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Application of Nanodiagnostics in Viral Infectious Diseases
C H A P T E R
10 Application of Nanodiagnostics in Viral Infectious Diseases Rahma Ait Hammou1, Mustapha Benhassou1,2,3 and Moulay Mustapha Ennaji1 1
Laboratory of Virology, Microbiology, Quality, Biotechnologies/EcoToxicology and Biodiversity, Faculty of Sciences and Techniques, Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco 2 Mohammed VI University of Health Sciences of Casablanca, Casablanca, Morocco 3School of Medicine and Pharmacy of Casablanca, University Hassan II of Casablanca, Casablanca, Morocco
ABBREVIATIONS BCA DNA ELISA HBV HCV HIV NP PCR RNA
Biobarcode amplification assay Deoxyribonucleic acid Enzyme-linked immunosorbent assays Hepatitis B virus Hepatitis C virus Human immunodeficiency virus Nanoparticles Polymerase chain reaction Ribonucleic acid
INTRODUCTION Viruses (Armstead and Li, 2011; Sharma, 2010), bacteria (Kelley et al., 2013; Hyde, 2011), fungi (Pappas et al., 2004), or parasites (Olliaro, 2009) are the main pathogens that cause infectious diseases and are one of the major causes of deaths, accounting for approximately 15 million annual
Emerging and Reemerging Viral Pathogens DOI: https://doi.org/10.1016/B978-0-12-814966-9.00010-X
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deaths worldwide (Von Groote-Bidlingmaier and Diacon, 2011). In spite of the great efforts to enhance and develop effective pharmaceuticals and new technologies to produce drugs at low cost, the remarkable increase in drug resistance of infectious agents prevents efficient treatment of these diseases. Therefore the consequences of drug resistance were higher mortality, increased cost due to the use of more expensive drugs, and increased burden on the public healthcare system. Consequently, it becomes crucial and mandatory to develop new strategies, pharmaceuticals, and devices to diagnose and treat diseases accurately, easily, and efficiently. Furthermore, in the aim of effective control and suitable infectious diseases, a number of nanotechnologybased materials have been studied (Blecher et al., 2011). These nanotechnologies served to enhance immune responses against antigens for effective vaccination, suitable use of pharmaceuticals in order to achieve the target site and to be released at a controlled rate, and for accurate, rapid, and low-cost detection and diagnosis of infectious diseases. This chapter will discuss the conventional methods of diagnosis and nanotechnologies developed to improve treatment, diagnostics, and prevention of infectious diseases.
CONVENTIONAL DIAGNOSIS FOR INFECTIOUS DISEASES AND LIMITATIONS Infectious diseases treatment and prevention requires up-to-date diagnostics to be more efficient. Furthermore, monitoring of efficacy of treatment is mandatory during therapy by detection of pathogens. Diverse conventional tools are available for the diagnosis of infectious disease including microscopy, tissue culture, lateral flow immunoassays (also known as dipsticks or immune chromatographic test), enzymelinked immunosorbent assays (ELISAs), and biochemical tests (Table 10.1). More recently, molecular diagnostic techniques, such as polymerase chain reaction (PCR) and real-time PCR, have been widely used to diagnose and monitor infections such as human immunodeficiency virus (HIV)/AIDS and hepatitis C virus (HCV) because they have a higher specificity and sensitivity than ELISA-based diagnostics. However, the cost of these techniques, time-consuming and require prior sample preparation, that allows their use only in developed countries but are often poorly suited for the developing countries, where infectious diseases are leading causes of morbidity and mortality, because the availability of trained clinical staff and suitable laboratory facilities may be limited (Sosnik and Amiji, 2010). Therefore development of new diagnostic technologies is required. The characteristics of the ideal tool of diagnostic for the developing countries would be a
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TABLE 10.1 Current Therapies Against Selected Virus and Their Limitations (Qasim et al., 2014) Disease name
Causative agent
Current treatment strategies
Hepatitis C
HCV
Combination of interferon and broad spectrum antiviral therapy
• Limited efficacy in patients with HCV genotype 1 • Drug resistance is rapidly emerging • Drug administration by injection over 72 weeks may result in chronic side effects
AIDS
HIV
HAART
Treatment should be continued throughout life • Potential emergence of drug resistance • Complete eradication is not possible • Side effects such as increased rate of heartbeat, diabetes, liver diseases, cancer, and premature aging
Cervical cancer
HPV
Cryosurgery, loop
• No treatment for existing cervical cancer except for the removal of cervix • Vaccine has side effects and is effective only before exposure to the virus
Electrosurgical excision Procedure (LEEP), laser therapy, hysterectomy
Limitations in treatment
Vaccine Hepatitis B
HBV
Interferon therapy
• No treatment available for acute hepatitis B • Cold chain issues for vaccine • A booster dose of vaccine is required; therefore, follow-up of patients is a major issue
Poliomyelitis
Polio virus
Vaccine
• No treatments available. Immunization for prevention only • Vaccine is expensive and requires a cold chain for transportation and storage • Issue of OPV degradation (Continued)
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TABLE 10.1
(Continued)
Disease name
Causative agent
Influenza virus
Influenza virus A and B
Vaccine
These drugs have activity only against influenza A strain • Amantadine carries a risk of neuropsychological, atropinic, and dopaminergic adverse effects • Zanamivir carries a risk of life-threatening bronchospasm • Emergence of drug resistance is a crucial problem for the treatment of influenza virus
Mumps, measles, and rubella
Paramyxovirus, mumps virus, and rubella
Vaccine
• No treatment available. Vaccine for prevention only • Potential side effects of vaccine
Current treatment strategies
Limitations in treatment
AIDS, Acquired immunodeficiency syndrome; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papilloma virus; OPV, oral polio vaccine.
cost-effective, portable, and point-of-source detection system that is also highly reliable, sensitive, and accurate (Hauck et al., 2010). Furthermore, to consider the technique as an ideal, it should be able to detect multiple pathogens in a single reaction. Diagnostic is usually realized using conventional molecular diagnostic technologies that are mainly based on the amplification of specific DNA sequences from extracted nucleic acids (DNA or RNA), for example, target amplification (e.g., PCR, reverse transcriptase PCR, and strand displacement amplification), signal amplification (e.g., branched DNA assays and hybrid capture), probe amplification (e.g., ligase chain reaction, cleavage-invader, and cycling probes), or postamplification analysis (e.g., sequencing the amplified products or melting curve analysis), although sensitivity of amplification methods may be false positive due to trace contamination of the specimen or equipment. In addition, these techniques basically depend on enzymatic activity; false negatives can occur when samples contain contaminants that inhibit the enzymes (Hartman et al., 2005). One of the latest methods for rapid diagnostics of infectious diseases area DNA microarrays or DNA chips DNA microarrays which are
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essentially a high-throughput version of the Southern blot method (Schena et al., 1995). Each microarray contains a number of different DNA oligonucleotides that recognize specific target genes from a pathogen through complementary DNA DNA binding. The detection is based on oligonucleotides hybridized to pathogen genes for the diagnosis of infectious diseases. However, with their potential in diagnostics and practical use in clinical settings, this technique is hampered by several considerations, especially difficulties in the identification of pathogen-unique target genes and in the design of oligonucleotide primers for multiplex PCR. The first difficulty lies in finding a gene that is unique to a particular pathogen among a tremendous number of genes (Janda and Abbott, 2007). Another challenge is the design of oligonucleotides that will amplify particular pathogen genes in multiplex PCR without nonspecific amplifications. Emerging nanotechnology-based techniques have recently attracted interest as an approach that may overcome the problems of current diagnostic techniques through their specific mode of actions and unique physical properties (i.e., shape, size, surface charge, and dimension) (Daum et al., 2012). These techniques may be applied to develop accurate, reliable, rapid, safe, cost-effective, sensitive, specific, and easily accessible techniques for the detection of pathogens (Rosi and Mirkin, 2005). In the following section, we discuss new nanotechnology-based methods for the treatment, diagnosis, or prevention of infectious diseases.
APPLICATION OF NANOTECHNOLOGY IN INFECTIOUS DISEASE Nanodiagnostics is defined currently as the use of nanotechnology in diagnostic applications. This new tool has been extensively studied to meet the requirements of clinical diagnostics with high sensitivity and earlier detection of various diseases (Baptista, 2014). The ability of rapid and real-time detection which can be realized using very small volumes of samples from patients is the specific and unique property of nanomaterials or nanostructures used in nanodiagnostic platforms. Therefore nanodiagnosis represents another interesting property since it has a huge potential to be low-cost, user friendly, and robust systems. Actually, diagnosis and detection of pathogens in infectious diseases and cancer biomarkers are mainly based on nanodiagnostic applications. For the infectious diseases the nanodiagnostic platforms have the ability to achieve reliable and rapid conclusions with simple and portable devices just by using blood, sputum, or urine samples from patients (Kaittanis et al., 2010). In addition, especially in resource-poor areas in the developing countries, it could be suitable to use
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nanodiagnostics platforms, which has an important potential to be robust, affordable, and reproducible in the diagnosis of infectious diseases.
Nanoparticle-Based Diagnosis for Infectious Diseases Many nanoparticles (NPs) are currently available for nanodiagnosis, particularly fluorescent NPs, metallic NPs, and magnetic NPs, which have been successfully utilized for the diagnosis of infectious diseases. Sensitivity and photostability of fluorescent NPs allow this category to be used to label many different biological targets. They have been demonstrated as new strategies to perform disease diagnosis in real time through bioimaging or sensing activities. Furthermore, gold and silver NPs constitute the most used metallic NPs in the diagnosis applications which could emit intense absorption when excited with electromagnetic radiation (Tallury et al., 2010). The gold NPs are the first nanomaterials as nanodiagnostics for the detection of DNA in 1996 (Mirkin et al., 1996). The changes in the color of gold NPs in solution from red to blue have been demonstrated after DNA-guided aggregations, which make them ideal nanomaterials for nanodiagnostics because of their unique color changes and other chemical and physical properties. Thus conjugation of diverse molecules, such as antibodies, antigens, and enzymes with gold particles as electrochemical labels, optical probes, and signal transfer amplifiers, can be used in the diagnosis of various diseases. For instance, the gold nanorods have been used to diagnose HIV through their second-order nonlinear optical properties. A 100 pM target DNA can be recognized by a 145-mer oligonucleotide probe, which was recorded by a hyper-Rayleigh scattering (HRS) spectroscopy with high sensitivity and selectivity. Detection of single-base-mismatch HIV-1 virus DNA through the HRS intensity changes using the gold nanorods was rapid, simple, and efficient (Darbha et al., 2008). In addition, a similar HRS technique with gold NPs has also been developed to detect HCV for infectious diseases. Ragarding bioimaging, cancer therapy, and nanodiagnostics, magnetic NPs have also been successfully applied in this biomedical applications (Wu et al., 2016; Kolosnjaj-Tabi et al., 2016; Duguet et al., 2006; Gu et al., 2006; Moraes Silva et al., 2016). This diagnosis is based on the enhanced separation and detection of aligned magnetic NPs bonded with targeting agents under an applied magnetic field (Shinde et al., 2012). For magnetic resonance imaging magnetic NPs, iron oxide NPs, composed of magnetite or maghemite cores, have been used. Therefore modification and conjugation of surface of the iron oxide NPs with antibodies, proteins, and nucleic acids is commonly used in order to detect
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many different infecting pathogens, such as viruses, bacteria, and parasites. The early and efficient diagnosis of malaria using magnetic NPs with iron oxide core and silver shell is considered a successful example of this method (Yuen and Liu, 2012).
Nanodevice-Based Diagnosis for Infectious Diseases Simple NP-based nanodiagnostics for infectious diseases have been extensively studied and used but they are still far from meeting the real demands in the clinic. Since many infecting pathogens, such as HIV, always have multiple strain types, and infection may be with multiple pathogens such as HIV and hepatitis B virus (HBV) together for patients. For that, development of complicated diagnosis and more advanced nanodiagnostics of infectious diseases are greatly required. Actually, integration of many techniques with the nanotechnology in order to develop nanodevice-based diagnosis platforms for the diagnosis of infectious diseases is available. Among them, lab-on-a-chip and microfluidics techniques have shown good promise for the detection of infectious diseases (Dixon et al., 2016; Cabibbe et al., 2015). These integrated techniques represent many advantages that could greatly potentiate to build low-cost and portable devices (Murdock et al., 2017; Sackmann et al., 2014; Li et al., 2016; Su et al., 2015). Since multiple assays could be integrated into one single device (Tay et al., 2016) which can lead to decrease in the volume of samples from infected patients, the consumption of materials, and the analysis time. A successful integrated nanodevice with high-throughput and multiplexed detecting ability for the most important blood-borne infecting agents such as HIV, HBV, and HCV in serum samples has been developed through the combination of nanotechnology (quantum dots) and microtechnology (microfluidics) (Klostranec et al., 2007). Using this diagnosis, multiple pathogens could be detected precisely using the human serum samples simultaneously.
Nanobiosensors A biosensor is defined as an analytical device based on conversion of molecular recognition of a target analyte into a measurable signal using a transducer. Glucose sensor is considered the most well-known example in use today, which has had a transformative effect on the management of diabetes since its introduction in the current form 30 years ago. Other example bases on lateral flow assays are widely used such as pregnancy test (Luong et al., 2008; Ngom et al., 2010). Regarding infectious diseases, biosensors have a variety of advantages and offer the
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possibility of an easy-to-use, are considered as a sensitive and inexpensive technology platform that can identify pathogens rapidly and predict effective treatment (Foudeh et al., 2012; Pejcic et al., 2006; D’orazio, 2011). These advantages include also a small fluid volume manipulation (less reagent and lower cost), short assay time, low energy consumption, high portability, high-throughput, and multiplexing ability (Whitesides, 2006). Development of biosensors with ability to perform complex molecular assays for diagnosis of many infectious diseases is due to current advances in micro- and nanotechnologies. In addition, significant progress has been made in parallel to understand pathogen genomics and proteomics and their interactions with the host (Fournier and Raoult, 2011; Hodges and Connor, 2013; Mairiang et al., 2013). Biosensor-based immunoassays may improve the detection sensitivity of pathogen-specific antigens, while multiplex detection of host immune response antibodies (serology) may improve the overall specificity. To facilitate assay development, further system integration which integrates both pathogen-specific targets and biomarkers representative of host immune responses at different stages of infection may be developed (Mohan et al., 2011). Label-Free Biosensors Label-free biosensors are based primarily on changes that occur when target analytes bind to immobilized molecular capture elements on a solid support or cause changes in interfacial capacities or resistance (Hunt and Armani, 2010; Rapp et al., 2010). Label-free biosensors require only a single recognition element, leading to simplified assay design, decreased assay time, and reduction in reagent costs. This recognition mode is especially appropriate for small molecular targets, which can be buried within the binding pocket of the capturing element, leaving little room for interaction with a detector agent that would be required in a labeled assay. Ability to perform quantitative measurement of molecular interaction in real time constitutes another advantage of label-free method, which allows continuous data recording. Also, target analytes are detected without labeling or chemical modification in their natural and then can be preserved for further analysis. The label-free sensing strategies for various infectious diseases discussed below operate through a binding-event-generated perturbation in optical, electrical, or mechanical signals (Table 10.2). Optical Transducer Optical transducers are widely used due to their high sensitivity with several well established optical phenomena such as surface plasmon changes, scattering, and interferometry (Citartan et al., 2013). Surface
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TABLE 10.2
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Examples of Label-Free Detection Strategies
Label-tree assay
Technology
Advantages
Disadvantages
Optical transducer
Surface plasmon resonance
Real-time detection; possibility of high throughput
Sensitive to sample matrix effects; sensor surface functionalization challenging; bulky optical equipment
Electrical transducer
Redox electrochemistry (amperometric)
Simple sensor design; detection platform amenable to inexpensive and miniaturization
Redox species required to increase current production; no real-time detection; sensitive to sample matrix effects
Impedance spectroscopy
Simple electrode design; real-time detection
Sensitive to sample matrix effects; bulky equipment; data analysis may not be trivial (theoretical model may be required)
Potentiometry
Real-time detection; consecutive measurements on different samples are possible
Bulky equipment, sensitive to sample matrix; complicated sample preparation steps; careful control of temperature is essential
Field effect transistor
Real-time detection; stable sensor response; detection platform amenable to POC system
Sensitive to sample matrix effects; bulky equipment; data analysis may not be trivial (theoretical model may be required)
Microcantilever
Real-time detection; multiplex and high throughput are possible
Sensitive to sample matrix effects; careful control of temperature is essential; bulky equipment
Quartz crystal microbalance
Simple electrode design; real-time detection; detection platform amenable to POC system
Sensitive to sample matrix effects; careful control of temperature and stress is essential
Mechanical transducer
POC, Point-of-care.
plasmon resonance is the excitation of an electromagnetic wave propagating along the interface of two media with dielectric constants of opposite signs, such as metal and sample buffer, by a specific angle of incident light beam (Guo, 2012). The signal is based on total internal reflection that results in a reduced intensity of the reflected light.
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The angle at which the resonance occurs is sensitive to any change at the interface, such as changes in refractive index or formation of a nanoscale film thickness due to surface molecular interactions. Therefore these changes can be measured by monitoring the light intensity minimum shift over time. Most label-free optical biosensors require precise alignment of light coupling to the sensing area, which is a major drawback for point-ofcare applications. Therefore optical sensing can be significantly improved when this approach is used in an integration scheme. Integrated optics allow several passive and active optical components on the same substrate, allowing flexible development of minimized compact sensing devices, with the possibility of fabrication of multiple sensors on one chip. This system was used to demonstrate the recognition of small enveloped RNA viruses (vesicular stomatitis virus and pseudotyped ebola) as well as large enveloped DNA viruses (vaccinia virus) at clinically relevant concentrations (Yanik et al., 2010). Electrical Transducer With high innate sensitivity and simplicity to be effectively conjugated to miniaturized hardware, electrical analytical methods are considered common sensing approaches. Common types of electrical biosensors that have been applied to infectious disease diagnostics include voltammetric, amperometric, impedance, and potentiometric sensors (Luo and Davis, 2013). Voltammetric and amperometric sensors involve current measurement of an electrolyte with a DC voltage applied across the electrode as a function of voltage and time, respectively. An immunosensor based on the amperometric approach has been developed for the detection of hepatitis B surface antigen, a major index of hepatitis B viruses (Qiu et al., 2011). Mechanical Transducer Emergence of micro- and nanoscale mechanical transducers able to detect changes in force, motion, mechanical properties, and mass that comes along with molecular recognition events was facilitated by the advanced development of micro- and nanofabrication technologies (Tamayo et al., 2013; Arlett et al., 2011). Therefore cantilever and quartz crystal microbalances (QCMs) are the main established tools among this category of biosensors. Thus Peduru Hewa et al. (2009) developed a QCM-based immunosensor for the detection of influenza A and B viruses. By conjugating Au NPs to the antiinfluenza A or B monoclonal antibodies, a detection limit of 1 3 103 pfu/mL for laboratory-cultured preparations and clinical samples (nasal washes) was achieved. In 67 clinical samples the QCM-based immunosensor was comparable with
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standard methods such as shell vial and cell culture and better than ELISA in terms of sensitivity and specificity. Generally, this type of sensors does not include signal amplification; improvement of specificity and sensitivity of a given device depends largely on the selection and combination of capturing elements and transducers. Otherwise, advances in biochemistry and molecular biology may ensure the diversity of capturing elements with higher affinity, specificity, and stability. Translation of technologies from detection using laboratories solutions to real-world clinical samples such as serum, blood, or urine represents a real challenge for application of these technologies. The complex sample matrices of clinical samples can lead to nonspecific binding and aberrant signals. Labeled Biosensors
This class of biosensors is the most common and robust method of biosensing. Classically, in labeled assays, the analyte is sandwiched between the capture and detector agents (Peruski and Peruski, 2003). Electrodes, glass chips, nano- or microparticles constitute solid surfaces on which are immobilized captures agents, while flurophores, enzymes, or NPs considered signaling tags are typically conjugated to detector agents (Ju et al., 2011). As with label-free assays, optical, electrical or mechanical transducers can be coupled to the signaling tag. Optical sensors are used to detect fluorescent (Li et al., 2013), colorimetric (Nam et al., 2007) or luminescent tags (Sapsford et al., 2006), electrochemical sensors used to detect redox reactions from enzyme tags (Mach et al., 2009), and magnetoresistive sensors used to detect magnetic tags (Haun et al., 2010). Furthermore, using these systems, detection of the analyte can be quantitative or semiquantitative by relating the signal generated by the analyte of interest. In general, binding sites are different among capture and detector elements, thereby the specificity increased and the background reduced. However, the multistep protocol can make the assay more costly and complicated. The standard sandwich immunoassay mostly used for infectious disease applications in clinical laboratories is ELISA (Peruski and Peruski, 2003). This technique is based on capture of antibody and a detector antibody modified with an enzyme tag for catalyzing the conversion of chromogenic substrate into colored molecules. Regarding quantitative ELISA, the optical density of the colored product from the sample is compared with a standard serial dilution of a known concentration of the target molecule. Furthermore, nucleic acids can also be detected with sandwich assays. Most wellknown commercially available examples include home pregnancy tests and urinalysis strips. Lateral flow assays have been proposed for saliva- or blood-based HIV tests, blood-based malaria antigen test, and
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TABLE 10.3
Examples of Label-Free Detection Strategies
Technology
Advantages
Disadvantages
Redox electrochemistry (amperometric)
Detection platform amenable to POC system; easy integration with other electric field-driven modules
No real-time detection; multiple steps assay
Biobarcode
Detection platform amenable to POC system; easily interpreted results
No real-time detection; complicated protocol for probe preparations; multiple steps assay
Metal nanoparticles
Detection platform amenable to POC system; easily interpreted results; multiplex
No real-time detection; temperature fluctuations can affect the results; multiple steps assay
POC, Point-of-care.
serum-based tuberculosis test (Ngom et al., 2010). These assays have wide range of advantages including mainly low cost, minimal to no sample preparation, and straightforward interpretation of the results (Martinez et al., 2010). Moreover, poor sensitivity for many of the clinically relevant targets and qualitative or semiquantitative results are the most important disadvantages of this technique. Thus current efforts have essentially focused on signal amplification to improve the limit of detection. In order to develop the field of nanotechnology, functionalization of NPs with different biological molecules was established over the years, and this made it ideal labels for diverse signal amplification processes in the biosensor platforms. Due to their high surface-to-volume ratio, NPs are attractive means of signal amplification to improve sensitivity and versatility of biosensing devices (D’orazio, 2011; Ju et al., 2011; Wang and Wang, 2014). Labeled biosensors are based essentially on biobarcode, metal NPs, and magnetic NPs (Table 10.3). Biobarcode Biobarcode amplification assay (BCA) is one of the most promising NP-based approaches. This technique has the ability to detect both proteins and nucleic acids without enzymatic reactions (Nam et al., 2003, 2007). In addition, BCA is an involvement of sandwich assay with targets captured with micro- or NPs conjugated with oligonucleotides (barcode DNA) using as surrogates for signal amplification. Thus many strands are released with capture of every target for subsequent detection with other means such as electrochemical or optical. This tool was applied recently to detect HIV capsid (p24) antigen, a useful marker for
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ultimate prediction of CD4 1 T-cell decline, disease progression, and early detection of HIV-1 infection (Tang et al., 2007). Metal Nanoparticles Based on their unique optical properties, metal NPs are also used as signal amplification labels for bio-recognition processes (Cao et al., 2011; Lin et al., 2013). Gold and silver NPs exhibit plasmon absorbance bands in the visible light spectrum which are determined by the size of the respective particles. Magnetic Nanoparticles These particles coupled with detectors for biosensing can serve for signal amplification and are amenable to use in solution phase sandwich assays, such as diagnostic magnetic resonance (Haun et al., 2010; Soelberg et al., 2009). Significantly faster assay times compared to diffusion-dependent surface structure-based assays. Using diagnostic magnetic resonance, the capture and detection agents are both in solution and related to magnetic particles. Therefore the magnetic particles cluster as the antibodies bind to analyte of interest once it is present.
CONCLUSION This chapter presented current and conventional diagnosis used for infectious diseases and limitations of the current advances facilitated by nanotechnologies to address the limitations. Therefore modern nanobased tools are more reliable than conventional techniques. This field should be developed further for practical use in daily life as it already provides new directions for the advancement of treatments and diagnostics for infectious diseases. Furthermore, in order to control infectious diseases and improve public health, development of this nanotechnology-based therapeutics, vaccines, and diagnostics may foster easy, cheap, safe, and portable use of end products, especially in the developing countries. To ensure more advanced and improved than traditional diagnosis, NPs make a great leap especially in control of many parameters in diagnosis and treatment such as controlled slow release of encapsulated drugs. But, for more development of NPs-based technologies, it is crucial to develop the design of these particles with a targeted function; efficient encapsulation of drugs; specific binding to targets, on-site release, etc. In addition, infectious diseases are ideal applications for the emerging biosensor technologies. For many infectious diseases, rapid diagnosis and timely initiation of effective treatment can be critical for patient outcome and public health. When integrated with advanced
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microfluidic systems, biosensor can form the foundation of rapid pointof-care devices with the potential to positively impact patient care.
Acknowledgments All the authors are thankful to the contributors of the Team of Virology, Oncology, and Medical Biotechnologies of Laboratory of Virology, Microbiology, Quality, and Biotechnologies/ETB and also to the Fondation Lalla Salma de lutte contre le cancer.
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10 Application of Nanodiagnostics in Viral Infectious Diseases Rahma Ait Hammou1, Mustapha Benhassou1,2,3 and Moulay Mustapha Ennaji1 1
Laboratory of Virology, Microbiology, Quality, Biotechnologies/EcoToxicology and Biodiversity, Faculty of Sciences and Techniques, Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco 2 Mohammed VI University of Health Sciences of Casablanca, Casablanca, Morocco 3School of Medicine and Pharmacy of Casablanca, University Hassan II of Casablanca, Casablanca, Morocco
ABBREVIATIONS BCA DNA ELISA HBV HCV HIV NP PCR RNA
Biobarcode amplification assay Deoxyribonucleic acid Enzyme-linked immunosorbent assays Hepatitis B virus Hepatitis C virus Human immunodeficiency virus Nanoparticles Polymerase chain reaction Ribonucleic acid
INTRODUCTION Viruses (Armstead and Li, 2011; Sharma, 2010), bacteria (Kelley et al., 2013; Hyde, 2011), fungi (Pappas et al., 2004), or parasites (Olliaro, 2009) are the main pathogens that cause infectious diseases and are one of the major causes of deaths, accounting for approximately 15 million annual
Emerging and Reemerging Viral Pathogens DOI: https://doi.org/10.1016/B978-0-12-814966-9.00010-X
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deaths worldwide (Von Groote-Bidlingmaier and Diacon, 2011). In spite of the great efforts to enhance and develop effective pharmaceuticals and new technologies to produce drugs at low cost, the remarkable increase in drug resistance of infectious agents prevents efficient treatment of these diseases. Therefore the consequences of drug resistance were higher mortality, increased cost due to the use of more expensive drugs, and increased burden on the public healthcare system. Consequently, it becomes crucial and mandatory to develop new strategies, pharmaceuticals, and devices to diagnose and treat diseases accurately, easily, and efficiently. Furthermore, in the aim of effective control and suitable infectious diseases, a number of nanotechnologybased materials have been studied (Blecher et al., 2011). These nanotechnologies served to enhance immune responses against antigens for effective vaccination, suitable use of pharmaceuticals in order to achieve the target site and to be released at a controlled rate, and for accurate, rapid, and low-cost detection and diagnosis of infectious diseases. This chapter will discuss the conventional methods of diagnosis and nanotechnologies developed to improve treatment, diagnostics, and prevention of infectious diseases.
CONVENTIONAL DIAGNOSIS FOR INFECTIOUS DISEASES AND LIMITATIONS Infectious diseases treatment and prevention requires up-to-date diagnostics to be more efficient. Furthermore, monitoring of efficacy of treatment is mandatory during therapy by detection of pathogens. Diverse conventional tools are available for the diagnosis of infectious disease including microscopy, tissue culture, lateral flow immunoassays (also known as dipsticks or immune chromatographic test), enzymelinked immunosorbent assays (ELISAs), and biochemical tests (Table 10.1). More recently, molecular diagnostic techniques, such as polymerase chain reaction (PCR) and real-time PCR, have been widely used to diagnose and monitor infections such as human immunodeficiency virus (HIV)/AIDS and hepatitis C virus (HCV) because they have a higher specificity and sensitivity than ELISA-based diagnostics. However, the cost of these techniques, time-consuming and require prior sample preparation, that allows their use only in developed countries but are often poorly suited for the developing countries, where infectious diseases are leading causes of morbidity and mortality, because the availability of trained clinical staff and suitable laboratory facilities may be limited (Sosnik and Amiji, 2010). Therefore development of new diagnostic technologies is required. The characteristics of the ideal tool of diagnostic for the developing countries would be a
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TABLE 10.1 Current Therapies Against Selected Virus and Their Limitations (Qasim et al., 2014) Disease name
Causative agent
Current treatment strategies
Hepatitis C
HCV
Combination of interferon and broad spectrum antiviral therapy
• Limited efficacy in patients with HCV genotype 1 • Drug resistance is rapidly emerging • Drug administration by injection over 72 weeks may result in chronic side effects
AIDS
HIV
HAART
Treatment should be continued throughout life • Potential emergence of drug resistance • Complete eradication is not possible • Side effects such as increased rate of heartbeat, diabetes, liver diseases, cancer, and premature aging
Cervical cancer
HPV
Cryosurgery, loop
• No treatment for existing cervical cancer except for the removal of cervix • Vaccine has side effects and is effective only before exposure to the virus
Electrosurgical excision Procedure (LEEP), laser therapy, hysterectomy
Limitations in treatment
Vaccine Hepatitis B
HBV
Interferon therapy
• No treatment available for acute hepatitis B • Cold chain issues for vaccine • A booster dose of vaccine is required; therefore, follow-up of patients is a major issue
Poliomyelitis
Polio virus
Vaccine
• No treatments available. Immunization for prevention only • Vaccine is expensive and requires a cold chain for transportation and storage • Issue of OPV degradation (Continued)
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TABLE 10.1
(Continued)
Disease name
Causative agent
Influenza virus
Influenza virus A and B
Vaccine
These drugs have activity only against influenza A strain • Amantadine carries a risk of neuropsychological, atropinic, and dopaminergic adverse effects • Zanamivir carries a risk of life-threatening bronchospasm • Emergence of drug resistance is a crucial problem for the treatment of influenza virus
Mumps, measles, and rubella
Paramyxovirus, mumps virus, and rubella
Vaccine
• No treatment available. Vaccine for prevention only • Potential side effects of vaccine
Current treatment strategies
Limitations in treatment
AIDS, Acquired immunodeficiency syndrome; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papilloma virus; OPV, oral polio vaccine.
cost-effective, portable, and point-of-source detection system that is also highly reliable, sensitive, and accurate (Hauck et al., 2010). Furthermore, to consider the technique as an ideal, it should be able to detect multiple pathogens in a single reaction. Diagnostic is usually realized using conventional molecular diagnostic technologies that are mainly based on the amplification of specific DNA sequences from extracted nucleic acids (DNA or RNA), for example, target amplification (e.g., PCR, reverse transcriptase PCR, and strand displacement amplification), signal amplification (e.g., branched DNA assays and hybrid capture), probe amplification (e.g., ligase chain reaction, cleavage-invader, and cycling probes), or postamplification analysis (e.g., sequencing the amplified products or melting curve analysis), although sensitivity of amplification methods may be false positive due to trace contamination of the specimen or equipment. In addition, these techniques basically depend on enzymatic activity; false negatives can occur when samples contain contaminants that inhibit the enzymes (Hartman et al., 2005). One of the latest methods for rapid diagnostics of infectious diseases area DNA microarrays or DNA chips DNA microarrays which are
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essentially a high-throughput version of the Southern blot method (Schena et al., 1995). Each microarray contains a number of different DNA oligonucleotides that recognize specific target genes from a pathogen through complementary DNA DNA binding. The detection is based on oligonucleotides hybridized to pathogen genes for the diagnosis of infectious diseases. However, with their potential in diagnostics and practical use in clinical settings, this technique is hampered by several considerations, especially difficulties in the identification of pathogen-unique target genes and in the design of oligonucleotide primers for multiplex PCR. The first difficulty lies in finding a gene that is unique to a particular pathogen among a tremendous number of genes (Janda and Abbott, 2007). Another challenge is the design of oligonucleotides that will amplify particular pathogen genes in multiplex PCR without nonspecific amplifications. Emerging nanotechnology-based techniques have recently attracted interest as an approach that may overcome the problems of current diagnostic techniques through their specific mode of actions and unique physical properties (i.e., shape, size, surface charge, and dimension) (Daum et al., 2012). These techniques may be applied to develop accurate, reliable, rapid, safe, cost-effective, sensitive, specific, and easily accessible techniques for the detection of pathogens (Rosi and Mirkin, 2005). In the following section, we discuss new nanotechnology-based methods for the treatment, diagnosis, or prevention of infectious diseases.
APPLICATION OF NANOTECHNOLOGY IN INFECTIOUS DISEASE Nanodiagnostics is defined currently as the use of nanotechnology in diagnostic applications. This new tool has been extensively studied to meet the requirements of clinical diagnostics with high sensitivity and earlier detection of various diseases (Baptista, 2014). The ability of rapid and real-time detection which can be realized using very small volumes of samples from patients is the specific and unique property of nanomaterials or nanostructures used in nanodiagnostic platforms. Therefore nanodiagnosis represents another interesting property since it has a huge potential to be low-cost, user friendly, and robust systems. Actually, diagnosis and detection of pathogens in infectious diseases and cancer biomarkers are mainly based on nanodiagnostic applications. For the infectious diseases the nanodiagnostic platforms have the ability to achieve reliable and rapid conclusions with simple and portable devices just by using blood, sputum, or urine samples from patients (Kaittanis et al., 2010). In addition, especially in resource-poor areas in the developing countries, it could be suitable to use
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nanodiagnostics platforms, which has an important potential to be robust, affordable, and reproducible in the diagnosis of infectious diseases.
Nanoparticle-Based Diagnosis for Infectious Diseases Many nanoparticles (NPs) are currently available for nanodiagnosis, particularly fluorescent NPs, metallic NPs, and magnetic NPs, which have been successfully utilized for the diagnosis of infectious diseases. Sensitivity and photostability of fluorescent NPs allow this category to be used to label many different biological targets. They have been demonstrated as new strategies to perform disease diagnosis in real time through bioimaging or sensing activities. Furthermore, gold and silver NPs constitute the most used metallic NPs in the diagnosis applications which could emit intense absorption when excited with electromagnetic radiation (Tallury et al., 2010). The gold NPs are the first nanomaterials as nanodiagnostics for the detection of DNA in 1996 (Mirkin et al., 1996). The changes in the color of gold NPs in solution from red to blue have been demonstrated after DNA-guided aggregations, which make them ideal nanomaterials for nanodiagnostics because of their unique color changes and other chemical and physical properties. Thus conjugation of diverse molecules, such as antibodies, antigens, and enzymes with gold particles as electrochemical labels, optical probes, and signal transfer amplifiers, can be used in the diagnosis of various diseases. For instance, the gold nanorods have been used to diagnose HIV through their second-order nonlinear optical properties. A 100 pM target DNA can be recognized by a 145-mer oligonucleotide probe, which was recorded by a hyper-Rayleigh scattering (HRS) spectroscopy with high sensitivity and selectivity. Detection of single-base-mismatch HIV-1 virus DNA through the HRS intensity changes using the gold nanorods was rapid, simple, and efficient (Darbha et al., 2008). In addition, a similar HRS technique with gold NPs has also been developed to detect HCV for infectious diseases. Ragarding bioimaging, cancer therapy, and nanodiagnostics, magnetic NPs have also been successfully applied in this biomedical applications (Wu et al., 2016; Kolosnjaj-Tabi et al., 2016; Duguet et al., 2006; Gu et al., 2006; Moraes Silva et al., 2016). This diagnosis is based on the enhanced separation and detection of aligned magnetic NPs bonded with targeting agents under an applied magnetic field (Shinde et al., 2012). For magnetic resonance imaging magnetic NPs, iron oxide NPs, composed of magnetite or maghemite cores, have been used. Therefore modification and conjugation of surface of the iron oxide NPs with antibodies, proteins, and nucleic acids is commonly used in order to detect
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many different infecting pathogens, such as viruses, bacteria, and parasites. The early and efficient diagnosis of malaria using magnetic NPs with iron oxide core and silver shell is considered a successful example of this method (Yuen and Liu, 2012).
Nanodevice-Based Diagnosis for Infectious Diseases Simple NP-based nanodiagnostics for infectious diseases have been extensively studied and used but they are still far from meeting the real demands in the clinic. Since many infecting pathogens, such as HIV, always have multiple strain types, and infection may be with multiple pathogens such as HIV and hepatitis B virus (HBV) together for patients. For that, development of complicated diagnosis and more advanced nanodiagnostics of infectious diseases are greatly required. Actually, integration of many techniques with the nanotechnology in order to develop nanodevice-based diagnosis platforms for the diagnosis of infectious diseases is available. Among them, lab-on-a-chip and microfluidics techniques have shown good promise for the detection of infectious diseases (Dixon et al., 2016; Cabibbe et al., 2015). These integrated techniques represent many advantages that could greatly potentiate to build low-cost and portable devices (Murdock et al., 2017; Sackmann et al., 2014; Li et al., 2016; Su et al., 2015). Since multiple assays could be integrated into one single device (Tay et al., 2016) which can lead to decrease in the volume of samples from infected patients, the consumption of materials, and the analysis time. A successful integrated nanodevice with high-throughput and multiplexed detecting ability for the most important blood-borne infecting agents such as HIV, HBV, and HCV in serum samples has been developed through the combination of nanotechnology (quantum dots) and microtechnology (microfluidics) (Klostranec et al., 2007). Using this diagnosis, multiple pathogens could be detected precisely using the human serum samples simultaneously.
Nanobiosensors A biosensor is defined as an analytical device based on conversion of molecular recognition of a target analyte into a measurable signal using a transducer. Glucose sensor is considered the most well-known example in use today, which has had a transformative effect on the management of diabetes since its introduction in the current form 30 years ago. Other example bases on lateral flow assays are widely used such as pregnancy test (Luong et al., 2008; Ngom et al., 2010). Regarding infectious diseases, biosensors have a variety of advantages and offer the
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possibility of an easy-to-use, are considered as a sensitive and inexpensive technology platform that can identify pathogens rapidly and predict effective treatment (Foudeh et al., 2012; Pejcic et al., 2006; D’orazio, 2011). These advantages include also a small fluid volume manipulation (less reagent and lower cost), short assay time, low energy consumption, high portability, high-throughput, and multiplexing ability (Whitesides, 2006). Development of biosensors with ability to perform complex molecular assays for diagnosis of many infectious diseases is due to current advances in micro- and nanotechnologies. In addition, significant progress has been made in parallel to understand pathogen genomics and proteomics and their interactions with the host (Fournier and Raoult, 2011; Hodges and Connor, 2013; Mairiang et al., 2013). Biosensor-based immunoassays may improve the detection sensitivity of pathogen-specific antigens, while multiplex detection of host immune response antibodies (serology) may improve the overall specificity. To facilitate assay development, further system integration which integrates both pathogen-specific targets and biomarkers representative of host immune responses at different stages of infection may be developed (Mohan et al., 2011). Label-Free Biosensors Label-free biosensors are based primarily on changes that occur when target analytes bind to immobilized molecular capture elements on a solid support or cause changes in interfacial capacities or resistance (Hunt and Armani, 2010; Rapp et al., 2010). Label-free biosensors require only a single recognition element, leading to simplified assay design, decreased assay time, and reduction in reagent costs. This recognition mode is especially appropriate for small molecular targets, which can be buried within the binding pocket of the capturing element, leaving little room for interaction with a detector agent that would be required in a labeled assay. Ability to perform quantitative measurement of molecular interaction in real time constitutes another advantage of label-free method, which allows continuous data recording. Also, target analytes are detected without labeling or chemical modification in their natural and then can be preserved for further analysis. The label-free sensing strategies for various infectious diseases discussed below operate through a binding-event-generated perturbation in optical, electrical, or mechanical signals (Table 10.2). Optical Transducer Optical transducers are widely used due to their high sensitivity with several well established optical phenomena such as surface plasmon changes, scattering, and interferometry (Citartan et al., 2013). Surface
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TABLE 10.2
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Examples of Label-Free Detection Strategies
Label-tree assay
Technology
Advantages
Disadvantages
Optical transducer
Surface plasmon resonance
Real-time detection; possibility of high throughput
Sensitive to sample matrix effects; sensor surface functionalization challenging; bulky optical equipment
Electrical transducer
Redox electrochemistry (amperometric)
Simple sensor design; detection platform amenable to inexpensive and miniaturization
Redox species required to increase current production; no real-time detection; sensitive to sample matrix effects
Impedance spectroscopy
Simple electrode design; real-time detection
Sensitive to sample matrix effects; bulky equipment; data analysis may not be trivial (theoretical model may be required)
Potentiometry
Real-time detection; consecutive measurements on different samples are possible
Bulky equipment, sensitive to sample matrix; complicated sample preparation steps; careful control of temperature is essential
Field effect transistor
Real-time detection; stable sensor response; detection platform amenable to POC system
Sensitive to sample matrix effects; bulky equipment; data analysis may not be trivial (theoretical model may be required)
Microcantilever
Real-time detection; multiplex and high throughput are possible
Sensitive to sample matrix effects; careful control of temperature is essential; bulky equipment
Quartz crystal microbalance
Simple electrode design; real-time detection; detection platform amenable to POC system
Sensitive to sample matrix effects; careful control of temperature and stress is essential
Mechanical transducer
POC, Point-of-care.
plasmon resonance is the excitation of an electromagnetic wave propagating along the interface of two media with dielectric constants of opposite signs, such as metal and sample buffer, by a specific angle of incident light beam (Guo, 2012). The signal is based on total internal reflection that results in a reduced intensity of the reflected light.
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The angle at which the resonance occurs is sensitive to any change at the interface, such as changes in refractive index or formation of a nanoscale film thickness due to surface molecular interactions. Therefore these changes can be measured by monitoring the light intensity minimum shift over time. Most label-free optical biosensors require precise alignment of light coupling to the sensing area, which is a major drawback for point-ofcare applications. Therefore optical sensing can be significantly improved when this approach is used in an integration scheme. Integrated optics allow several passive and active optical components on the same substrate, allowing flexible development of minimized compact sensing devices, with the possibility of fabrication of multiple sensors on one chip. This system was used to demonstrate the recognition of small enveloped RNA viruses (vesicular stomatitis virus and pseudotyped ebola) as well as large enveloped DNA viruses (vaccinia virus) at clinically relevant concentrations (Yanik et al., 2010). Electrical Transducer With high innate sensitivity and simplicity to be effectively conjugated to miniaturized hardware, electrical analytical methods are considered common sensing approaches. Common types of electrical biosensors that have been applied to infectious disease diagnostics include voltammetric, amperometric, impedance, and potentiometric sensors (Luo and Davis, 2013). Voltammetric and amperometric sensors involve current measurement of an electrolyte with a DC voltage applied across the electrode as a function of voltage and time, respectively. An immunosensor based on the amperometric approach has been developed for the detection of hepatitis B surface antigen, a major index of hepatitis B viruses (Qiu et al., 2011). Mechanical Transducer Emergence of micro- and nanoscale mechanical transducers able to detect changes in force, motion, mechanical properties, and mass that comes along with molecular recognition events was facilitated by the advanced development of micro- and nanofabrication technologies (Tamayo et al., 2013; Arlett et al., 2011). Therefore cantilever and quartz crystal microbalances (QCMs) are the main established tools among this category of biosensors. Thus Peduru Hewa et al. (2009) developed a QCM-based immunosensor for the detection of influenza A and B viruses. By conjugating Au NPs to the antiinfluenza A or B monoclonal antibodies, a detection limit of 1 3 103 pfu/mL for laboratory-cultured preparations and clinical samples (nasal washes) was achieved. In 67 clinical samples the QCM-based immunosensor was comparable with
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standard methods such as shell vial and cell culture and better than ELISA in terms of sensitivity and specificity. Generally, this type of sensors does not include signal amplification; improvement of specificity and sensitivity of a given device depends largely on the selection and combination of capturing elements and transducers. Otherwise, advances in biochemistry and molecular biology may ensure the diversity of capturing elements with higher affinity, specificity, and stability. Translation of technologies from detection using laboratories solutions to real-world clinical samples such as serum, blood, or urine represents a real challenge for application of these technologies. The complex sample matrices of clinical samples can lead to nonspecific binding and aberrant signals. Labeled Biosensors
This class of biosensors is the most common and robust method of biosensing. Classically, in labeled assays, the analyte is sandwiched between the capture and detector agents (Peruski and Peruski, 2003). Electrodes, glass chips, nano- or microparticles constitute solid surfaces on which are immobilized captures agents, while flurophores, enzymes, or NPs considered signaling tags are typically conjugated to detector agents (Ju et al., 2011). As with label-free assays, optical, electrical or mechanical transducers can be coupled to the signaling tag. Optical sensors are used to detect fluorescent (Li et al., 2013), colorimetric (Nam et al., 2007) or luminescent tags (Sapsford et al., 2006), electrochemical sensors used to detect redox reactions from enzyme tags (Mach et al., 2009), and magnetoresistive sensors used to detect magnetic tags (Haun et al., 2010). Furthermore, using these systems, detection of the analyte can be quantitative or semiquantitative by relating the signal generated by the analyte of interest. In general, binding sites are different among capture and detector elements, thereby the specificity increased and the background reduced. However, the multistep protocol can make the assay more costly and complicated. The standard sandwich immunoassay mostly used for infectious disease applications in clinical laboratories is ELISA (Peruski and Peruski, 2003). This technique is based on capture of antibody and a detector antibody modified with an enzyme tag for catalyzing the conversion of chromogenic substrate into colored molecules. Regarding quantitative ELISA, the optical density of the colored product from the sample is compared with a standard serial dilution of a known concentration of the target molecule. Furthermore, nucleic acids can also be detected with sandwich assays. Most wellknown commercially available examples include home pregnancy tests and urinalysis strips. Lateral flow assays have been proposed for saliva- or blood-based HIV tests, blood-based malaria antigen test, and
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TABLE 10.3
Examples of Label-Free Detection Strategies
Technology
Advantages
Disadvantages
Redox electrochemistry (amperometric)
Detection platform amenable to POC system; easy integration with other electric field-driven modules
No real-time detection; multiple steps assay
Biobarcode
Detection platform amenable to POC system; easily interpreted results
No real-time detection; complicated protocol for probe preparations; multiple steps assay
Metal nanoparticles
Detection platform amenable to POC system; easily interpreted results; multiplex
No real-time detection; temperature fluctuations can affect the results; multiple steps assay
POC, Point-of-care.
serum-based tuberculosis test (Ngom et al., 2010). These assays have wide range of advantages including mainly low cost, minimal to no sample preparation, and straightforward interpretation of the results (Martinez et al., 2010). Moreover, poor sensitivity for many of the clinically relevant targets and qualitative or semiquantitative results are the most important disadvantages of this technique. Thus current efforts have essentially focused on signal amplification to improve the limit of detection. In order to develop the field of nanotechnology, functionalization of NPs with different biological molecules was established over the years, and this made it ideal labels for diverse signal amplification processes in the biosensor platforms. Due to their high surface-to-volume ratio, NPs are attractive means of signal amplification to improve sensitivity and versatility of biosensing devices (D’orazio, 2011; Ju et al., 2011; Wang and Wang, 2014). Labeled biosensors are based essentially on biobarcode, metal NPs, and magnetic NPs (Table 10.3). Biobarcode Biobarcode amplification assay (BCA) is one of the most promising NP-based approaches. This technique has the ability to detect both proteins and nucleic acids without enzymatic reactions (Nam et al., 2003, 2007). In addition, BCA is an involvement of sandwich assay with targets captured with micro- or NPs conjugated with oligonucleotides (barcode DNA) using as surrogates for signal amplification. Thus many strands are released with capture of every target for subsequent detection with other means such as electrochemical or optical. This tool was applied recently to detect HIV capsid (p24) antigen, a useful marker for
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ultimate prediction of CD4 1 T-cell decline, disease progression, and early detection of HIV-1 infection (Tang et al., 2007). Metal Nanoparticles Based on their unique optical properties, metal NPs are also used as signal amplification labels for bio-recognition processes (Cao et al., 2011; Lin et al., 2013). Gold and silver NPs exhibit plasmon absorbance bands in the visible light spectrum which are determined by the size of the respective particles. Magnetic Nanoparticles These particles coupled with detectors for biosensing can serve for signal amplification and are amenable to use in solution phase sandwich assays, such as diagnostic magnetic resonance (Haun et al., 2010; Soelberg et al., 2009). Significantly faster assay times compared to diffusion-dependent surface structure-based assays. Using diagnostic magnetic resonance, the capture and detection agents are both in solution and related to magnetic particles. Therefore the magnetic particles cluster as the antibodies bind to analyte of interest once it is present.
CONCLUSION This chapter presented current and conventional diagnosis used for infectious diseases and limitations of the current advances facilitated by nanotechnologies to address the limitations. Therefore modern nanobased tools are more reliable than conventional techniques. This field should be developed further for practical use in daily life as it already provides new directions for the advancement of treatments and diagnostics for infectious diseases. Furthermore, in order to control infectious diseases and improve public health, development of this nanotechnology-based therapeutics, vaccines, and diagnostics may foster easy, cheap, safe, and portable use of end products, especially in the developing countries. To ensure more advanced and improved than traditional diagnosis, NPs make a great leap especially in control of many parameters in diagnosis and treatment such as controlled slow release of encapsulated drugs. But, for more development of NPs-based technologies, it is crucial to develop the design of these particles with a targeted function; efficient encapsulation of drugs; specific binding to targets, on-site release, etc. In addition, infectious diseases are ideal applications for the emerging biosensor technologies. For many infectious diseases, rapid diagnosis and timely initiation of effective treatment can be critical for patient outcome and public health. When integrated with advanced
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microfluidic systems, biosensor can form the foundation of rapid pointof-care devices with the potential to positively impact patient care.
Acknowledgments All the authors are thankful to the contributors of the Team of Virology, Oncology, and Medical Biotechnologies of Laboratory of Virology, Microbiology, Quality, and Biotechnologies/ETB and also to the Fondation Lalla Salma de lutte contre le cancer.
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