromise the nomenclature system. The numbering system HxNy was developed in a time period when the resources for the current sequencers of genetic materials were not available (Chanock, 1972).
1.3.2.1.3 Biomarkers for the Dengue Virus
Dengue fever, classically called break-bone fever, is a mosquito-borne tropical disease caused by the dengue virus. Dengue viral symptoms are fever, headache, muscle and joint pains, and skin rash, just like measles. A small proportion of this infection can eventually develop into a life-threatening dengue hemorrhagic fever (DHF). This can be manifested by bleeding, low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome (DSS), which will cause dangerously low blood pressure in the infected person. The first ever recorded instance that is similar to dengue fever is in the Chinese Medical Encyclopedia from the Jin Dynasty (265–420 AD), which was recorded as water poison, associated with flying insects. Aedes Aegyptus is known as the main vector that mediated the outbreak of this disease in Africa in the 15th to 19th centuries, mainly caused by the rise in globalization related to the slave trade. And the most marked outbreak of dengue was during and after World War II (Halstead et al., 2002).
Dengue is caused by dengue virus (DENV). This is a virus originated from the family flaviviridae, and the genus flavivirus. It is a positive-sense, single-stranded RNA that is mosquito-borne. Dengue can cause a number of health conditions, such as self-limited dengue fever, which is a life-threatening syndrome; dengue haemorrhagic fever (DHF), and dengue shock syndrome (DSS) (Rodenhuis-Zybert et al., 2010). There are four types of serotypes (subtypes) of dengue, with 60%–80% homology between each other called DENV1, DENV2, DENV3, and DENV4 (Fig. 1.9). The major difference between these viruses is in their surface protein, and each of the viruses will induce different types and levels of immunity of the body against the virus. According to the World Health Organization (WHO), the approximate number of people reportedly suffering from dengue fever and/or dengue hemorrhagic fever globally in the years 2000 to 2007 was 968,564. That is 101.8% higher than a decade before, from the years 1990 to 1999, with the approximate total of 479,848. And in Malaysia, for the year 2015
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