INTRODUCTION:

There is no doubt that the increase interest for the development of new materials applicable in electro analytical techniques has been associated with the necessity to control specific molecules present in the human body and the environment. This includes the possibility to improve the quality of life by development of efficient electrochemical devices and biodevices^1-2.

It is challenging to develop more sensitive and selective electrochemical devices that provide the possibility to detect small quantities of molecules utilizing efficient transducing elements and specific recognition materials for biosensing. The study of biological recognition elements and their specific functions has enabled the development of a new class of electrochemical modified electrodes called biosensors. These are analytical tools for the analysis of bio-material samples to gain an understanding of their bio-composition, structure and function by converting a biological response into an electrical signal proportional to the concentration of chemical species. More technically, biosensor is a probe which integrates a biological and electronic component to yield a measurable signal. Several biosensors are being developed for different applications, including environmental and bioprocess control, quality control of food, agriculture, and military and more significantly in the medical and pharmaceutical fields.^3-9. The development of efficient biosensors which can analyze the minutest details of the biological interactions even at a very small scale with extreme precision and maximum possible sensitivities deserves urgent attention. Nanomaterials can be wonderful incumbents in this dimension as they have high surface area to volume ratios which allow the surface to be used in a better and far more diversely functional manner¹⁰.They are acquiring a big impact on development of electrochemical biosensors. Nanotechnology brings new possibilities for biosensors construction and for developing novel electrochemical bioassays. It is the study, manipulation, creation, use of materials, devices and systems of dimensions less than 100nm. Nanostructure wonders provided by nanotechnology have revolutionized the happenings in the domain of molecular biology which have provided an opportunity for manipulation of atoms and molecules and monitored the biological phenomenon at the physiological level with far greater precision. In general, the advantages of nonmaterial-based biosensors are fast response, small size, high sensitivity, high electrical conductivity, better shock bearing ability, versatile colour based detection mechanisms and portability^11-12.

The research in biosensor technology shows a constant increase in relation to the various nanomaterials with the interest to be implemented either into transducers or receptors operation parts, so as to enhance their multidetection capability and sensitivity. These nanomaterials are nanoparticle, nanotubes, quantum dots or other biological nanomaterials. These nanomaterials can contribute to either the bio-recognition element or the transducer or both. These materials are interesting tools with specific physical and chemical properties because of their quantum-size effects when compared to bulk materials. The exploration of these different characteristics provides the possibility to improve the sensitivity of biosensors. Interesting approaches have been reported on the increase in electronic properties with metallic nanostructures as components. These include the utilization of nanostructure materials with specific forms like quantum dots and nanoparticle (0D), Nanowires and carbon nanotubes (1D), and metallic platelets or graphene sheets (2D) orientations that reflect their properties. These devices offer improved sensitivities, due to their large surface-to-volume ratios, which enable the bound analyze molecules to more significantly affect the bulk electrical properties of the structure. They also improve the electrochemical signals of biocatalytic events that occur at the electrode/electrolyte interface. Functional nanoparticle that bound to biological molecules (e.g. peptides, proteins, nucleic acids) have also been developed for use in biosensors to detect and amplify various signals. Due to their small size, nanomaterials may be taken up by cells, and thus are promising candidates for in vivo sensing applications¹¹The ability to detect pathogenic and physiologically relevant molecules in the body with high sensitivity and specificity offers a powerful opportunity in early diagnosis and treatment of diseases. Early detection and diagnosis can be used to greatly reduce the cost of patient care associated with advanced stages of many diseases. These costs have been estimated to be $$75 billion and $$90 billion for cancer and diabetes, respectively. Currently, cancer can be detected by monitoring the concentration of certain antigens present in the bloodstream or other bodily fluids, or through tissue examinations. Correspondingly, diabetes is monitored by determining the glucose concentrations in the blood over time. However, despite their widespread clinical use, these techniques have a number of potential limitations. For example, a number of diagnostic devices have slow response times and are burdensome to patients. Furthermore, these assays are expensive and cost the health care industry billions of dollars every year. Therefore, there is a need to develop more efficient and reliable sensing and detection technologies.

Modern biosensors based on micro- and nanoscale techniques have the potential to greatly enhance methods of detecting foreign and potentially dangerous toxins and may result in cheaper, faster, and easier-to-use analytical tools. Furthermore, microscale biosensors may be more portable and scalable for point-of-care sample analysis and real-time diagnosis. The emergence of micro- and nanoscale technologies for biology has a great potential to lead to the development of next generation biosensors with improved sensitivity and reduced costs¹²

DESIGN AND COMPONENTS:

A biosensor is a sensing device or a measurement system designed specifically for estimation of a material by using the biological interactions and then assessing these interactions into a readable form with the help of a transduction and electromechanical interpretation. A key component of the biosensing is the transduction mechanisms which are responsible for converting the responses of bioanalyte interactions in an identifiable and reproducible manner i.e. the conversion of specific biochemical reaction energy into an electrical form. A typical biosensor functions at five different levels as illustrated in Fig. 1

The main function or purpose of a biosensor is to sense a biologically specific material. Often, these materials are antibodies, proteins, enzymes and immunological molecules. It is done by using another biologically sensitive material that takes part in the making of bioreceptor. So, a bioreceptor is that component of a biosensor which serves as a template for the material to be detected. There can be several materials which can be used as bioreceptors.

(a) Antibody/antigen: The high specificity between an antibody and an antigen can be utilized in this type of sensor technology. Biosensors utilizing this specificity must ensure that binding occurs under conditions where nonspecific interactions are minimized. Binding can be detected either through fluorescent labeling or by observing a refractive index or reflectivity change.

(b) Enzymes: Enzyme-based biosensors are composed of enzyme bioreceptors that use their catalytic activity and binding capabilities for specific detection. The products of reactions catalyzed by enzymes can be detected either directly or in conjunction with an indicator. The catalytic activity of the enzymes provides these types of biosensors with the ability to detect much lower limits than with normal binding techniques. This catalytic activity is related to the integrity of the native protein structure.

(c) Nucleic acids: The complementary relationships between adenosine, thymine, cytosine and guanosine in DNA form the basis of specificity in nucleic acid-based biosensors. These sensors are capable of detecting trace amounts of microorganism DNA by comparing it to a complementary strand of known DNA. By unwinding the target DNA strand, adding the DNA probe, and annealing the two strands, the probe will hydrolyse to the complementary sequence on the adjacent strand. If the probe is tagged with a fluorescent compound, then this annealing can be visualized under a microscope.

(d) Cells and viruses: Microorganisms such as bacteria and fungi can be used as biosensors to detect specific molecules or the overall ‘‘state’’ of the surrounding environment. For example, cell behavior such as cell metabolism, cell viability, cell respiration, and bioluminescence can be used as indicators for the detection of heavy metals.

(e) Biomimetic materials based: A biomimetic biosensor is an artificial or synthetic sensor that mimics the function of a natural biosensor. These can include apt sensors, where aptasensors use aptamers as the biocomponent. Aptamers are synthetic strands of nucleic acid that can be designed to recognize amino acids, oligosaccharides, peptides, and proteins.

The second component is the transducer system. The main function of this device is to convert the interaction of bioanalyte and its corresponding bioreceptor into an electrical form. The name itself defines the word as trans means change and ducer means energy. So, transducer basically converts one form of energy into another. The first form is biochemical in nature as it is generated by the specific interaction between the bioanalyte and bioreceptor while the second form is usually electrical in nature. This conversion of biochemical response into electrical signal is achieved through transducer by following different mechanisms,

(a) Optical-detection: Optical detection biosensors are the most diverse class of biosensors because they can be used for many different types of spectroscopy, such as absorption, fluorescence, phosphorescence, SERS, refraction, and dispersion spectrometry. In addition, these spectroscopic methods can measure all different properties, such as energy, polarization, amplitude, decay time, and/or phase. Amplitude is the most commonly measured as it can easily be correlated to the concentration of the analyte of interest.

(b) Electrochemical: Electrochemical biosensors measure the current produced from oxidation and reduction reactions. This current produced can be correlated to either the concentration of the electro active species present or its rate of production/consumption.

(c) Mass-sensitive: Biosensors that are based on mass-sensitive measurements detect small mass changes caused by chemical binding to small piezoelectric crystals. Initially, a specific electrical signal can be applied to the crystals to cause them to vibrate at a specific frequency. This frequency of oscillation depends on the electrical signal frequency and the mass of the crystal. As such, the binding of an analyte of interest will increase the mass of the crystal and subsequently change its frequency of oscillation, which can then be measured electrically and used to determine the mass of the analyte of interest bound to the crystal.

(d) Thermal detection: Thermal biosensors measure the changes in temperature in the reaction between an enzyme molecule and a suitable analyte. This change in temperature can be correlated to the amount of reactants consumed or products formed.

The third component is the detector system. This receives the electrical signal from the transducer component and amplifies it suitably so that the corresponding response can be read and studied properly.In addition to these components, a very essential requirement of the nanobiosensors is the availability of immobilization schemes which can be used to immobilize the bioreceptor so as to make its reaction with bioanalyte much more feasible and efficient. Immobilization makes the overall process of biological sensing cheaper, and the performance of the systems based on this technology is also affected by changes in temperature, pH, interference by contaminants, and other physicochemical variations^12-13

There are multitude factors which govern or decide the use of a particular kind of nanomaterials for biosensing applications. These factors are the chief ingredients of their physical and chemical properties along with their energy sensitive and selective responses. Before exactly implementing or adding a nanomaterial for the sensing applications, focus must be first made on their desired manufacturing which is a part of experimental design known as “Nanofabrication.” The technique of nanofabrication targets two vital operations, namely, the manufacturing and design of nanoscale adhesive surfaces via the technology of integrated circuits and the engineering of nanomaterial surfaces through the process of micromachining. This technique, thus developed for biosensing, uses the variations of four basic processes, namely, photolithography, thin film etching/growth, surface etching strategies, and chemical bonding parameters¹⁰

NANOBIOSENSORS: VARIATIONS AND TYPES¹⁰

The criteria for classification are based on the nature of nanomaterials being involved for improving the sensing mechanism. For instance, nanoparticle based biosensors include all the sensors which employ metallic nanoparticles as the enhancers of the sensing biochemical signals. Similarly, nanobiosensors are called nanotube based sensors if they involve carbon nanotubes as enhancers of the reaction specificity and efficiency while biosensors using nanowires as charge transport and carriers are termed as nanowire biosensors. Likewise there are quantum dots based sensors which employ quantum dots as the contrast agents for improving optical responses.

Nanoparticle Based Sensors:

Acoustic Wave Biosensors:

Acoustic wave biosensors have been developed to amplify the sensing responses so as to improve the overall preciseness of the limits of biodetection. There can be many stimulus based effects in these kinds of sensors. The mass based variant of these sensors involves the conjugation of antibody modified sol particles which bind themselves on the electrode surface that has been complexed with the particles of analyte conjugated in a manner that antibody molecules are immobilized over the electrode surface. The large mass of bound sol particles of the antibody results in a change in the vibrational frequency of the quartz based sensing platform, and this change acts as the basis of detection. In general, the preferred diameter of the sol based antibody particles is between 5 and 100 nm. Particles of gold, platinum, cadmium sulphide, and titanium dioxide are generally preferred²⁶

Magnetic Biosensors:

Magnetic biosensors utilize the specially designed magnetic nanoparticles. These are mostly ferrite based materials, either used individually or in combined form. These types of sensors are very useful with reference to the biomedical applications with the incorporation of magnetic nanoparticles; the conventionally used biodetection devices have further become more sensitive and powerful. Alloys of transition metals with iron and other materials having unpaired electrons in their d-orbitals have been highly versatile in their magnetic behaviours. A very popular kind of materials that have come to the fore involving these employs magnetic bioassay techniques that are used for specific isolation of magnetically labeled targets with the help of a magnetometer. Special devices such as superconducting quantum interference devices (SQUID) have been used for rapid detection of biological targets using the super paramagnetic nature of magnetic nanoparticles. These devices are used to screen the specific antigens from the mixtures by using antibodies bound to magnetic nanoparticles. These make use of super paramagnetic effect of magnetic materials which is particularly observed in the nanoscale particles²⁷

Electrochemical Biosensors:¹¹

These sensors basically work to facilitate or analyse the biochemical reactions with the help of improved electrical means. These devices are mostly based on metallic nanoparticles. The chemical reactions between the biomolecules can be easily and efficiently carried out with the help of metallic nanoparticles, which significantly help in achieving immobilization of one of the reactants. This ability makes these reactions very specific and eliminates any possibility of getting undesirable side products.

Nanotube Based Sensors:

Carbon nanotubes are one of the most popular nanomaterials. Since their discovery in 1990’s, they have attracted interest because of their extraordinary properties, like the electronic conductivity, flexible physical geometric features, and the ever dynamic physico-mechanical properties ranging from high aspect ratios to very good functionalization abilities along with having high mechanical strength and folding abilities. Because of these attributes, both single walled nanotubes as well as multi- walled nanotubes have been used in designing biosensors for better performances²⁸

Nanowire Based Sensors:^22-23

Nanowires are cylindrical arrangements just like those of carbon nanotubes, having lengths in the order of few micrometres to centimetres and diameters within the nanorange. Nanowires are the one- dimensional nanostructures with very good electron transport properties. Significantly, the motion of charge carriers in the nanowires is vigorously improved and different from those in bulk materials. Sensors based on nanowires are very less in number, but literature reports some exciting examples where use of nanowires has significantly improved the performance and detection of biological materials.

CURRENT AND EMERGING CLINICAL APPLICATIONS OF NANOBIOSENSORS: ^29-30

There is a big demand for fast, reliable and low-cost systems for the detection, monitoring and diagnosis of biological molecules and diseases in medicine. There are many applications of biosensor technologies in health care and for the treatment of infectious diseases. The current status and future potential of four of the most relevant applications are discussed below.

In Vivo Glucose Detection:

One of the main clinical applications of biosensors is to develop point-of-care glucose concentration measuring devices for patients suffering from diabetes. Originally introduced in the early 1980s, the latest generation of handheld glucose sensors has revolutionized the lifestyles of those suffering from diabetes. Patients are now able to self-monitor their glucose concentrations and self-administer insulin injections as required. Most enzyme-based biosensors to detect glucose concentrations use enzymes known as oxidoreductases and glucose dehydrogenase. Glucose biosensors generally make use of electrochemical transducers in their designs as they provide appropriate specificity and reproducibility and can easily be manufactured in large volumes at low costs. These traditional amperometric-based biosensors have undergone recent miniaturization to enable subcutaneous implantation. In the minimed-medtronic continuous glucose monitoring system (CGMS), a needle-type amperometric enzyme electrode is coupled to a portable data logger. The sensor is based on the aforementioned sensing technology and the data recorded from the logger can be downloaded to a portable computer after 3 days of sensing. The monitor is implanted in the subcutaneous tissue to measure interstitial fluid glucose concentrations. Although interstitial fluid and blood concentrations are similar at steady state, there is a significant delay when the blood glucose concentration is rapidly changing as occurs after a meal. Another micro scale in vivo glucose monitor is the GlucoWatch (Cygnus, Inc.). This sensor operates by reverse iontophoresis, which utilizes a glucose-containing interstitial fluid that is lured to the skin surface by a small current passing between two electrodes. Hydrogel pads containing a glucose oxidase biosensor are present on the surface and measure the glucose concentration present in the interstitial fluid. Again, the delay between the glucose concentrations variations in the interstitial fluid and corresponding changes in the blood creates a significant disadvantage. There is a clinical need for future glucose sensors to become increasingly noninvasive and sensitive to rapid changes in glucose concentrations. It is anticipated that the development of microscale devices as well as emerging nano-based detection strategies will be useful for these techniques³¹

Bacterial Urinary Tract Infections:

Bacterial infection in the urinary tract is the second most common organ system infection in the human body. Microbial culture techniques are currently employed to identify urinary tract pathogens. These methods, however, are cumbersome and are accompanied by a 2-day lag period between the collection of the specimen and the identification of the pathogen. As such, the development of tools to effectively decrease this lag period and increase diagnosis accuracy and efficiency is very appealing from an improved health care and reduced cost standpoint. Electrochemical DNA biosensors have been documented in the literature to detect and identify pathogens. In these designs, a layer of oligonucleotide probes functions as the sensory receptor and the sensory input is detected through the use of an electrochemical transducer. There are two basic modes to detect DNA with this configuration. The first method requires target immobilization followed by detection with a labeled probe. In the second method, known as ‘‘sandwich’’ hybridization, the DNA target initially binds to a surface oligonucleotide through hybridization. This is followed by hybridization to a marker probe for signal transduction. Pairs of capture and detection oligonucleotides in an array for the detection of a 16S rRNA target have been developed. This ‘‘microchip’’ required 45 min after applying the sample to provide readout signals and did not require amplification or labeling of the target sequence. This biosensing technique confirms the capabilities of direct detection techniques for the identification of bacteria present in clinical samples and could be of great clinical potential³²

Human Immunodeficiency Virus (HIV) Detection:

More than 80 million HIV-infected people live in the developing world, where resources are scarce. Effective antiretroviral therapy (ART) for HIV has been available in developed countries for more than a decade; however, only a small fraction of the infected people are currently receiving treatment due to lack of diagnostic tools and cost-effective therapies. To increase access to HIV care and improve treatment outcomes, there is an urgent need for low cost diagnostic tools that could be implemented in developing countries. Traditionally, HIV infections are diagnosed by either direct fluorescent antibody assays or viral load testing. Direct fluorescent antibody assays, such as enzyme-linked immuno sorbent assay (ELISA), use two antibodies to identify the presence of a virus. HIV presence in vivo can also be detected using viral load testing. This technique detects cell-free plasma viral RNA with the use amplification techniques such as PCR. These types of diagnostic techniques provide rapid results, however, are generally not sensitive enough to provide reliable and consistent results. The application of surface plasmon resonance-based (SPR) optical techniques could greatly enhance the understanding of HIV and lead to superior detection and quantification mechanisms. In SPR, the surface of the biosensor is initially covered with immobilized ligands. Microfluidic channels then carry an analyte across the ligand and specific binding between the ligand and the analyte occurs. The SPR detector then measures changes in the refractive index of the biosensor as ligands and analytes bind and detach from one another. This process has already had a tremendous impact on the understanding of HIV infections. This has potentially powerful applications in the development of HIV protease inhibitors, which may have profound impacts in the progress of therapies aimed at inhibiting the HIV replication cycle³³

Cancer Cell Targeting:

Currently, 60% of patients diagnosed with breast, colon, lung, or ovarian cancer already have cell metastases forming in other locations of their body. The development of effective diagnostic tools to detect these cells has been difficult due to the low number of circulating cancer cells and the lack of suitable markers to identify these cells. However, in vivo and in vitro applications of nanotechnology may be used to increase the selectivity and resolution and to make such diagnoses possible. Currently, there are several techniques to isolate tumor cells. These require laborious manual sample preparation steps that result in variable results and low sensitivity. Circulating tumor cells (CTCs) are rare even in patients with advanced cancer, representing as low as 1-10 cells/ml such that a reliable cell sorter for CTCs needs to detect approximately one CTC in one billion blood cells. The conventional cell separation methods rely on properties such as size, density and differential expression of surface antigens to isolate desired cell subpopulations, density gradient centrifugation, and preferential lysis of red blood cells, ficoll-hypaque density, porous filters, immunomagnetic bead sorting, and cell filtration. Molecular methods have also been developed that rely on PCR-based detection of tumor-associated RNA in blood as evidence of CTCs, including in melanoma, breast cancer and prostate cancer. Moreover, methods that allow recovery of living or intact cells for further morphological, immunocytochemical, genome-wide expression profiling, or functional evaluation are significant. These studies could add to the potential benefits of CTCs and circulating metastatic precursor cells³⁴

CONCLUSION:

Nanotechnology has really proved to be a very significant blessing in the development of biosensors. The development of ultra-sensitive biological and chemical sensors is one of the grand scientific, engineering, and educational challenges of the 21st century. The overall mechanisms have become quicker, smarter, less costly, and user friendly. Future argues very well for these dynamic, versatile, and quick recognition systems considering their multidimensional potential. These materials are right now being increasingly considered for the merging of chemical and biological sensors to make the overall process fast, easy to execute, and better in terms of performance. The next generation biosensor platforms require significant improvements in sensitivity and specificity, in order to meet the needs in a variety of fields including in vitro medical diagnostics, pharmaceutical discovery and pathogen detection. Advances in diagnostic technology have been essential to the progress of medicine. The ability to identify diseases and pathogens by detecting associated proteins, nucleic acid sequences, organelles, cell receptors, enzymes, and other markers, can provide biomedical researchers and healthcare professionals with a detailed knowledge of disease pathways and patient’s conditions. There is a need for rapid, trustworthy, low-cost, multiplexed screening to detect a wide range of biomaterials.

Nanobiosensor research focuses on developing innovative technologies that have the ability to make significant contributions in the areas of human and animal disease marker detection, promising therapeutic compound identification and analysis, nano-and biomaterials characterization, and biocatalyst development. Through miniaturization, it is possible to fabricate biosensors that are portable, cheap, and highly sensitive that can be used for resource-poor settings for diseases such as HIV/AIDS. Therefore, the continued progress in the development and use of micro- and nanotechnologies for biosensors shows great potential in improving methods to diagnose diseases or to monitor their progression in medicine. With the current progress and exhaustive research pace of nanomaterial exploration, the sensing technology has become more and more versatile, robust, and dynamic. No doubt, biosensor development for a task is still very cumbersome and costly due to its technical complexities, but the incorporation of nanomaterials has proved to be a big boon for this technology.

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Received on 01.12.2015 Modified on 25.12.2015

Res. J. Pharm. Dosage Form. & Tech. 8(1): Jan.-Mar. 2016; Page 37-45

DOI: 10.5958/0975-4377.2016.00006.9

Sr. no.	Nanomaterial used	Key benefits	References
(1)	Carbon nanotubes	Improved enzyme loading, higher aspect ratios, ability to be functionalized, and better electrical communication	[19]
(2)	nanoparticles	Aid in immobilization, enable better loading of bioanalyte, and also possess good catalytic properties	[20-21]
(3)	Quantum dots	Excellent fluorescence, quantum confinement of charge carriers, and size tunable band energy	[22]
(4)	Nanowires	Highly versatile, good electrical and sensing properties for bio- and chemical sensing; charge conduction is better	[23-24]
(5)	Nanorods	Good plasmonic materials which can couple sensing phenomenon well and size tunable energy regulation, can be coupled with MEMS, and induce specific field responses	[25-26]