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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                                                                                                             Review Article 

An insight into the multifarious applications of biosensors and the way forward

Mandeep Kaur* , Shikha Sharma, Deepak Kumar 

Global College of Pharmacy,  Anandpur Sahib, Distt. Ropar, Punjab Pincode 140117 India

Introduction                                                                                                                                                   

Biosensors are analytical devices for the investigation of bio-material samples to achieve an understanding of their bio-composition, layout, and principle by transforming a biological response into an electrical signal. The bio-recognition element (e.g. enzyme, antibody, nucleic acid, hormone, organelle, or whole cell) essentially a bioreceptor, is allowed to interact with a specific analyte (e.g. Glucose, urea, drug, pesticide) to get a measurable response.¹ Any biosensor consists of the following three basic components (a) a bioreceptor, which is a  selective membrane involving various biological structures;  (b) a transducer component (semi-conducting material/nanomaterial); and (c) an electronic system that includes a signal amplifier, processor & display.² 

However, the production of biosensors, transducing devices, equipment, and immobilization techniques requires multidisciplinary research in chemistry, biology, and engineering. The materials used in biosensors are categorized into three groups based on their mechanism.

• Bioaffinity-based biosensors include antibodies and nucleic acids.
• A biocatalytic group comprising enzymes.
• Microbe-based containing microorganisms.³  

Biosensor tools are applied in various fields and industries such as disease monitoring, drug discovery, detection of pollutants, disease-causing micro-organisms, and markers that measure disease in body fluids (blood, urine, saliva, sweat).⁴ 

History 

The history of biosensors started in the year 1962 with the development of enzyme electrodes by the scientist Leland C. Clark (Father of biosensors). He represented how “to formulate electrochemical sensors (pH, Polarographic, Potentiometric or Conductimetric) more brilliant” by adding “enzyme transducers”. The first example was exemplified by entangling the enzyme Glucose Oxidase in a dialysis membrane above an oxygen probe. The addition of glucose discovered a decrease in oxygen concentration. The first biosensor was delineated in the published paper inventing the term “enzyme electrode”. Then consequently in 1967 Updike and Hicks use the same term “enzyme electrode” to explain a similar appliance where once more the enzyme glucose oxidase was immobilized in a polyacrylamide gel onto a surface of an oxygen electrode for the quick and quantitative ascertainment of glucose.⁵

Principle and components of the biosensor

The principle of biosensors depends on the mechanism of signal transduction and biorecognition of elements. In a device, all biological materials can be used as sensors or detectors. The desired biological material is usually in the form of an enzyme and the deactivated enzyme is located in propinquity to the transducer. The analyte (which is tested) is associated with the specific enzyme (bio-receptor) and produces a transformation in the biochemical property of the enzyme. It gives an electronic response during an electron enzymatic approach. The electron enzymatic method is the chemical method of transforming the enzymes into corresponding electrical signals with the help of a transducer. Now, the electrical signal is a direct demonstration of the biological material (i.e. analyte and enzyme) being measured from a transducer. The electrical signal is usually changed into a physical display for its suitable investigation and demonstration. Principle of biosensor diagrammatically shown in fig-1.^{4, 6} 

Components of Biosensor 

It consists of a bio-recognition site, transducer component, and electronic organism which contains a signal amplifier, processor, and display. It combines high selectivity of biological/ chemical substances with high precision of solid state devices. However, interfacing poses complicated troubles. The biological material can be a membrane, enzyme, antibody/antigen, receptor, protein, intact cells, tissue, or whole organ and the analyte must achieve the reaction site in the biological material.⁷ 

It consists of the following components.

Analyte: An analyte is a compound (e.g. Glucose, urea, drug, pesticide) whose concentration has to be measured. For example, glucose is an ‘analyte’ in a biosensor designed to identify glucose.

Bioreceptor: A molecule that particularly identifies the analyte is known as a bioreceptor. Some examples of receptors are enzymes, cells, deoxyribonucleic acid (DNA), and antibodies. The method of signal generation (in the form of light, heat, pH, charge or mass change, etc.) that results from the interaction of the bioreceptor with the analyte is termed bio-recognition.

Transducer: The transducer is a component that transforms one form of energy into another. The main role of the transducer in a biosensor is to convert the bio-recognition event into a computable signal. This process of energy translation is known as signalization. Most transducers create either optical or electrical signals that are generally proportional to the quantity of analyte–bioreceptor interactions.

Electronics: The main work of this part of a biosensor is to process the transduced signal and make it ready for display. It consists of intricate electronic circuitry that performs signal conditioning such as amplification and translation of signals into the digital form. The processed signals are then evaluated by the display unit of the biosensor.

Detector: It consists of a user elucidation system such as the liquid crystal display of a computer or a direct printer that produces numbers or curves comprehensible by the user. This component frequently consists of a mixture of hardware and software that creates results of the biosensor in a user-friendly way. At the endpoint, the output signal on the display can be numeric, graphic, tabular, or an image.^{4, 8}

Components of biosensor diagrammatically shown in fig-2.⁹

Classifications of Biosensors

Biosensors can be assembled according to their biological element or transduction element. Biological elements consist of enzymes, antibodies, micro-organisms, biological tissue, and organelles. The technique of transduction depends on the type of physicochemical change resulting from the sensing occurrence. Mainly biosensors based on transducer components are mass-based (piezoelectric, etc), electrochemical biosensors (Potentiometric, Amperometric, etc), and optical types of biosensors. Various types of biosensors are represented in fig-3 ^{9, 10.}

Optical biosensor

In this type of biosensor, the optical fibers permit recognition of analyte on the origin of absorption, fluorescence, or light distribution. At this point, both catalytic and affinity reactions can be measured.⁹ These biosensors contain a light source and in addition, various optical segments to generate a light bar with particular qualities and to shortcut this light to a balancing operator, an adjusted detecting head alongside a photodetector.¹⁰ 

It mainly involves antibodies and enzymes like the transducing elements and these are classified into two types that are direct optical detection biosensors and labeled optical detection biosensors. Optical techniques like SPR (Surface Plasmon Resonance) and ellipsometry for the detection of bacterial pathogens are used by researchers.¹¹  

Amperometric biosensor 

These types of biosensors measure either the current or potential resulting from a chemical reaction of electroactive materials on the transducer surface whereas an invariable potential or current, respectively, is applied. The change in current is linked to the concentration of the target species.¹² 

Potentiometric biosensor

These types of biosensors have the potential to advance the detection of numerous biological compounds and assist in the timely diagnosis of various diseases and belong to the convenient analytical class of biosensors for monitoring biomarkers in the human body. They contain ion-sensitive membrane sensors which can be used to find out potassium, sodium, and chloride ions activity while being used as a biomarker to gauge human health. The Potentiometric-based ion-sensitive membrane systems can be joined with various techniques to make a sensitive device for the fast and early detection of cancer biomarkers and other critical biological compounds.¹³

Cell-based biosensor

The Cell-based sensor is the kind of biosensor, which consumes a living cell as the biospecific detecting element and depends on the ability of the living cell to identify the intracellular and extracellular microenvironment state, physiological parameter, and produces reaction during the collaboration between jolt and cell.¹⁰

Even though entire-cell-based biosensors are not as susceptible to environmental changes as molecular-based ones, cell-based sensing platforms are individually competent in providing functional information associated to sample toxicity or pharmacology by using the cell physiology appraisal, so becoming an important enabling resource for biological research and the pharmaceutical industry. Consequently, their applicative potentials become paramount in environmental and biomedical analysis and their developments are always in the spotlight.¹⁴

Conductimetric biosensor

This type of biosensors has vital advantages: they do not require the use of a reference electrode: they work at low-amplitude alternating voltage, therefore preventing Faraday processes on electrodes: they are insensible to light: and they can be miniaturized and integrated simply using a cheap thin-film standard technology.¹⁵

Calorimetric biosensor

These biosensors measure the change in temperature of the solution containing the analyte following enzyme action and interpret it in terms of the analyte concentration in the solution.

It is based on bioanalytical calorimetry rest upon the fact that most of the biological reactions are exothermic. Mainly the reactions are connected with high molar enthalpy changes (20-100KJ per mol) in a single enzymatic step. An enzyme immobilized electrode coupled to a calorimetric appliance forms a thermometric sensor. These are simple to use procedure-wise, insensible to the optical properties of the sample, and acquire high specificity.^{7, 16}  

Piezoelectric biosensor

 These types of biosensors are considered mass-based biosensors and it is based upon the principle of affinity interaction recording. It serves as an assembly of analytical devices. ¹⁷ 

These biosensors also generate an electrical signal when a mechanical force is applied. In this method, sensing molecules are attached to a piezoelectric surface a mass-to-frequency transducer in which interactions between the analyte and the sensing molecules set up mechanical vibrations that can be translated into an electrical signal proportional to the amount of the analyte. An example of a piezoelectric sensor is quartz crystal micro or nano balance.⁹ 

DNA biosensor

This class of biosensors is used for DNA discovery and is also known as bio-detectors. The purpose is to segregate and determine the potency of single DNA–DNA or antibody-antigen bonds, which in turn helps in detecting and characterizing single molecules of DNA or antigen. It has been shown as a great potential candidate for the next-generation biomedical detection device due to its strong chemical properties and customizable biosensing functions. DNA-based biosensor provides advantages as compared to conventional biosensors, such as wider detection targets, a more long-lasting lifetime, and minor fabrication costs. Furthermore, the inspired DNA structures can manage signal conduction near the biosensor surface, which could drastically improve the presentation of biosensors.^{18, 1} 

Enzyme based biosensor

An enzyme biosensor is a systematic device that combines an enzyme with a transducer in a sort to generate a signal proportional to the target analyte concentration. As compared to the cell-based biosensor, these are more specific sensors. It more rapidly responds due to shorter diffusion paths and they are pricey to produce due to the problem of isolating the enzyme. A Glucose biosensor is typically used biosensor. This type of biosensor always attracts the concentration of researchers due to its fabulous potential for upcoming bioanalysis, high sensitivity, and specificity.^{7, 19}

Immuno biosensor

Immuno-nanosensor is a type of biosensor to identify the development of an immunocomplex using an antibody or antigen as a bioreceptor with the help of nanomaterials. Several proteins such as a superior prostate-specific antigen, platelet-derived growth factor,  carbohydrate antigen,  interferon-γ, carcinoembryonic antigen, antigenic target 6-kDa protein, human chorionic gonadotropin, urinary lactoferrin,  etc., have been created to correlate with the incidence of different diseases. These proteins can be quantitatively analyzed by immuno-nanosensors. ²⁰    

Biomimetric biosensor 

Biomimetic sensors are novel technology with the major purpose to accumulate data and methods. These sensors propose is to diagnose the patients, such as those who suffer from diabetes or neurological diseases, and signify a window for information development related to the human body and wits.²¹ 

Fluorescence biosensor

Currently, one of the most ordinary approaches in the field of optical biosensors is to join the high sensitivity of fluorescence identification in a mixture with the high selectivity provided by the ligand-binding proteins. ²² Furthermore, Fluorescence-based biosensors have been explored for various applications such as medical diagnostics, drug delivery, drug discovery, environmental monitoring, and food safety. Maintenance of the basic principles in analysis, different working strategies can be planned for fluorescence biosensors to identify different analytes. Various parameters can be explored in fluorescence biosensors, for example, fluorescence anisotropy, decay time, energy transfer (radioactive or non-radioactive), quenching efficiency, fluorescence intensity, and quantum yield. ²³  

Surface Plasmon biosensor

These instruments are able of characterizing binding reactions in real-time devoid of labeling necessities. The SPR (Surface Plasmon Resonance) technique is based on the optical measurement of refractive index changes linked with the binding of analyte molecules in a sample to identify molecules immobilized on the SPR sensor.²⁴  Consequently, SPR biosensors have the chief device for the study of interactions of several biological systems from proteins, oligonucleotides, oligosaccharides, and lipids to small molecules, phages, viral particles, and cells in life science and pharmaceutical research.^{25, 26}    

Chemiluminescence based biosensor

Luminescence is the emanation of light from an electronically energized compound returning to the ground state. The source of excitation energy serves as a basis for the classification of the various types of luminescence. Chemiluminescence occurs in the path of some chemical reactions when an electronically excited state is created. Bioluminescence is a particular case of Chemiluminescence occurring in some living organisms and involves a protein, normally an enzyme.^{27, 28} 

Applications of biosensor 

A Biosensor is a diagnostic tool for the detection of an analyte that combines a biological element with a physio-chemical detector element. Consequently, the applications of biosensors are in an extensive variety. This comprises of drug discovery, pathogen detection, disease discovery, environmental monitoring, food quality monitoring, and various more as delineated in Fig-4. A review of the few elected representatives and instances of developed applications of biosensors are described below in fig-4.^{29, 30, 31, 32, 33}

Drug discovery

Different biosensors based on the cells, enzymes, antibodies, synthetic membranes, and whole animal tissues can be engaged in drug development and could lead to new proficient screening systems in the future. The main purpose of biosensors is to detect drug compounds can be considered an essential element of medical progress and testing. Curiosity in biosensor research is determined by the increasing requirement for specific sensors to facilitate fast routine measurements in many fields of analysis. A quite high number of newly developed biosensors are capable of detecting several hundreds of analytes, for example- sugars, enzyme cofactors, and amino acids, which are important for biological systems.

Electrical devices such as electrodes, semiconductors, and optical components are frequently used as transducer elements of biosensors. Few of these have been miniaturized to obtain chip-based sensory systems. These approaches in particular may succeed in drug screening because they allow a high throughput of samples with practical experimental apparatus.³⁴  

Modern attempts and strategies are described and precious approaches are summarized in Table 1.

Table 1: Current examples of bioactive compounds detectable by optical, whole cell, and enzymatic biosensors.

Pathogen detection

Pathogens are transmittable agents that cause disease. They include molecular-scale infectious agents, such as viruses, prions, and microorganisms, such as fungi, protozoans, and bacteria. Airborne, waterborne, and foodborne pathogens penetrate the body during different modes of infection and are responsible for millions of deaths annually worldwide. Some of the mainly general pathogens comprise viruses, such as influenza virus, norovirus, and bacteria, such as E. coli and S. aureus. Pathogens vary in various regards, such as virulence, contagiousness, mode of transmission, and infectious dose. For instance, the world is presently facing a global pandemic related to the COVID-19 virus, for which virulence and infectious dose statistics are still rising. Methodologies for susceptible and quick detection of pathogens in intricate matrices, such as body fluids and aerosols, and on surfaces are critical to the healing of infectious diseases and controlling the growth of the disease.

The methodology used to recognize and enumerate pathogens can be broadly illustrious as immunoassays or DNA-based assays. The use of DNA-based assays, as opposed to immunoassays, depends on different factors, including the period of infection and the accessibility of antibodies and DNA sequence data, such as toxin-producing genes, and viral DNA, in addition to species and strain-selective genes. Immunoassays are omnipresent across medical diagnostics and food protection applications. Pathogens can be recognized during the presence of generated antibodies in an organism, which may be present both during and after infection. In such assays, both the biorecognition element and the target are antibodies. If antibodies are accessible for the pathogen (e.g., anti-E.coli), one can also directly identify the pathogen using immunoassays. 

Pathogen detection via electrochemical biosensor -An electrochemical sensor is an appliance that transforms chemical information into an analytically valuable signal, for instance, the concentration of a particular sample component or total compositional analysis. The electrochemical technique utilized is a distinctive facet of an electrochemical biosensor. Additionally to the electrochemical process, the sample handling approach and sensor signal readout system also give distinguishing aspects of a biosensor-based approach for pathogen detection.^{50, 51}      

Disease detection

In the medical field, biosensors can be used for the discovery and identification of tumors and the measurement of blood glucose concentration in diabetic patients. An extremely useful application of biosensors is the quantitative measurement of the cardiac marker in serum (undiluted), immune-sensor for detection of leukemias, and most latest is quick detection of cancer markers by incorporation of the biochip. The diamond micro-needle electrode is another innovation used for neuro-chemical discovery.  

Techniques comprise immunoaffinity column assay, fluorometric, and enzyme-linked immunosorbent assay used for the detection of cardiovascular disease. These are difficult, time-consuming, and necessitate qualified employees. Biosensors recognized on electric measurement employ biochemical molecular identification for the preferred selectivity with a particular biomarker of curiosity.

Furthermore, the rapid spread of the new severe acute respiratory syndrome coronavirus disease, COVID-19, brought major societal challenges. Significantly, appropriate medical analysis procedures and clinical administration of the disease are developing needs, which must be anchored on novel investigative techniques and devices. New molecular analytical devices relying on nucleic acid augmentation testing have emerged worldwide and are the recent gold standard in COVID-19 identification. However, the necessity for widespread testing methodologies for quick, valuable testing in numerous epidemiological scenarios remains a vital step in the battle against the COVID-19 epidemic. Paper and cellulose-based biosensors can be predominantly related in the pandemic period, for renewability, secure environmental disposal, and the possibility of mass fabrication with sustainable methodologies. ^{52, 53, 54, 32}       

Future aspects

The biosensor is a very essential and promising technique. In the future, these techniques will investigate the developing variety of choices to create precision drugs, instruments, and diagnostics. Biosensor chip technology could be inserted into the body to identify complex blood DNA mutations before any disease signs in the early stages of development. A Biosensor can also be used for constant tracking of implantable equipment. It can observe samples, such as salivary, exhaled condensate breath, minimally invasively in blood and interstitial fluid, using intelligent wristbands when they are fixed into wearable systems. The most important key to the enlargement of a successful biosensor involves a better combination of bio-sensing and bio-fabrication with synthetic biological approaches using either electrochemical or bio-electronic principles. Incessantly, research will be helpful to overcome all challenges with the use of biosensors in cancer. Furthermore, various biosensors used for different kinds of purposes like   nanomaterial-based biosensors, optical biosensors, DNA-based biosensors, electrochemical biosensors, etc, show great attractive prospects, which will be mostly applied in food analysis, clinical diagnosis, process control, pathogen detection, drug discovery and environmental monitoring in the future, etc. ^{55,  56,  57}      

Discussion and Conclusion

In this review paper, we have chiefly focused on various applications of biosensors in detail. First and foremost, we have studied the introduction and basic components of a biosensor and afterward reviewed different types of biosensors, their working, principles, and in brief applications of various biosensors are described. Mainly commercial biosensors developed to date are required to focus on clinical applications. An accurate investigation or diagnosis of a disease is necessary for a successful treatment and improvement of patients suffering from it. Diagnostics techniques must be easy, susceptible, and capable to identify numerous biomarkers that exist at low concentrations in biological fluids. Biosensors can accomplish these necessities.

References

1. Mohanty Saraju P, Kougianos Elias, “Biosensors: A tutorial review”. IEEE Potentials, 2006; 25(2): 35-40. DOI: https://doi.org/10.1109/MP.2006.1649009 
2. Korotkaya. E. V, “Biosensors: Design, classification, and applications in the food industry” Foods Raw Mater, 2014; 2(2):161-171. DOI: https://doi.org/10.12737/5476 
3. Mehrotra P, “Biosensors and their applications-a review” J Oral Biol Craniofac Res, 2016; 6(2):153-159. DOI: http://dx.doi.org/10.1016/j.jobcr.2015.12.002
4. Bhalla N, Jolly P, “Introduction to biosensors: a review” Essays Biochem, 2016; 60(1): 1-8. DOI: 10.1042/EBC20150001
5. Palchetti. I, Mascini.M, “Biosensor Technology: A Brief History” Sensors and Microsystems, 2009; 54(2): 15-23. DOI: https://doi.org/10.1007/978-90-481-3606-3_2 
6. Last accessed on 15.8.2022. https://www.onlinebiologynotes.com/biosensors-components-working-principle-and-types/.
7. Dar SA, Sofi MS, “Biosensors: Components and Applications-A Review” 2018; 414-420. DOI: http://data.conferenceworld.in/OUCIP19MAY18/50.pdf
8. Colomer-Farrarons J, Miribel P, “Portable Bio-Devices: Design of electrochemical instruments from miniaturized to implantable devices” InTech, 2011; DOI: https://doi.org/10.5772/17212 
9. Malhotra S, Verma A, Tyagi N, Kumar V, “Biosensors: Principle, types and applications” IJARIIE, 2017; 3(2): 3639-3644. DOI: https://doi.org/16.0415/IJARIIE-4676 
10. Kaur H, Bhosale A, Shrivastav S, “Biosensors: classification, fundamental characterization and new trends: a review” International Journal of Health Sciences and Research, 2018; 8(6):  315-333
11. Hasan A, Nurunnabi Md, Morshed M, Paul A, Polini A, KuilaT, Hariri MA, Lee Yong-kyu, Jaffa A, “Recent Advances in Application of Biosensors in Tissue Engineering” BioMed Research International, 2014; 18: DOI: http://dx.doi.org/10.1155/2014/307519
12. Adrián Javier , Fernández Fátima, Muriano Alejandro , Obregon Raquel ,Ramón-Azcon Javier, Tort Nuria , and Marco M.-Pilar,“Biosensors for Pharmaceuticals and Emerging Contaminants Based on Novel Micro and Nanotechnology Approaches” Hdb Env Chem, 2009; 5: 47–68. DOI: https://doi.org/10.1007/698_2008_10 .
13. Karimi Maleh Hassan,Orooji Yasin, Karimi Fatemeh, “A critical review on the use of potentiometric based biosensors for biomarkers detection” Biosens. Bioelectron, 2021; 184:113252.  Doi: https://doi.org/10.1016/j.bios.2021.113252 
14. Gheorghiu Mihaela, “A short review on cell-based biosensing: challenges and breakthroughs in biomedical analysis” J Biomed Res, 2021; 35(4): 255-263. Doi: https://doi.org/10.7555/JBR.34.20200128 

15. Dzyadevych. S, Jaffrezic-Renault

16. .N, “6 - Conductometric biosensors” WP, 2014: 153-193. Doi: https://doi.org/10.1533/9780857099167.2.153

17. Danielsson Bengt, “Calorimetric biosensors” J. Biotechnol, 1990; 15(3): 187-200. Doi: https://doi.org/10.1016/0168-1656(90)90026-8
    
    
    

18. Pohanka Miroslav, “Overview of Piezoelectric Biosensors, Immunosensors and DNA Sensors and Their Applications” Materials (Basel), 2018; 11(3):  448.  Doi:10.3390/ma11030448

19. Hua Yu, Ma Jiaming, Li Dachao, and Wang Ridong,“DNA-Based Biosensors for the Biochemical Analysis: A Review” Biosensors (Basel), 2022; 12(3): 183. Doi: https://doi.org/10.3390/bios12030183 

20. Rocchitta Gaia, Spanu Angela, Babudieri Sergio, Latte Gavinella, Madeddu Giordano,     Galleri Grazia, Nuvoli  Susanna, Bagella Paola, Demartis  Maria Ilaria , Fiore Vito , Manetti Roberto, and Serra Pier Andrea, “Enzyme Biosensors for Biomedical Applications: Strategies for Safeguarding Analytical Performances in Biological Fluids” sensors (Basel), 2016; 16(6): 780. Doi: https://doi.org/10.3390/s16060780   

21. Asal Melis , Ozen Ozlem, Sahinler Mert  and Polato ˙Ilker, “Recent Developments in Enzyme, DNA and Immuno-Based Biosensors” Sensors, 2018; 18(6): 1-16. Doi: https://doi.org/10.3390/s18061924

22.  Stroble J.K, Stone R.B, Watkins S.E, “An overview of biomimetic sensor technology” Emerald insight, 2009;  29(2): 112-119. Doi: https://doi.org/10.1108/02602280910936219 

23.  Strianese Maria , Staiano Maria , Ruggiero Giuseppe , Labella Tullio , Pellecchia Claudio , D'Auria Sabato, “Fluorescence-based biosensors” Methods Mol Biol, 2012; 875: 193-216. Doi:  https://doi.org/10.1007/978-1-61779-806-1_9 .

24. Sharma A, Khan  R, Catanante G,  Sherazi TA, Bhand S, Hayat A,   Louis MJ,  “Designed Strategies for Fluorescence-Based Biosensors for the Detection of Mycotoxins” Toxins (Basel), 2018; 10(5): 197. Doi: 10.3390/toxins10050197

25. Rich Rebecca L , Myszka David G,  “Advances in surface plasmon resonance biosensor analysis” Elsevier sci, 2000; 11(1): 54-61. Doi: https://doi.org/10.1016/S0958-1669(99)00054-3 

26. Piliarik Marek , Vaisocherová Hana, Homola Jirí,   “Surface plasmon resonance biosensing” Methods Mol Biol, 2009; 503: 65-88. Doi: https://doi.org/10.1007/978-1-60327-567-5_5 .

27. Dudak Fahriye Ceyda , Boyaci Ismail Hakki, “Rapid and label-free bacteria detection by surface plasmon resonance (SPR) biosensors” Biotechnol j, 2009; 4(7): 1003-1011. Doi: https://doi.org/10.1002/biot.200800316 

28.  Aboul-Enein Hassan Y, Stefan Raluca-Ioana & Staden Jacobus F.Van, “Chemiluminescence-Based (Bio)Sensors — An Overview” Crit Rev Anal Chem, 2010; 29(4): 323-331. Doi: https://doi.org/10.1080/10408349891199338
29. Aboul-Enein Hassan Y, Stefan Raluca-Ioana,  Staden Jacobus F.Van, ZhangXinrong R,    Garcia-Campana Ana M &    Baeyens   Willy R. G, “Recent Developments and Applications of Chemiluminescence Sensors” Crit Rev Anal Chem, 2007; 30(4): 271-289. Doi: https://doi.org/10.1080/10408340008984161 
30. Tetyana Phumlani, Shumbula Poslet Morgan and Njengele-Tetyana Zikhona, “Biosensors: Design, Development and Applications” InTech, 2021;   1-172.  Doi: https://doi.org/10.5772/intechopen.97576 
31. Haleem Abid, Javaid Mohd, Pratap Singh Ravi, Suman Rajiv, Rab Shanay, “Biosensors applications in medical field: A brief review” SI, 2021; 2: 1-10. Doi: https://doi.org/10.1016/j.sintl.2021.100100
32. Yakoh A, Pimpitak U, Rengpipat S, Hirankarn N, Chailapakul O, Chaiyo S, “Paper-based electrochemical biosensor for diagnosing COVID-19: Detection of SARS-CoV-2 antibodies and antige” Biosens. Bioelectron, 2021;176: 1-8.Doi:  http://www.elsevier.com/locate/bios
33. Fatima A, Younas I, Fatima MWA, “An Overview on Recent Advances in Biosensor Technology and its Future Application” Archive, 2022; 13(1): 5-10. Doi: https://doi.org/10.51847/LToGI43ji1

34. Saleem Muhammad, “Biosensors a promising future in measurements” Mater. Sci. Eng, 2013; 51: 1-10. Doi: https://doi.org/10.1088/1757-899X/51/1/012012 

35.  Keusgen M, “Biosensors: new approaches in drug discovery” Commun. Biol, 2002; 89: 433-444. Doi: https://doi.org/10.1007/s00114-002-0358-3 
36. Gambari Roberto, Feriotto Giordana, Rutigliano Cristina, Bianchi Nicoletta, And Mischiati Carlo, “Biospecific Interaction Analysis (BIA) of Low-Molecular Weight DNA-Binding Drugs” J. Pharmacol. Exp. Ther,2000; 294(1): 370–377. Doi: https://doi.org/0022-3565/00/2941-0370$03.00/0 

37. Rothmund M. ,   Schütz Armin , Brecht Andreas , Gauglitz Günter , Berthel Günther  &  Gräfe Dieter Fresenius,  “Label free binding assay with spectroscopic detection for pharmaceutical screening” Anal. Chem., 1997; 359: 15-22. Doi: https://doi.org/10.1007/s002160050529 

38. Seifert Martin , Haindl Stefanie , Hock Bertold, “Development of an enzyme linked receptor assay (ELRA) for estrogens and xenoestrogens” Elsevier sci, 1999; 386(3): 191-199. Doi: https://doi.org/10.1016/S0003-2670(99)00044-6

39. Alterman Mathias,         Sjöbom Hans    ,         Säfsten     Pär  ,             Markgren  Per-Olof,    Danielson    U.Helena  ,       Hämäläinen      Markku  ,    Löfås  Stefan  ,    Hultén   Johan,     Classon    Björn,   Samuelsson    Bertil  ,   Hallberg   Anders,   “P1/P1′ modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays” Eur J Pharm Sci., 2001; 13(2): 203-212. Doi: https://doi.org/10.1016/S0928-0987(01)00109-9 

40.  Keusgen Michael  ,   Jünger  Martina  ,   Krest     Ingo,     J.Schöning Michael,       “Development of a biosensor specific for cysteine sulfoxides” Biosens. Bioelectron, 2003; 18(5- 6): 805-812. Doi: https://doi.org/10.1016/S0956-5663(03)00045-9   

41. Poghossian Arshak,  Jablonski   Melanie  ,  Koch Claudia,  S.Bronder Thomas,  Rolka David,   Wege  Christina,      J. Schöning Michael,  “Field-effect biosensor using virus particles as  scaffolds for enzyme immobilization” Biosens. Bioelectron, 2018; 110: 168-174. Doi: https://doi.org/10.1016/j.bios.2018.03.036

42. Michael Keusgen, “Biosensors: New approaches in drug discovery” Sci. Nat.,2002; 89(10): 433-444. Doi: https://doi.org/10.1007/s00114-002-0358-3 

43. Romani. A,  Minunni  M, Mulinacci  N, Pinelli. P, Vincieri.F. F, Carlo M. Del, and   Mascini M, “Comparison among Differential Pulse Voltammetry, Amperometric Biosensor, and HPLC/DAD Analysis for Polyphenol Determination” J. Agric. Food Chem. 2000;  48(4) : 1197–1203. Doi; https://doi.org/10.1021/jf990767e

44. Catriona Brian R, Hickey Eggins, Toft Stephen A , Zhou  D. Min, “Determination of flavanols in beers with tissue biosensors” Anal. Chim. Acta, 1997; 347(3): 281-288. Doi: https://doi.org/10.1016/S0003-2670(97)00162-1

45. Leech Donal, Rechnitz Garry A, “Crayfish walking leg neuronal biosensor for the detection of pyrazinamide and selected local anesthetics” Anal. Chim. Acta, 1993; 274(1): 25-35. Doi: 10.1016/0003-2670(93)80601-g

46. Melzig Matthias F, Bader Gerd  , Loose Renate, “Investigations of the Mechanism of Membrane Activity of Selected Triterpenoid Saponins” Planta Med, 2001; 67(1): 43-48.
     DOI: https://doi.org/10.1055/s-2001-10632 

47. Garippa Ralph J,  Hoffman Ann F , Gradl Gabriele  , Kirsch Achim,  “[7] - High‐Throughput Confocal Microscopy for β‐Arrestin–Green Fluorescent Protein Translocation G Protein‐Coupled Receptor Assays Using the Evotec Opera” Methods Enzymol, 2006; 414: 99-120. Doi: https://doi.org/10.1016/S0076-6879(06)14007-0

48. Arenas M Yaiza, Cabrerea-Pastor Andrea, Juciute Nora, Mora-Navarro Eloy, Felipo Vicente, “Blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum through ADAM17-TNFR1-NF-κβ pathway” J Neuroinflammation, 2020; 11;17(1) : 269. Doi: https://doi.org/10.1186/s12974-020-01941-y .

49. Zahn Martin  , Renken Joachim  , Seeger Stefan,   “Fluorimetric multiparameter cell assay at the single cell level fabricated by optical tweezers” FEBS Lett, 1999; 443(3): 337-340.  Doi: https://doi.org/10.1016/S0014-5793(98)01693-7

50. Jardemark K, Farre C, Jacobson I, Zare R N, Orwar, “Screening of receptor antagonists using agonist-activated patch clamp detection in chemical separations” Anal. Chem., 1998; 1;70(13): 2468-74. Doi: https://doi.org/10.1021/ac971147k .

51. Cesewski Ellen, N. Johnson Blake, “Electrochemical biosensors for pathogen detection”  Biosens. Bioelectron, 2020; 159: 1-29. Doi: https://doi.org/10.1016/j.bios.2020.112214 
52. Kaya Hüseyin Oğuzhan, E. Cetin Arif  , Azimzadeh Mostafa, Topkaya Seda Nur, “Pathogen detection with electrochemical biosensors: Advantages, challenges and future perspectives” J. Electroanal. Chem, 2021; 882: 1-18. Doi: http://dx.doi.org/10.1016/j.jelechem.2021.114989
53. Raya Monalisa, Raya Asit , Dasha Swagatika , Mishraa Abtar , Acharyb K. Gopinath , Nayaka Sanghamitra , Singh Shikha, “Fungal disease detection in plants: Traditional assays, novel diagnostic techniques and biosensors” Biosens. Bioelectron, 2017; 87: 708-723. Doi: http://dx.doi.org/10.1016/j.bios.2016.09.032
54. Pinheiro Tomás  , Cardoso A. Rita, E. A. Sousa Cristina, C. Marques Ana, Tavares Ana P. M., Matos Ana Miguel, Cruz Maria Teresa, T. C. Moreira Felismina, Martins Rodrigo, Fortunato Elvira, and F. Sales M. Goreti, “Paper-Based Biosensors for COVID-19: A Review of Innovative Tools for Controlling the Pandemic” ACS Omega, 2021; 6:  29268−29290. Doi: https://doi.org/10.1021/acsomega.1c04012
55. Gopinath P. G,  Anitha V. R, and Mastani  S. Aruna, “Microcantilever based Biosensor for Disease Detection Applications” J Med Biol Eng, 2015; 4: 307-311. Doi: doi: 10.12720/jomb.4.4.307-311
56. Vigneshvar Senthilkumaran,  Senthilkumaran Balasubramanian, “Current technological trends in biosensors, nanoparticle devices and biolabels: Hi‐tech network sensing applications” Med. Devices Sens, 2018; 1: 1-14. Doi: https://doi.org/10.1002/mds3.10011

57. Byfield M.P, Abuknesha R. A, “Biochemical aspects of biosensors” Biosens. Bioelectron, 1994; 9(4-5): 373-399.Doi: https://doi.org/10.1016/0956-5663(94)80038-3

58.  T. Nemane  Shraddha, B. Gholve Sachin, G. Bhusnure Omprakash, T. Mule Shrikrishna, V. Ingle Priyanka, “Biosensors: An Emerging Technology in Pharmaceutical Industry” JDDT, 2019; 9(4): 643-647. Doi: http://dx.doi.org/10.22270/jddt.v9i4.3034