Recent Advances in Biosensor Technology: Volume 1 9789815123739, 9789815123753, 9789815123746, 9815123734

Table of contents :
Cover
Title
Copyright
End User License Agreement
Contents
Foreword
Preface
List of Contributors
Nanomaterials for Biosensing Applications
Abhay Dev Tripathi1, Soumya Katiyar1, Avinash K. Chaurasia2 and Abha Mishra1,*
INTRODUCTION
NANOMATERIALS IN BIOSENSING APPLICATION
Carbon Nanostructures
Carbon Nanotubes (CNTs)
Graphene
Nanodiamonds
Organic Nanoparticles As A Biosensor
Dendrimers
Polymeric Nanoparticles
Nanogels
Inorganic Nanoparticles
Quantum Dots
Magnetic Nanoparticles As A Biosensor
Gold Nanoparticles (AuNPs)
Silver Nanoparticles (AgNPs)
THE MAJOR LIMITATION OF NANOMATERIALS
CONCLUSION AND FUTURE PERSPECTIVE
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCE
Carbon-Based Nanomaterials for Sensing Applications
Rakesh Kumar Ameta1,*
INTRODUCTION
CBNMs As Environmental Sensors
CBNMS AS BIOSENSORS
CNT
Graphene Oxide (GO)
Graphene Quantum Dots (GQD)
CBNMs As Electrochemical Sensors For Toxic Metal Ions
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES
Graphene-Based Nanomaterials and Their Sensing Application
Vikash Kumar Vaishnav1,*, Khageshwar Prasad1, Rashmi Yadav1, Amitabh Aharwar2 and Bhupendra Nath Tiwary1
INTRODUCTION
HISTORY OF GRAPHENES
CHARACTERIZATION OF GRAPHENE
FUNCTION OF GRAPHENE
SYNTHESIS OF GRAPHENE
Top-Down
Radiation Based Method
Intercalation of Graphite
Chemical Reduction of Graphite Oxide
Bottom-Up
Chemical Vapor Deposition (CVD) Methods
Pyrolysis or Solvothermal
Dry Ice Synthesis
Epitaxial Growth Onto Sic
Thermal CVD Technique
Plasma-Enhanced CVD Technique
Other Synthesis Techniques
Thermal Decomposition of Ruthenium Crystal
Thermal Decomposition of SIC
Unzipping of CNTs
Organic Synthesis Technique
APPLICATION OF GRAPHENE-BASED NANOMATERIAL
Application of Graphene-based Nanomaterials For Catalysis
Energy-Related Reactions
Water Splitting
Water Splitting With Photocatalysis
Applications of Graphene-based Nanomaterials For Sensing
Applications of Graphene-Based Nanomaterials In Healthcare
Bioimaging
Drug Delivery
Photothermal Therapy
Treatment of Cancer Using Graphene Oxide
Applications of Nanomaterials Based on Graphene in the Optical and Optoelectronic Fields
Electrodes with Transparent Conductivity
Phototransistors and Photodetectors
Environmental Applications Of Carbon-based Nanomaterials
CONCLUSION
CONSENT FOR PUBLICATON
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
SPR-Based Biosensors in the Diagnostics and Therapeutics
Anjali Bhargav1 and Neeraj Kumar Rai*, 1
INTRODUCTION
FUNDAMENTALS OF SPR TECHNIQUE
APPLICATIONS OF SURFACE PLASMONIC RESONANCE
Surface Enhanced Raman Scattering (SERS)
Fluorescence Enhancement
Surface Plasmon Resonance imaging (SPRi)
SPR - Electrogenerated Chemiluminescence (SPR-ECL)
SPR - Biolayer Interferometry (SPR-BLI)
SPR IN DIAGNOSTICS AND DISEASE DETECTION
SPR in Viral Disease Detection
SPR in Molecular Sensing
SPR in the study of Live Cell
SPR in Healthcare Testing
SPR in Cancer Diagnosis
SPR in Detection of Infectious Disease
CONCLUSION
CONSENT FOR PUBLICATON
CONFLICT OF INTEREST
ACKNOWLEDGMENT
REFERENCES
Implication of Biosensors For Cancer Diagnosis And Therapeutics
Shubha Gupta1, Navitra Suman2 and Neeraj Kumar Rai2,*
INTRODUCTION
Biomarkers of Cancer
Biosensors and Cancer
Biosensor recognition elements
Enzymes
Nucleic Acids
Biosensor Transducer
Optical Biosensors
Mass-Based Biosensors
Calorimetric Biosensors
Biosensors and Nanotechnology
CONCLUSION
CONSENT FOR PUBLICATON
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Recent Advances in the Application of Nano-Biosensor in Tissue Engineering
Soumya Katiyar1, Shikha Kumari1, Ritika Singh2, Abhay Dev Tripathi1, Divakar Singh1, Pradeep K. Srivastava1 and Abha Mishra1,*
INTRODUCTION
Bioanalytes
Bioanalyte receptor system
Transducer
Signal Processing Unit
NEED FOR NANOBIOSENSORS IN THE FIELD OF TISSUE ENGINEERING
NANOMATERIALS USED FOR BIOSENSING APPLICATIONS IN TE
Carbon-Based Nanomaterials
Graphene-Based Biosensors
Quantum Dots
Metallic Nanomaterials
Magnetic Nanomaterials
INTRODUCTION OF NANOBIOSENSORS
Classification of Biosensors Based on Biosensing Element
Classification Of Biosensors Based On Transducers
Types Of Nanobiosensors And Their Application In TE
Quantum-Dot Based Nano-Biosensors
Carbon Nanotubes-Based Nano-Biosensors
Microfluidic Based Nanobiosensors
Lab-on-a-Chip
Nanowire (NW)-Based Biosensors
Nanorods-Based Biosensors
Gold Nanoparticle-Based Nano-Biosensors
Silver Nanoparticles (AgNPs)-Based Nano-Biosensors
Metal Oxide-Based Nanoparticles
THE MAJOR CHALLENGES OF NANOBIOSENSORS AND FUTURE DIRECTIONS
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES
DNA Biosensors: Effective Tool in Biotechnology
Arpita Mishra1, Avanish Kumar Shrivastav2,* and Vivek Kumar Chaturvedi3
INTRODUCTION
Types of DNA-Based Biosensors
Aptamer Based
Electrochemical Based
Hybridization Based
Fluorescent Based Biosensors
Application of DNA Sensors
Food Quality Analysis
Detection of Environmental Contaminants
Pharmaceutical Applications
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Biosensors for the Diagnosis and Therapeutics of Cardiovascular Diseases
Avanish Kumar Shrivastav1, Dhitri Borah2,* and Sudeshna Mandal3
INTRODUCTION
Biosensor's Distinct Characteristics in Healthcare Services
Biomarkers for Cardiovascular Diseases
Biosensor
Optical Biosensor
Piezoelectric/Acoustic Biosensor
Electrochemical Biosensor
Variety of Diagnostic Biosensors for Cardiovascular Diseases
Triage Cartridge
RAMP Cardiac Marker System
CONCLUDING REMARK
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Biosensors for Food Analysis, Food Additives, Contaminants and Packaging
Amitabh Aharwar1, Khageshwar Prasad2, Annpurna Sahu2 and Dharmendra Kumar Parihar2,*
INTRODUCTION
BIOSENSOR
Biosensor Principle
Adsorption
Entrapment
Covalent Bonding
Cross-Linking
Basic Attributes of Biosensors
Limit of Detection
Specificity
Dynamic response
Lifetime
Sensitivity
Linearity
Biosensor classification
Optically Based Biosensors
Potentiometric Biosensor
Thermal Biosensors
Piezoelectric Biosensors
Amperometric Biosensors
Enzyme Biosensors
Immunosensor
Microbial Sensors
Biosensor Based on Nucleic Acids
BIOSENSORS FOR FOOD QUALITY AND ADDITIVES CONTROL
BIOSENSOR FOR FOOD CONTAMINATION DETECTION
BIOSENSORS FOR FOOD PACKAGING
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
ACKNOWLEDGEMENT
REFERENCES
Biosensors For Monitoring Heavy Metals Contamination In The Wastewater
Gaurav Kumar Pandit1, Ritesh Kumar Tiwari1, Ashutosh Kumar1, Veer Singh2, Nidhi Singh3 and Vishal Mishra2,*
INTRODUCTION
Biosensors
Types of Biosensors and Their Applications
Bacterial Biosensor
Enzyme Based Biosensors
Optical Fibre Biosensor
DNA Enzyme Based Biosensor
Electrochemical Biosensors
Combining Nanotechnology with Biosensors
Piezoelectric Biosensor
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Subject Index
Back Cover

Citation preview

Recent Advances in Biosensor Technology (Volume 1) Edited by Vivek K. Chaturvedi

Department of Gastroenterology Institute of Medical Sciences Banaras Hindu University Varanasi-221005 India

Dawesh P. Yadav

Department of Gastroenterology Institute of Medical Sciences Banaras Hindu University Varanasi-221005 India

& Mohan P. Singh

Centre of Biotechnology University of Allahabad Prayagraj-211002 India

Recent Advances in Biosensor Technology (Vol. 1) Editors: Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh ISBN (Online): 978-981-5123-73-9 ISBN (Print): 978-981-5123-74-6 ISBN (Paperback): 978-981-5123-75-3 © 2023, Bentham Books imprint. Published by Bentham Science Publishers Pte. Ltd. Singapore. All Rights Reserved. First published in 2023.

BSP-EB-PRO-9789815123739-TP-216-TC-10-PD-20230410

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CONTENTS FOREWORD ........................................................................................................................................... i PREFACE ................................................................................................................................................ ii LIST OF CONTRIBUTORS .................................................................................................................. iii CHAPTER 1 NANOMATERIALS FOR BIOSENSING APPLICATIONS ................................... Abhay Dev Tripathi, Soumya Katiyar, Avinash K. Chaurasia and Abha Mishra INTRODUCTION .......................................................................................................................... NANOMATERIALS IN BIOSENSING APPLICATION .......................................................... Carbon Nanostructures ............................................................................................................ Carbon Nanotubes (CNTs) ..................................................................................................... Graphene ................................................................................................................................. Nanodiamonds ........................................................................................................................ Organic Nanoparticles As A Biosensor .................................................................................. Dendrimers .............................................................................................................................. Polymeric Nanoparticles ......................................................................................................... Nanogels ................................................................................................................................. Inorganic Nanoparticles .......................................................................................................... Quantum Dots ......................................................................................................................... Magnetic Nanoparticles As A Biosensor ................................................................................ Gold Nanoparticles (AuNPs) .................................................................................................. Silver Nanoparticles (AgNPs) ................................................................................................. THE MAJOR LIMITATION OF NANOMATERIALS ............................................................ CONCLUSION AND FUTURE PERSPECTIVE ....................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCE .................................................................................................................................. CHAPTER 2 CARBON-BASED NANOMATERIALS FOR SENSING APPLICATIONS ......... Rakesh Kumar Ameta INTRODUCTION .......................................................................................................................... CBNMs As Environmental Sensors ........................................................................................ CBNMS AS BIOSENSORS ........................................................................................................... CNT ......................................................................................................................................... Graphene Oxide (GO) ............................................................................................................. Graphene Quantum Dots (GQD) ............................................................................................ CBNMs As Electrochemical Sensors For Toxic Metal Ions .................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGMENTS .............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 3 GRAPHENE-BASED NANOMATERIALS AND THEIR SENSING APPLICATION ....................................................................................................................................... Vikash Kumar Vaishnav, Khageshwar Prasad, Rashmi Yadav, Amitabh Aharwarand Bhupendra Nath Tiwary INTRODUCTION .......................................................................................................................... HISTORY OF GRAPHENES ....................................................................................................... CHARACTERIZATION OF GRAPHENE .................................................................................

1 1 4 5 5 7 8 9 10 11 12 13 13 14 16 17 18 19 20 20 20 20 30 30 33 34 34 34 35 35 38 38 38 38 39 45 45 46 47

FUNCTION OF GRAPHENE ....................................................................................................... SYNTHESIS OF GRAPHENE ...................................................................................................... Top-Down ............................................................................................................................... Radiation Based Method ............................................................................................... Intercalation of Graphite .............................................................................................. Chemical Reduction of Graphite Oxide ........................................................................ Bottom-Up .............................................................................................................................. Chemical Vapor Deposition (CVD) Methods ............................................................... Pyrolysis or Solvothermal ............................................................................................. Dry Ice Synthesis ........................................................................................................... Epitaxial Growth Onto Sic ............................................................................................ Thermal CVD Technique ............................................................................................... Plasma-Enhanced CVD Technique ............................................................................... Other Synthesis Techniques .................................................................................................... Thermal Decomposition of Ruthenium Crystal ............................................................. Thermal Decomposition of SIC ..................................................................................... Unzipping of CNTs ........................................................................................................ Organic Synthesis Technique ........................................................................................ APPLICATION OF GRAPHENE-BASED NANOMATERIAL ............................................... Application of Graphene-based Nanomaterials For Catalysis ................................................ Energy-Related Reactions ............................................................................................. Water Splitting .............................................................................................................. Water Splitting With Photocatalysis ............................................................................. Applications of Graphene-based Nanomaterials For Sensing ................................................ Applications of Graphene-Based Nanomaterials In Healthcare ............................................. Bioimaging .................................................................................................................... Drug Delivery ................................................................................................................ Photothermal Therapy .................................................................................................. Treatment of Cancer Using Graphene Oxide ............................................................... Applications of Nanomaterials Based on Graphene in the Optical and Optoelectronic Fields Electrodes with Transparent Conductivity .................................................................... Phototransistors and Photodetectors ............................................................................ Environmental Applications Of Carbon-based Nanomaterials ............................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATON .................................................................................................. CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

48 49 50 51 51 51 52 52 52 52 53 53 53 53 53 54 54 54 57 57 57 58 59 59 61 61 62 63 64 64 64 65 65 66 66 66 66 66

CHAPTER 4 SPR-BASED BIOSENSORS IN THE DIAGNOSTICS AND THERAPEUTICS ... Anjali Bhargav and Neeraj Kumar Rai INTRODUCTION .......................................................................................................................... FUNDAMENTALS OF SPR TECHNIQUE ................................................................................ APPLICATIONS OF SURFACE PLASMONIC RESONANCE .............................................. Surface Enhanced Raman Scattering (SERS) ......................................................................... Fluorescence Enhancement ..................................................................................................... Surface Plasmon Resonance imaging (SPRi) ......................................................................... SPR - Electrogenerated Chemiluminescence (SPR-ECL) ...................................................... SPR - Biolayer Interferometry (SPR-BLI) ............................................................................. SPR IN DIAGNOSTICS AND DISEASE DETECTION ............................................................ SPR in Viral Disease Detection ..............................................................................................

78 78 81 84 84 84 84 85 86 87 87

SPR in Molecular Sensing ...................................................................................................... SPR in the study of Live Cell ................................................................................................. SPR in Healthcare Testing ...................................................................................................... SPR in Cancer Diagnosis ........................................................................................................ SPR in Detection of Infectious Disease .................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATON .................................................................................................. CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGMENT ................................................................................................................ REFERENCES ............................................................................................................................... CHAPTER 5 IMPLICATION OF BIOSENSORS FOR CANCER DIAGNOSIS AND THERAPEUTICS .................................................................................................................................... Shubha Gupta, Navitra Suman and Neeraj Kumar Rai INTRODUCTION .......................................................................................................................... Biomarkers of Cancer ............................................................................................................. Biosensors and Cancer ............................................................................................................ Biosensor recognition elements .............................................................................................. Enzymes .................................................................................................................................. Nucleic Acids .......................................................................................................................... Biosensor Transducer .............................................................................................................. Optical Biosensors .................................................................................................................. Mass-Based Biosensors .......................................................................................................... Calorimetric Biosensors .......................................................................................................... Biosensors and Nanotechnology ............................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATON .................................................................................................. CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 6 RECENT ADVANCES IN THE APPLICATION OF NANO-BIOSENSOR IN TISSUE ENGINEERING ....................................................................................................................... Soumya Katiyar, Shikha Kumari, Ritika Singh, Abhay Dev Tripathi, Divakar SinghPradeep K. Srivastava and Abha Mishra INTRODUCTION .......................................................................................................................... Bioanalytes .............................................................................................................................. Bioanalyte receptor system ..................................................................................................... Transducer ............................................................................................................................... Signal Processing Unit ............................................................................................................ NEED FOR NANOBIOSENSORS IN THE FIELD OF TISSUE ENGINEERING ............. NANOMATERIALS USED FOR BIOSENSING APPLICATIONS IN TE ......................... Carbon-Based Nanomaterials ................................................................................................. Graphene-Based Biosensors ................................................................................................... Quantum Dots ......................................................................................................................... Metallic Nanomaterials ........................................................................................................... Magnetic Nanomaterials ......................................................................................................... INTRODUCTION OF NANOBIOSENSORS ....................................................................... Classification of Biosensors Based on Biosensing Element ................................................... Classification Of Biosensors Based On Transducers .............................................................. Types Of Nanobiosensors And Their Application In TE ....................................................... Quantum-Dot Based Nano-Biosensors .........................................................................

88 89 90 91 92 92 93 93 93 93 97 98 99 100 101 101 102 102 104 104 105 105 107 107 107 107 107 112 113 114 114 114 115 116 118 121 122 123 124 125 126 127 128 131 131

Carbon Nanotubes-Based Nano-Biosensors ................................................................. Microfluidic Based Nanobiosensors ............................................................................. Lab-on-a-Chip ............................................................................................................... Nanowire (NW)-Based Biosensors ................................................................................ Nanorods-Based Biosensors ......................................................................................... Gold Nanoparticle-Based Nano-Biosensors ................................................................. Silver Nanoparticles (AgNPs)-Based Nano-Biosensors ............................................... Metal Oxide-Based Nanoparticles ................................................................................ THE MAJOR CHALLENGES OF NANOBIOSENSORS AND FUTURE DIRECTIONS ... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGMENTS .............................................................................................................. REFERENCES ...............................................................................................................................

131 132 132 133 133 134 134 134 135 136 137 137 138 138

CHAPTER 7 DNA BIOSENSORS: EFFECTIVE TOOL IN BIOTECHNOLOGY ...................... Arpita Mishra, Avanish Kumar Shrivastav, and Vivek Kumar Chaturvedi INTRODUCTION .......................................................................................................................... Types of DNA-Based Biosensors ........................................................................................... Aptamer Based .............................................................................................................. Electrochemical Based .................................................................................................. Hybridization Based ...................................................................................................... Fluorescent Based Biosensors ...................................................................................... Application of DNA Sensors .................................................................................................. Food Quality Analysis ................................................................................................... Detection of Environmental Contaminants ................................................................... Pharmaceutical Applications ........................................................................................ CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

147

CHAPTER 8 BIOSENSORS FOR THE DIAGNOSIS AND THERAPEUTICS OF CARDIOVASCULAR DISEASES ........................................................................................................ Avanish Kumar Shrivastav, Dhitri Borah, and Sudeshna Mandal INTRODUCTION .......................................................................................................................... Biosensor's Distinct Characteristics in Healthcare Services ................................................... Biomarkers for Cardiovascular Diseases ................................................................................ Biosensor ................................................................................................................................. Optical Biosensor .......................................................................................................... Piezoelectric/Acoustic Biosensor .................................................................................. Electrochemical Biosensor ............................................................................................ Variety of Diagnostic Biosensors for Cardiovascular Diseases ............................................. Triage Cartridge ........................................................................................................... RAMP Cardiac Marker System ..................................................................................... CONCLUDING REMARK ........................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

147 148 148 150 151 152 152 152 153 155 156 156 156 156 156 163 163 164 166 167 169 170 170 171 172 172 174 174 174 174 174

CHAPTER 9 BIOSENSORS FOR FOOD ANALYSIS, FOOD ADDITIVES, CONTAMINANTS AND PACKAGING ................................................................................................................................. Amitabh Aharwar, Khageshwar Prasad, Annpurna Sahu and Dharmendra Kumar Parihar INTRODUCTION .......................................................................................................................... BIOSENSOR ................................................................................................................................... Biosensor Principle ................................................................................................................. Adsorption ..................................................................................................................... Entrapment .................................................................................................................... Covalent Bonding .......................................................................................................... Cross-Linking ................................................................................................................ Basic Attributes of Biosensors ................................................................................................ Limit of Detection .......................................................................................................... Specificity ...................................................................................................................... Dynamic response ......................................................................................................... Lifetime .......................................................................................................................... Sensitivity ...................................................................................................................... Linearity ........................................................................................................................ Biosensor classification .......................................................................................................... Optically Based Biosensors ........................................................................................... Potentiometric Biosensor .............................................................................................. Thermal Biosensors ....................................................................................................... Piezoelectric Biosensors ............................................................................................... Amperometric Biosensors ............................................................................................. Enzyme Biosensors ........................................................................................................ Immunosensor ............................................................................................................... Microbial Sensors ......................................................................................................... Biosensor Based on Nucleic Acids ................................................................................ BIOSENSORS FOR FOOD QUALITY AND ADDITIVES CONTROL ................................. BIOSENSOR FOR FOOD CONTAMINATION DETECTION ............................................... BIOSENSORS FOR FOOD PACKAGING ................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 10 BIOSENSORS FOR MONITORING HEAVY METALS CONTAMINATION IN THE WASTEWATER ............................................................................................................................ Gaurav Kumar Pandit, Ritesh Kumar Tiwari, Ashutosh Kumar, Veer Singh, Nidhi Singh and Vishal Mishra INTRODUCTION .......................................................................................................................... Biosensors ............................................................................................................................... Types of Biosensors and Their Applications .......................................................................... Bacterial Biosensor ....................................................................................................... Enzyme Based Biosensors ............................................................................................. Optical Fibre Biosensor ................................................................................................ DNA Enzyme Based Biosensor ...................................................................................... Electrochemical Biosensors .......................................................................................... Combining Nanotechnology with Biosensors ...............................................................

178 178 180 180 181 181 182 182 182 182 182 182 182 183 183 183 183 184 185 185 186 186 186 187 187 187 189 191 195 196 196 196 196 196

203 203 204 205 206 206 206 206 207 207

Piezoelectric Biosensor ................................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ...............................................................................................................................

208 208 208 208 208 209

SUBJECT INDEX ................................................................................................................................. 212

i

FOREWORD Recently, there has been a tremendous surge in the research and development of nanoscience and nanotechnology, especially in precisely engineering the size, shape, and composition. A plethora of novel nanomaterials have been developed that possess excellent intrinsic properties of absorbance, fluorescence, chemiluminescence and catalysis. These properties are being harnessed to realize the actual potential of nanotechnology for several applications, such as electronics, optical, nanomedicine, drug delivery, catalysis and biosensing. The use of nanomaterials in developing biosensors holds special promise due to their indispensable role in clinical diagnosis, biomolecule engineering, cancer detection, and sensing of bacteria, viruses, pathogens, and toxic metabolites. Additionally, incorporating suitable nanoparticles has also led to the construction of new biosensors with improved detection ability and ease of handling. Signal transduction-based biosensing technologies incorporating nanoparticles have shown their utility for the multiplexed detection of samples available in extremely low concentrations. Although nanotechnology-based biosensing employs several methodologies, several of these could be merged into the form of a portable “lab-on-a-chip” device that would be capable of running multiple analyses. The readout of such devices could be integrated with cell phones and thus shared with doctors and clinicians. Personalized medicine is another emerging area where nanotechnology could be of tremendous application. Nanotechnology-enabled wearable devices are another such kind that could provide the analysis of essential ions, biomarkers, glucose, and other biomolecules in the blood. The obtained database would be recorded on a microchip, which could be shared as and when required. Such innovations are expected to be an integral part of the future biosensing technologies that would better predict an individual's health state. Considering the above discussion on biosensing, this book is very timely and includes relevant background and the most recent advancements in the field. Graphene and carbon-based nanomaterials produce excellent biosensing platforms; therefore, a comprehensive analysis of their applications has been covered in this book. Other areas, such as heavy metal detection from contaminated wastewater and COVID-19 detection using nanotechnologies, have also been given significant attention. Nutrition, food contamination, and food packaging are other growing areas; producing nanotechnology-based innovations has also found a place in this book. A chapter is also dedicated to the role of biosensing technology in tissue engineering. This book is a must-read for researchers engaged in basic and clinical research related to biosensing technologies. The editors of this book are learned academicians and have produced this book very thoughtfully to provide readers with comprehensive information on biosensor technologies.

Sanjay Singh National Institute of Animal Biotechnology Hyderabad – 500032 Telangana India

ii

PREFACE A biosensor is a potential device that covers medical, agricultural, economical, industrial, and medical applications. Over the past few decades, glucose biosensors have emerged as the most acceptable and reliable biosensors; they are inexpensive, fast, and reliable. Biosensors also play a very promising role in detecting and managing COVID-19 cases worldwide. It is notable that modernization, industrialization, and environmental damage have greatly impacted human lives over the past few decades and led to major health concerns. Nowadays, even after exhausting several resources to prevent and treat chronic diseases, the human world bears the never-ending global burden of diseases. In recent years, the development of biosensors has significantly influenced the healthcare sector due to the promising role of biosensors in healthcare management. Biosensors work on the principle of converting a biochemical signal to optical or electrical signals. Signal transduction and its performance depend upon the selection of materials and interaction in biosensors. The application of biosensors is not restricted to detecting, diagnosing, and treating a myriad of chronic diseases; it extends toward monitoring and managing patient health. Therefore, biosensor-based therapies have emerged as possible and crucial approaches to delivering point-of-care diagnostics that match and surpass conventional standards regarding specificity, sensitivity, time, response, accuracy, and cost. In this book, considering the growing number of cancer cases and fatalities due to late illness detection worldwide, we have covered several biosensors and biomarkers as possible tools for early cancer detection. In addition, this book focuses on many types of nanomaterials, such as gold nanoparticles, quantum dots, polymeric nanoparticles, carbon nanotubes, nanodiamonds, and graphene nanostructured materials, which are currently being utilized in biosensors for clean and healthy environments. The study includes the fundamental as well as modern biosensors and their sensitivity and specificity; it also sheds light on their significant applications with attractive prospects in different interdisciplinary fields. This book comprises several new efficient techniques for developing biomaterials to accelerate wound healing and bone tissue engineering. It would interest readers in the areas of health, agriculture, food, industries, and biomedical sciencesrelated research. Due to its quality content, this book will cater to the academic needs of a long range of readers. Vivek Kumar Chaturvedi Department of Gastroenterology Institute of Medical Sciences Banaras Hindu University Varanasi-221005 India

Dawesh P. Yadav Department of Gastroenterology Institute of Medical Sciences, Banaras Hindu University Varanasi-221005 India & Mohan P. Singh Centre of Biotechnology Institute of Interdisciplinary Studies, University of Allahabad Prayagraj-211002 India

iii

List of Contributors Abha Mishra

School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University, Varanasi, India

Annpurna Sahu

Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India

Arpita Mishra

Department of Life Sciences, Kristu Jayanti College, Bengaluru, India

Amitabh Aharwar

Government College Harrai, Chhindwara, Madhya Pradesh, India

Avanish Kumar Shrivastav

Department of Biotechnology, Delhi Technological University, Delhi, India

Anjali Bhargav

Central University of South Bihar, Gaya, India

Ashutosh Kumar

Department of Botany, Patna University, Patna, India

Abhay Dev Tripathi

School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University, Varanasi, India

Avinash K.Chaurasia

School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India

Bhupendra Nath Tiwary

Department of Biotechtechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur,C.G., India

Dhitri Borah

Department of Zoology, Biswanath College, Biswanath Chariali, Assam, India

Dharmendra Kumar Parihar

Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India

Gaurav Kumar Pandit

Department of Botany, Patna University, Patna, India

Khageshwar Prasad

Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India

Neeraj Kumar Rai

Central University of South Bihar, Gaya, India

Navitra Suman

Department of Biotechnology, Central University of South Bihar Gaya,

Nidhi Singh

Centre of Bioinformatics, University of Allahabad, Prayagraj, India

Rakesh Kumar Ameta

Sri M M Patel Institute of Sciences and Research, Kadi Sarva Vishwavidhyalaya, Gandhinagar, Gujarat, India

Rashmi Yadav

Department of Biotechtechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur,C.G., India

Ritika Singh

School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India.

Ritesh Kumar Tiwari

Department of Botany, Patna University, Patna, India

Soumya Katiyar

School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University, Varanasi, India

Shubha Gupta

College of Medical Technology and Allied Health Sciences Sanjay Gandhi Post Graduate, Institute of Medical Sciences Lucknow, Uttar Pradesh, India

iv Shikha Kumari

School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, India

Sudeshna Mandal

Department of Zoology, Visva-Bharati, West Bengal, India

Vikash Kumar Vaishnav

Department of Biotechtechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur,C.G., India

Vivek Kumar Chaturvedi

Department of Gastroenterology, Banaras Hindu University, Varansi, India

Vishal Mishra

School of Biochemical Engineering, Indian Institute of Technology, Varanasi, India

Veer Singh

School of Biochemical Engineering, Indian Institute of Technology, Varanasi, India

Recent Advances in Biosensor Technology, 2023, Vol. 1, 1-29

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CHAPTER 1

Nanomaterials for Biosensing Applications Abhay Dev Tripathi1, Soumya Katiyar1, Avinash K. Chaurasia2 and Abha Mishra1,* School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, India 2 School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi – 221005, India 1

Abstract: A biosensor is a device that detects the presence of analytes with its biological receptor entity, having unique specificities corresponding to their analytes. Most of these analytes are usually physical in nature, such as DNA, proteins, antibodies, and antigens, but they may also be simple compounds, including glucose, H2O2, toxins, and so on. Biosensors’ significance rises in providing real-time quantitative and qualitative information on analyte composition. The sensing mechanism involves the transduction of target binding interactions into optical, electrochemical signals, etc ., which can be amplified and detected. Nanomaterials (NMs) have shown significant potential in biological sensing—these allow close interactions with target biomolecules due to their extremely small size and suitable surface modifications. Nanomaterials appear to be potential possibilities because of their capacity to immobilize a greater number of bioreceptor units in confined devices and even act as a transduction element, allowing for enhanced sensitivity and reduced detection limits down to specific molecules. Nanomaterials have been widely used for in vitro detection of disease-related molecular biomarkers and imaging, contrasts to map out the distribution of biomarkers in vivo. This chapter summarizes nanomaterials such as gold nanoparticles, quantum dots, polymeric nanoparticles, carbon nanotubes, nanodiamonds, and graphene nanostructured materials that are currently being researched or utilized as biosensors.

Keywords: Biosensors, Carbon nanostructures, Graphene nanostructure, Nanodiamonds, Nanomaterials, Quantum dots. INTRODUCTION Nanomaterials (NMs) have piqued the interest of many people because of the increasing preference to regulate highly favoured molecular systems not only in Corresponding author Abha Mishra: Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India; E-mail: [email protected] *

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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the human body but also in the environment. The interface of nanomaterials with bioactive molecules such as proteins, enzymes, and nucleic acid has arisen as a multidisciplinary area described as “nanotechnology” which refers to the scientific ways by which nanoparticles or nanomaterials are integrated to generate instruments for investigating biological mechanisms [1]. According to the European Commission's 2011 suggestion, nanomaterials (NMs) “are a natural, incidental, or manufactured material containing particles, in an unbound state, as an aggregate, or as an agglomerate, and where, for 50% or more of the particles in the number size distribution, one or more external dimensions are in the size range 1 nm-100 nm” [2]. NMs have distinctive characteristics, including a high specific surface/volume ratio, high sensitivity, excellent electrical properties, and outstanding magnetic and catalytic capabilities, among several others [3]. Adsorption and catalytic activity are very efficient due to active binding sites and an abundant supply of reactive surface functional groups of NMs. As a result, NMs may be employed in a variety of industries, including biosensors, medicines, cosmetics, agriculture, and energy, among others [4]. The increased total surface area of all nanomaterials allows for the immobilization of a more significant number of bio-recognition units. Nano-biochip materials, nanoscale biocompatible materials, nanomotors, nanocomposites, interface biomaterials, nano biosensors, and nano-drug-delivery platforms offer immense potential for industrial, security, food, forensic analysis, and therapeutic applications. NMs are classified into three types depending on the materials used in their production, including (i) carbon-based nanostructures (e.g., Carbon nanotubes or CNTs, Graphene, Nanodiamonds, Fullerenes, etc.), (ii) organic (e.g., Quantum dots, Nanofilms, Nanogels, Dendrimers, etc.) or (iii) inorganic (e.g., Magnetic nanoparticles, Ag/Au nanoparticles, Nanoshells, Nanowires, etc.). Carbon-based nanostructures (such as carbon nanotubes or graphene) seem to be the most often employed NMs in biological investigations due to their diverse surface properties, and electrical and optical properties [5]. Among metallic NPs, Gold NPs are promising candidates because of their excellent oxidative stability and low toxic effects as contrasted to others, such as Ag, which oxidize and demonstrate cytotoxicity in vivo [6]. The large specific surface area of all NMs allows for the immobilization of an increased number of biorecognition units. Nevertheless, one of several ongoing hurdles is the immobilization technique employed to bind the specific analyte intimately onto such nanostructured materials. As a consequence, one of the most important elements in constructing a via ble biosensing system is the approach utilized to encapsulate the enzymes. The elements of NMs appropriateness in better transducer circuits are the size and shape-based energy of system distributions. For example, nanorods (NRs), nanotubes (NTs) or

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cylindrical architectures facilitate many contacts simultaneously at the same time, decreasing the overall reaction time and even expense. In this manner, even little changes in the typical reaction might be efficiently noticed. A biological or biomimetic receiver element with distinct specificities toward related bioanalytics defines a biosensor system. Over the past ten years, substantial work has been spent on pioneering and continuing to develop biosensors with better specificity, responsiveness, affordability, simplicity, and detection time accuracy. In summary, a biosensing system is composed of a selective bioreceptor element (DNA, peptides, cells, aptamers, etc.) for analyte acquisition, a physical transducer (e.g., optical, electrochemical, thermal, acoustic, etc.), and signal processing unit for the electronic assessment of the accompanying interactions. Among the most essential difficulties in biosensing systems is achieving excellent sensitivity while maintaining an incredibly simple format to use, and the selection of an appropriate biological recognition interface is vital to this goal. Nanomaterials, like most other technical segments, have proved their inherent suitability for biological sensing applications. The main purpose of incorporating NMs into a biosensing operation is to optimize and improve responsiveness with the lowest detection limit in the shortest period. Due to their fast reaction times, nano biosensors are becoming more desirable for fast and real-time analyte monitoring and identification. Minimal LOD biosensors are applied to detect bioanalytics at trace amounts or volumes. The LOD is the lowest analyte concentration that a biosensing unit can recognize but not quantify, meanwhile, the LOQ is the lowest analyte concentration that a biosensor can quantify with therapeutic high precision and specificity. The appropriate employment of such nanostructured devices resulted in demonstrably improved performances, higher efficacy with improved sensitivities, and a lower sample amount requirement. Approaches towards engineering the NMs for a predictable output by manipulation of their interacting coordinates are presently being rapidly optimized for biosensing applications. The final attribute of NMs' usage in biosensing is unquestionably their large surface area, which confers stronger surface functionalization capacities, allowing for the tracking of any stimulus of the reactions in biological and environmental settings. The following surface modification methods are significant for attaching bio-physiological constituents to NM surfaces, including thiol-based NM, streptavidin-biotin association, π-π interactions, and EDC-NHS reactions. The foremost objective of this chapter is to discuss an assessment of developments in the fields of innovative NM-based biosensor systems. We explain the production of carbon-based nanostructured materials, metals/metal oxides, and nanoparticle-based sensor systems, as well as their current and future applications for accurate and consistent monitoring of bioanalytics with higher

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sensitivity and specificity. Additionally, we identify the limitations related to many of these NMs in order to encourage widespread interest from researchers in the fabrication of novel nanomaterial-based biosensor devices. NANOMATERIALS IN BIOSENSING APPLICATION Nanomaterials as a biosensing tool have shown great potential as these allow close interactions with target biomolecules due to their nanostructured size and their capacity to immobilize a greater number of bioreceptor units in confined devices and suitable surface modifications (Fig. 1).

Fig. (1). Schematic representation for a biosensor using nanomaterials and nanostructures: Cytosensors, Nanoparticle tagged DNA/RNA for detection of several proteins involved in binding with these materials, Enzyme based sensors, Immunosensors.

NMs can be generally divided into three types based on their chemical composition, namely carbon allotropes-based nanomaterials with only carbon atoms, inorganic nanomaterials with metallic or non-metallic elements, and organic nanoparticles with mostly polymeric nanomaterials. Below is the descriptive list of the categories (Fig. 2).

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Carbon Nanostructures The extraordinary attributes of nano-structured carbons, including carbon nanotubes/nanodots, graphene, or nanodiamonds, have led to their widespread application as electrical or electrochemical transducers in biosensing systems. The rising use of these NMs in bio-physiological sensing systems is attributed to their numerous incomparable and distinct physical properties. Carbon NMs are gaining popularity for biosensing purposes due to their high surface area, stable thermal optical, flexibility, electrical, and physical characteristics [7, 8]. The exceptional applicability of all these NMs in biosensing is mostly due to tetravalent interaction in carbon, and also catenation-facilitated expanded binding capacity, which has shown to be extremely effective in medical diagnostics and real-time assessment [9]. The biosensor based on all these NMs not only has good specificity and various innovative functional processes but also has a better resolution (for localized monitoring) and may be used in real-time assessment, even without the need for labels or markers. The following section of the chapter highlights significant structural characteristics of carbon-nanostructured-based materials, as well as some current sensing breakthroughs.

Fig. (2). Different types of nanomaterials used for different biosensing applications.

Carbon Nanotubes (CNTs) CNTs are made up of hexagonal pattern-organized carbon atoms that form sixmember carbon rings. These rings interlink to produce a graphene sheet, which

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subsequently generates CNTs, which become uniform cylindrical tubes and have a length of micrometres and a diameter of roughly 100 nm [10]. CNTs are classified into two types depending on the layered architecture of graphene sheets: single-walled carbon nanotubes or SWCNTs (diameters ranging from 0.4 to 2 nm), which include just one layer of the graphene sheet, and multi-walled carbon nanotubes or MWCNTs (diameter ranges from 0 to 3 nm.), which comprise several stacked graphene layers [11, 12]. Their additional benefit over other NMs is a unique blend of electromagnetic, optical, mechanical, and electrochemical attributes that hold promising potential for a variety of implementations, particularly biosensing [13]. These biosensors are classified as electromechanical transducers, electrochemical-based CNT biosensors, immunosensors, and opticalbased CNT sensors based on their substrate identification and processing mechanisms. CNTs have outstanding physicochemical qualities, including excellent mechanical properties, ultra-lightweight, unique electronic frameworks, and great thermochemical persistence. Additionally, their simplicity of use and well-studied organic modifications adds novel features to the nanostructured working electrodes, such as specified docking sites for macromolecules or redox regulation of bio-electrochemical events. CNTs also have the capacity to easily penetrate biological membranes allowing them to be used in vivo with minimum intrusiveness, and they could also be used for photoacoustic cell imaging. Importantly, CNTs have quite a high specific surface area (SSA) that allows for the immobilization of a significant number of multifunctional entities at the CNTs surface, including receptor molecules for biosensing purposes. CNTs also have intrinsic optical features such as powerful resonance Raman scattering as well as near-infrared photoluminescence properties [14].CNTs may be constructed using three different fabrication methodologies: chemical vapour deposition, electric arc deposition, as well as laser deposition [15].They also have semi- and metallic conducting qualities, making them good materials for disease diagnosis, food hygiene, and environmental pollution monitoring. One of the biggest challenges with CNTs for biological implementations is their innate complexity in handling. CNTs prefer to accumulate into bundles due to their strong, attractive associations that are hard to break. The addition of reactive groups to the surface of CNTs, therefore, aids in their solubilization and enables their analysis [16]. The specific electric characteristics of carbon nanotubes (CNTs) have been used in field-effect transistor (FET) biosensing systems, within which variations in the conductivity of the CNT medium or alternation of the Schottky barrier after the specific analyte recognition event contributed to high specificity and low detection thresholds down to single compounds [17]. For example, a FET-CNT immunosensor has been designed to measure osteopontin protein (OPN), a biomarker of prostate tumor, by anchoring a genetically-engineered single-chain dynamic segment protein with a strong affinity for OPN, and is being used to track this molecular

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marker in the presence of a high concentration of bovine serum albumin (BSA) [18]. MWCNTs have great prospects in biosensors due to their convenience of immobilization while retaining protein inherent activity [19]. Beden et al. (2015) constructed electroactive adducts to create an electrochemical sensor device for sub-nanomolar sensing of dopamine. For enhanced quantitative metrics, the biosensor was upgraded using MWCNTs and AuNPs. When the electrodes were changed using nano-hybrids, the sensing device responded better. The sensor demonstrated an excellent and broad linear range, as well as a reduced sensing threshold [20]. Graphene Graphene, a two-dimensional (2D) carbon substance with a one-atom-thick, has emerged as a popular study issue in the realm of biosensing. Graphene, like carbon nanotubes, is tightly packed in a honeycomb lattice arrangement. Graphene and its variants, such as graphene oxide (GO), reduced graphene oxide (rGO) and so on, have various admirable qualities due to its peculiar architecture, notably high heat conductance, remarkable electrical properties, enhanced optical features, high flat surface, excellent flexibility, high degree of freedom, and good tensile stability [21, 22]. GO is a functionalized graphene generated via oxidative extraction of graphite, which has a morphology comparable to graphene. Chen et al. constructed a fluorescent biosensing device based on GO to detect and quantify dopamine in biological sample specimens. This monitoring methodology relied on dopamine assembly onto the surface of GO via various non-covalent contacts, and considerable fluorescence quenching revealed its effectiveness as a tag-free fluorescent biosensor for dopamine sensing method with a limit of detection (LOD) of 94 nM [23]. Nanobiosensing (NBS) devices have been developed based on graphene-based materials that can be used in various detection methods, including optical, electrochemical, and electrical. These remarkable features allow graphene to be an appealing contender for the construction of a new line of NBS devices with several benefits, such as excellent performance, specificity, affordability, scalability, flexibility, and stability. Graphene and graphene-related NMs are currently in production using a variety of physicochemical methods, including physical exfoliation of graphite, chemical vapour deposition or CVD of hydrocarbons on metallic surfaces, and thermochemical or liquid-phase exfoliation of graphite oxide layer [24]. Graphene-based glucose biosensors are often constructed by immobilizing glucose oxidase (GOx) enzyme onto the surface of graphene sheets, as in the graphene-FET described by Huang et al. [25]. Among the most critical concerns for graphene's biological uses would be its short and long-term toxicity. Reduced graphene oxide (rGO) is formed out of GO that has been reduced chemically or physically. Due to their diverse capabilities, reduced GO may be effectively employed to construct

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extremely efficient electrochemical and biochemical sensors that can be tailored to be very susceptible to minor changes in the biochemical environment [26]. In recent times, efficient multifunctional biosensors with multiple detection outputs on a single system have been proposed [27]. Ouyang et al. demonstrated a unique dual-spectroscopic all-in-one approach for quantifying aristolochic acids in complicated biological specimen matrices. After extraction, aristololactam (AAT), a bioproduct of aristolochic acid I (AAI), was identified instantly by fluorescence spectrometer, whereas AAI was identified by Surface-enhanced Raman scattering or SERS using a graphene-enhanced absorption and magnetically recovery method [28]. Despite several valuable findings on graphene's in vitro cytotoxic activity effects, there is currently no comprehensive knowledge of the associated processes of graphene's cellular toxicity in the previous research; hence, this problem needs to be thoroughly investigated. After extraction, aristololactam (AAT), a biological product of aristolochic acid I (AAI), was identified instantly by fluorescence spectrometer, whereas AAI was identified by Surface-enhanced Raman scattering or SERS using a grapheneenhanced absorption and magnetically recovery method. Nanodiamonds Nanodiamonds (NDs) have already been emphasized as a novel group of carbonbased nanostructured materials due to their distinctive qualities, such as nontoxicity, sustained fluorescence, accessible functionalization, inherent biocompatibility, and many other basic traits of pure diamonds [29 - 31]. Since the first NDs production in the 1960s [48], a substantial number of ND research have been published over the last several years. NDs of various architectures and sizes have been synthesized using various processing techniques and are extensively used in various applications, including drug administration, biomedical imaging, biosensor, power storage systems, and catalysis [32 - 34]. Prominent methods for producing NDs of various sizes and architectures include detonation methods, high pressure and temperature (HPHT), ball milling, laser ablation, and chemical vapour deposition (CVD) [35 - 37]. NDs appear to be a much more biocompatible and non-toxic variant in their family among carbonbased NMs. Other studies found that ND had no effect on cell survival, cell membrane oxidative stress, or intracellular oxidative stress, and that their biological effects were less than those of other nanocarbons [38, 39]. As a result, biological characteristics, including aggregate formation, metabolism, internalization, and toxic effects, may be regulated, providing a superior riskbenefit ratio for medicinal and biomedical imaging approaches. NDs are categorized into many classes according to their core size and biosynthesis mechanism. Detonation nanodiamonds (DNDs), also called ultra-dispersed diamonds, comprise diamond NPs sizes ranging from 3 to 10 nm produced by

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carbon-containing explosives detonated under circumstances of negative oxygen equilibrium [40]. FNDs (fluorescent nanodiamonds), which have a wider size distribution than DNDs, are primarily formed from costly high-pressure and temperature (HPHT) diamonds and mechanical procedures, which give them very stable flaws [41, 42]. Chemical vapour deposition or pulsed laser ablation in liquids can also produce nano-sized diamonds, although these methods are less frequent and more expensive [41, 43]. NDs are processed to remove impurities (non-diamond carbons, metals, oxides, and many other impure particles) and manage their surface morphology and chemistry before being used in bio application formulations. Different solutions regulated by physical principles or chemical changes can be used to solve the restricted aggregation effect of bare NDs, which is a commonly debated subject. NDs have adapted to work with a variety of medications, displaying favourable input and less adverse effects. For example, tests of materials containing doxorubicin (DOX) revealed remarkable tumour growth inhibition, delayed cytoplasmic release, and enhanced drug uptake in the nucleus of cancer cells [44]. NDs have outstanding luminescent features, such as high quantum yield and stable emission from colour centres, such as Nitrogen-Vacancy centres glowing in the far-red/near-infrared, making them ideal for biological labelling [45]. NDs have been shown in previous investigations to have nitrogen-vacancy centres with intrinsic fluorescence characteristics, making them useful imaging and diagnostic tools [46]. Furthermore, because NDs have a higher refractive index (RI) than cytoplasm, they usually generate a powerful light scattering response, allowing optical microscopy to easily discern them in a cell [47]. The surface of NDs has a high affinity for proteins. Li et al. investigated the receptor-mediated endocytosis of fluorescent NDs connected to transferrin because of this high affinity for proteins. Their findings revealed that crosslinking nanoparticles with proteins improves cellular absorption stability and efficiency [48]. Biocompatibility has been demonstrated for NDs in a variety of biosensing and biomedical applications. Despite its unique properties, the idea of improving its compatibility with various solvents and polymers has not been fully investigated. Furthermore, it has been difficult to disperse NDs in an aqueous solution for successful usage in the biomedical field until now, thus future research should look into particle systems for this reason. Organic Nanoparticles As A Biosensor Organic compounds may be encountered in numerous sectors, ranging from medicines to consumer goods and services, including dyes, ink solvents, flavouring agents and household cleaning products. Chemical modifications are used to improve the quality and performance of many of these organic molecules. Many chemicals necessary for formulation are insoluble in nature, which limits their activity and application. Organic substances are essentially and eventually

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miscible in aqueous or aquatic conditions, but at a considerably slower speed than their inorganic equivalents, hence organic nanoparticles (NPs) will not be discovered in the environment for an extended period of time, considering them environmentally advantageous. These organic NPs are more environmentally benign, less expensive, and better suited to a variety of biological applications [49]. Organic nanoparticles or polymers include liposomes, dendrimers, micelles, and ferritin. Certain organic NPs, such as micelles and liposomes, also known as nano-capsules, are susceptible to temperature and electromagnetic radiation like heat and light, as well as some organic NPs, are biocompatible, biodegradable, and non-toxic in behaviour. These NPs have distinctive attributes that render them suitable for therapeutic medicine administration as well as a wide range of biological functions. Aside from the conventional qualities like size, structure, chemical composition, surface form, and delivery methods, the drug-carrying potential and resilience, whether an entrapped drug or immobilized drug system, affect their range of applicability and performance. Since they are effective and can be administered into the body system, organic NPs are most typically used in medical applications, including targeted drug delivery applications. The term “targeted drug delivery system” refers to a system that delivers drugs to specified regions of the body [50]. Dendrimers Dendrimers are symmetrically nano-sized molecules containing a small atom surrounded by uniform branches called dendrons. Dendrimers are branching molecules with features similar to polymers and tiny entities. Dendrimers can have a structure of up to 4 nm, but most are in the 1-2 nm range [51]. Unlike other NPs such as lipid nanoparticles and micelles, these nanostructures do not have a completely central cavity and would instead be comprised of a polymeric matrix of repeating units that expands from the inside out. The NM's framework is built in the manner of an onion, with the shells representing repeating units that have been joined to the next inner cell, incrementally shrinking at the core. Thus, every generation begins with the core, and the beginning of the shell can be thought of as a focal point where the new repeating units begin. A dendrimer is sometimes a tree-like structure since it has a confined branch-like structure. The dendrimer's structure is made up of three structural components [52]. Dendrimers' cores are shielded from the environment, providing a unique microclimate. The outer shell consumes a well-defined micro-environment immediately beneath the surface. A large number of possible active sites can be found on the multivalent surface. Dendrimers' most appealing applications are in the pharmaceutical and medical fields. Dendrimer is used as a contrast agent in

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magnetic resonance imaging (MRI) and as a medication delivery carrier in cancer treatment. Dendrimers are widely employed in the biomedical industry as analogues of biomolecules such as proteins, enzymes and viruses. They are primarily used to focus target cells while being attached to the host dendrimer cells [53]. Dendrimers are commonly employed in magnetic resonance imaging to increase image quality. Metallic dendrimers, for example, are utilised in magnetic resonance imaging contrast agents [54]. Dendrimers can also be utilised as a mimicking molecules to imitate other biomolecules and create a microenvironment [55]. Dendrimers also improve the solubility profile of insoluble medicines, resulting in higher drug bioavailability [56]. The dendritic architecture aids in the stability of the components within the core by creating interactive inner compartments into which neutral molecules and ions can be placed to avoid deterioration. Dendrimers can also help with site-specific drug delivery by attracting ligands and conjugates to the surface of the dendrimer [57]. Due to their uniform size, dendrimer molecules have the ability to permeate cell plasma membranes, which aids in a variety of pharmacological activities [58]. As it has a tertiary amine group at the branching point, poly(amidoamine) (PAMAM) dendrimers are employed as nanoparticles. Metal ions are introduced to the dendrimer-containing water solution, and the metal ions form complexes with the tertiary amines' lone electron pairs. The ions are then reduced to zero-valent states, resulting in nanoparticles contained within the dendrimer [59]. Various dendrimeric formulations, such as polylysine (PPL) dendrimers with sulfonated naphthyl groups, have been employed as nanodrugs in various disorders. PPL dendrimers with tertiary alkyl-ammonium groups immobilized on the surface of chitosan dendrimer composites are antimicrobial compounds [60]. Polymeric Nanoparticles Due to their small size, polymeric nanoparticles (NPs) have attracted much interest in recent years [61, 62]. The ability to protect pharmaceuticals and other molecules with their biological activity against the environment, and broaden their bioavailability and therapeutic index are all advantages of polymeric nanoparticles as drug carriers for drug delivery [61, 63]. Nano capsules and nanospheres, which differ in appearance and structure, are classified as “nanoparticles” [64]. Nano capsules are composed of an oily core with the drug incorporated and a polymeric coating that regulates the rate of drug release from the core. The drug can be incorporated into or adsorbed onto the surface of nanospheres, composed of a continuous polymeric matrix [64 - 66]. Nanocapsules and nanospheres are two forms of polymeric NPs. Alternative types of pharmaceuticals can be loaded into polymeric NPs and their supply into a specific administration route, and different methods for producing the particles can be used [67]. The two most popular processes include monomer polymerization and dispersion of the pre-made

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materials [68, 69]. Organic solvents are typically employed in the first step to dissolving the polymer in most procedures requiring premade polymers [69]. Organic solvents have the potential to cause toxicity and environmental harm. As a result, the remaining solvent residues in the product must be eliminated. In loading chemicals into polymeric NPs, monomer polymerization allows for more efficient insertion in a single reaction step [70]. The products are commonly obtained as aqueous colloidal suspensions, regardless of the preparation technique [69]. Nanogels Nanogels are three-dimensional structures composed of chemically or physically crosslinked polymeric materials, including swellable hydrophilic or amphiphilic complex molecular chains. Nanogels can retain much water but don't dissolve the structure; instead, they keep it intact. Due to the increased water percentage, biologically active compounds often smaller than the gel pore diameter possess fluid-like transport properties. Nanogels can be produced from a mixture of synthetic polymers, natural polymers, or a mix of the two. They can be crosslinked chemically or physically using non-covalent bonds such as hydrogen bonds, electrostatic interactions, and hydrophobic interactions. The inclusion of hydrophilic functional groups along the macromolecular chains of the polymeric matrix, such as -OH, -CONH-, -CONH2-, and -SO3H-, is attributed to the polymer's high water-retaining capability. Nanoparticles are crosslinked chains that can be as small as 100 nm [71] but can also be as large as 200 nm [72] or even 1000 nm [73]. Physically cross-linked nanogels can be used as solid lipid nanoparticles for drug carriers in biological systems by self-assembling sterols with polysaccharides in water via the self-organization of amphiphilic polymers [74]. Artificial muscle, biosensing, biomaterials, biochemical purification, biocatalysts, photonics, cultured cell systems, biomimicry, drug carriers, anticancer therapy, and other nanomedicine applications benefit from nanogel-based preparations. Nanogels have been employed in synthetic operations for a long time, not just for drug delivery systems but also in other fields such as quantum dots, MRI contrast agents, and other diagnostic agents [75 - 77]. Nanogel formulations have a multipurpose benefit due to the heterogeneity of natural polymers and the ease with which their physicochemical properties can be synthesized. Nanogels can be employed as a delivery mechanism for various therapeutic combinations for various malignancies and immunological diseases. In future applications, the system believed to enfold bioactive compounds with various chemical and functional features, such as vaccinations, nasal vaccines, and nucleic acid, produces a new essential solution in malignancy or even autoimmune illness.

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Inorganic Nanoparticles Inorganic NPs have a more excellent surface-to-volume ratio than their bulk counterparts, due to which inorganic nanoparticle-modified electrochemical surfaces have more significant electrochemically active regions, resulting in an improved sensitivity for target-molecule. Researchers have been drawn to inorganic nanoparticles (NPs) because of the effect that inorganic nanoparticles offer, in electrical, optical, magnetic, or catalytic properties. These also have a high degree of stability, customizable compositions, a wide range of physicochemical functionality, and unique biological properties. Some inorganic nanoparticles, particularly metallic NPs, can readily act as amplifiers for electron transport between the electrode and the detecting molecules, resulting in a quicker current response for the target molecules [78]. Quantum Dots Quantum dots (QD) are zero-dimensional crystals in the nanometres range. QD has a more significant extinction coefficient and a higher state density than higher dimensional structures. As a result, they are particularly important for optical applications. The size of a QD is usually between 2 and 20 nm. The possibility of adjusting the size of quantum dots is useful in various applications. Larger quantum dots, for example, have a higher spectrum shift towards red and less prominent quantum features than smaller quantum dots [79]. A few Properties of quantum dots are listed below: ● ● ●

●

When excited, the luminosity is very high. Photobleaching resistance is high. The size (called the “size quantization effect”) and the composition of their cores and shells can influence the emission spectra. Multiple signals can be recognized simultaneously with a single excitation source, significant excitation, and limited symmetrical emission spectra.

There are numerous approaches to modulating QD luminescence as a selective response to the presence of a target analyte. BRET (bioluminescence resonance energy transfer), FRET (fluorescence resonance energy transfer), CT (charge transfer quenching), and ECL (electrochemiluminescence) are only a few examples. CT reactions profoundly impact QD photoluminescence (PL), and QDs are good donors in FRET and acceptors in BRET. Many detection methods have been based on the substantial distance dependency of these processes. And to produce an analytical signal, variations in PL spectra and intensity, as well as

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modification of ECL intensity from QDs utilizing analyte reactivity, enzyme turnover, or changes in co-reactant mass transfer, are employed [80]. The first QD-aptamer probe for FRET-based thrombin sensing was constructed by Levy et al. [81]. For transduction, Nutiu and Li's structure-switching signaling technique was applied [82]. In place of secondary-structure-driven target binding, a Watson-Crick base-paired oligonucleotide is displaced from the aptamer. Levy et al. revealed that when thrombin was introduced to a QD525-thrombin binding aptamer (TBA) compound, a short dark quencher-labeled complementary oligonucleotide could be dislodged from the coupling, restoring QD PL and providing an analytical response [81]. The Benson team has designed several unimolecular biosensing systems (QD-CT construct detecting thrombin) by combining CT quenching and QD-protein conjugates labeled with ruthenium complex structures [80]. In the construction of biosensors, the surface modifications employed with QDs are crucial factors. FRET and BRET as transduction approaches are compatible with compact and thick ligand-based QD coatings. Magnetic Nanoparticles As A Biosensor Magnetic nanoparticle-based biosensing technologies have gained much interest because they have distinct benefits over other approaches. Magnetic nanoparticles, for example, are inexpensive to manufacture, have a larger surface area, are physically and chemically stable, have high mass transference, are biocompatible, and are ecologically friendly. Furthermore, biological samples have an almost little magnetic background, allowing for exceedingly sensitive observations. These MNPs work best in the 10-20 nm size range because of their super magnetism, making them highly suitable for a faster response of the signal in an applied magnetic field. Now, because the characteristics of MNPs are substantially influenced by their dimensions, their synthesis and preparation must be carefully planned to produce particles with appropriate size-dependent physicochemical properties [83, 84]. Examples of MNPs include Iron oxides Fe2O3 and Fe3O4, FePt, CoPt, ferrites of cobalt, manganese, nickel, and multifunctional composites (FePt-Ag, Fe3O4-Au, CdS-FePt, Fe3O4-Ag) heterodimers of NPs. Below is the list of biosensors developed using magnetic nanomaterials (Table 1).

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Table 1. Biosensors developed using magnetic nanoparticles. Molecule Type

Target

Magnetic Nanoparticle (MNPs) Sensors

Reference

Protein

GFP

Anti-GFP-CLIO (cross-linked iron oxide)

[85]

Avidin

Biotin-CLIO

[86, 87]

α-fetoprotein

Anti-α-fetoprotein-CLIO

[86]

VEGF

Anti-VEGF-CLIO

[86]

CA-125

Anti-CA-125-CLIO

[86]

folate

Folate-CLIO; anti-folate

[88]

Calcium

Calmodulin-CLIO; M13-CLIO or chelators

[89, 90]

Glucose

Glucose-CLIO; concavalin

[88]

Drugs, enantiomers

D-Phenylalanine-CLIO

[91]

Trypsin

Biotin-(G)4RRRR(G)3K-Biotin or Biotin-GPARLAI-Biotin; Av-CLIO

[92]

Caspase-3

CLIO-Av-Biotin-GDEVDG-CLIO

[85]

Peroxidases

Phenol-CLIO, tyrosines-CLIO

[93]

Renin

Biotin-IHPFHLVIHTK-Biotin; Av-CLIO

[92]

DNA

Telomeres

(CCCTAA)3-CLIO

[94]

RNA

GFP

CLIO-ATTTGCCGGTGT and CLIO-TCAAGTCGCACA

[85]

Organism and Cells

Tumor cell lines

Anti-Her2-CLIO; Anti-EGFR-CLIO; Anti-EpCAM-CLIO

[86]

Herpes simplex virus

Anti-gpD(HSV-1)-CLIO; Anti-HSV1-CLIO

[95]

S. aureus

Vancomycin-CLIO

[86]

Small molecules

Enzyme Activity

MNPs have shown considerable promise in early-stage cancer sensing. Pal et al., for example, used monoclonal antibodies (mAbs) to multiplex MNPs for sensing several ovarian cancer biomarkers such as CA-125 (cancer antigen 125), β2-M (β2-microglobulin), and ApoA1 (Apolipoprotein A1) [96]. Lee et al. used GSPE to produce functionalized Fe3O4 core-Au shell structures for the detection of ECP protein (eosinophil cationic protein), an asthma biomarker [97]. MNPs have a wide range of applications, including piezoelectric and magnetic sensors in addition to electrochemical and optical sensors. Sinha et al. used a planar Hall magneto-resistive (PHR) sensor to detect HαT. Pulmonary and cardiovascular diseases can be identified by a known biomarker, Human α thrombin (HαT) [98].

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Gold Nanoparticles (AuNPs) AuNPs are conductive NPS with a large surface area and unique optical properties. As AuNPs have a localized surface plasmon resonance (LSPR), their color changes as size increases from 100nm from red to yellow. The morphology of AuNPs may influence temperature and light scattering caused by surface plasmonic breakdown. The degree of aggregation of AuNPs is another element that can influence optical characteristics. Biosensors and optical immunoassays can both benefit from this characteristic. Multifunctional AuNPs are now commonly employed to detect biomarkers for cancer, neurological diseases, diabetes, nucleic acids, amino acids, haemoglobin and a variety of infections [99]. Frens et al. demonstrated the synthesis of AuNP in 1970. It was reported that a 10-20 nm AuNP may be generated by reacting hot chloroauric acid solution with sodium citrate solution. Sodium citrate is employed as a reducing and capping agent in this synthesis [100]. In the later years, Perrault et al. successfully synthesized Au NPs with sizes ranging from 50 to 200 nm using hydroquinone as a reducing agent [101]. Many research groups have spent substantial time and effort in recent years establishing new synthesis strategies for producing various sizes and shapes of Au NPs using various combinations of capping and reducing agents. The seed-mediated technique for producing Au nanorods in a micellar solution was developed by Jana et al. They discovered that CTAB surfactants play a key role in influencing the aspect ratio of AuNP, resulting in a faster production rate. The similar group also reported that utilising a similar seed-mediated approach reaction method, Au NPs with diameters of 5-40 nm and low size distribution could be generated [102]. They also manufactured varied shapes and sizes of AuNPs by modifying the reaction parameters of the growth fluid using a similar approach. Chaichi and Ehsani constructed an optical glucose sensor by immobilizing GOx on chitosan shells with Fe3O4 cores and coupling it with luminol chemiluminescence systems. They employed AuNPs to catalyse the luminol CL reaction as well as the H2O2 production process between GOx and glucose. The neoteric sensor had a detection limit was 4.3 × 10−7 M and a linear range of 1 × 10−4-8.5 × 10−7 M [103]. Ahirwal et al. employed a electrochemical sandwich ELISA where AuNPs were covalently tagged to antibody (Ab1) via a spacer molecule, and later this conjugated AuNP-Ab1 was coupled to an Au electrode immunoassay. Identification and susceptibility evaluations were performed using cyclic voltammetry using HRP (horse radish peroxidase) as a reporter enzyme on the specific secondary antibody and tetramethyl benzidine as an electro-active dye. This electrode had a detection limit of 2 ng/mL analyte [104].

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Silver Nanoparticles (AgNPs) Noble metals have significant physiochemical and surface characteristics, which eventually strengthen biosensor efficacy for precise and reliable biomolecular monitoring [105 - 107]. Silver (AgNPs) nanoparticles are particularly appealing in biomedical sectors, such as antibacterial, diagnosis and clinical applications [108, 109]. Due to its remarkable optical qualities, achievements with NMs are rising quicker, acquiring massive favour with many researchers, and encountering new ways to progress smart and wearable sensing technologies and bioimaging. Moreover, it is also found in biosensor materials, cosmetics, conductive polymers, and electrical items. The use of AgNPs in biosensors increased the LOD of the targets due to their strong thermal, biochemical, electrical, and catalytic performance [110].The index of refraction of AgNPs is lower than most of the other nanoparticles. Whenever a biomolecule of interest is attached to an AgNP, the surrounding refractive index increases, and the Ag extinction shifting is seen. Various monitoring sensors have proven excellent identification of target molecules using these modifications with AgNPs. Different chemical and physical methodologies have been used to stabilize AgNPs, which were then used in a variety of biosensing units such as surface plasmon resonance (SPR), enzymelinked immunosorbent assay (ELISA), electrochemical sensors, etc ., to assess diverse diagnostic biomarkers with increased precision and specificity [111, 112]. AgNPs of different forms, such as spheres, plates, rods, and wires, and sizes (10100 nm), have already been produced and used for a variety of functions. Ag NPs could be generated using one of two processes: chemical reduction (with different reducing agents such as Tollens reagent, sodium citrate, etc.), or physical or biological approaches [113]. In recent times, the biological production of AgNPs utilizing plant extracts was proven to be of great. In one investigation, AgNPs were biosynthesized by utilizing the leaves extract of the plant Protium serratum, which has unique medicinal properties [114]. Biologically produced NPs have exceptional stability and are non-immunogenic, which are required for therapeutic diagnostics such as medication administration, biosensors, and biomedical imaging. In one previous research, it was demonstrated that luminous AgNPs were employed as imaging agents to detect leukaemia and neural stem cells, and that they may pass through the cell membrane (CM) of the leukemia cell and have a harmful impact on a range of up to 100 M [115]. Furthermore, drug-related and targeted-delivery methods are being developed to implement appropriate AgNP uses. These investigations are basically moving forward by combining AgNPs with several other possible particles. Additionally, the size and structure of AgNPs must be tuned in conjunction with many other biomedical approaches.

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THE MAJOR LIMITATION OF NANOMATERIALS The choice of nanoparticles employed in biological investigations but also tests in a system, is a fundamental restriction of nanomaterials. Earlier, during, and after the experiments, it is necessary to evaluate the physicochemical parameters, the ability for aggregating and sedimentation, and many other aspects, as well as to identify the nanoparticles. The necessity to investigate the pathway for synthetic nanoparticle ingestion by organisms in a variety of situations. Choice of species for therapy that can be employed in research, as well as possible measurement points [116]. Due to the potential toxicity hazards of polymeric NPs, monitoring nanoparticle action in living systems is crucial, and an effective measure to validate nanoparticle safety can be taken [117]. The interaction of nanoparticles on living cells and their toxicity are the two main risks associated with their use [118]. Nanoparticles may also alter the composition of a medium (chemical, physical), encouraging nanoparticles to form and degrade, disrupting its bioactivity and in vivo behaviour [116, 119]. To ensure that the results produced through preliminary assessment of toxicity, screening, and evaluation of the nanoparticles' toxicity are accurate, they must be able to detect very low quantities of toxicological biomarkers while avoiding interference from other substances in the sample. Multiple sources should be examined throughout the evaluation of the analytical technique, with the first step being the creation of nanoparticles under optimal conditions for obtaining the required nanoparticle [120, 121]. The second most important step is nanoparticle separation, which uses centrifugation and, in some cases, microfiltration to ensure that all undesirable particles are removed. The electrostatic interaction or collision of nanoparticles on a membrane places them there. Separation of nanoparticles differ in size compared to their diffusion coefficient was also accomplished using field flow fractionation. Other procedures for nanoparticle separation and purification according to size include affinity chromatography or size exclusion chromatography [122, 123]. To optimise diverse reaction parameters, it is necessary to improve nanoparticle formation and stability with a short reaction time. Despite all the limitations of using nanoparticles for biomedical imaging and therapy, these nanoparticles have proven to be one of the hot topics for research in the present era, because of which nanomaterials-based sensors and therapies are widely available among various disciplines (Fig. 3) [124].

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Fig. (3). Multiple applications of nanomaterial for biosensing.

CONCLUSION AND FUTURE PERSPECTIVE Accurate diagnosis, targeted therapies, food safety, defence and environmental pollution monitoring technological advances are of tremendous importance to business, government programs, and research experts. Biosensing methods have been recognized as an effective strategy among these technological advances, notably for biosensors that incorporate immensely desirable properties, such as accuracy (appropriately identifying the target analyte), strong sensitivity (assessing low amounts or the absence of the analyte in a sample), rapid outcomes (from minutes to a few hours), high specificity, long storage life, and ease of operation. In this chapter, we have provided a detailed overview of many NMs that can operate as reliable and accurate biosensing devices in both native and functionalized variants. With both the outburst of nanostructured materials and the advent of nanotechnology with distinct physical and chemical properties, a new category of biosensors known as nano biosensors, which includes nanostructures and nanotubes, has emerged, combining the benefits of NMs, particularly their small shape and high surface-to-volume ratio, with the specifications of “macro”biosensors. NMs have become critical elements in the bioanalytical system because they substantially improve susceptibility and recognition limits down to specific single molecules. The unique features of such nano-objects often provide benefits over traditional transduction approaches. Furthermore, combining multiple nanostructured materials, each one with unique properties, to improve the functionality of biosensors is a very well-accepted method. In a brief period, the need for biosensors for initial disease detection has been generally acknowledged as a point-of-care diagnostic with adequate accuracy. Extremely sensitive

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biosensing methods are necessary for rapid and early disease diagnosis since the related biomarkers are often synthesized in extremely low quantities. Numerous biosensors with a broad array of application fields have been investigated and produced during the last five decades. On the contrary, there are just a few commercially accessible biosensors. Merely a few detecting systems have been developed for monitoring biomarkers with the needed picomolar (pM) sensitivity for significant sensing of biomolecules, and they are frequently highly advanced and expensive. Carbon-based, organic, and inorganic nanostructured materials have recently been generally considered superior to many other traditional materials for the construction of sensitive and precise biosensors. The major functions of all these NMs on biosensor electrode surfaces are to increase the surface area available for biomolecule analyte immobilization and signal augmentation (as an intermediator through catalytic processes and depositing electroactive species), and also to act as signal-generating probes, catalysts, and enzyme mimics. Nonetheless, the durability of NMs on electrode surfaces must always be considered for the long-term resilience of biosensors. The advancements in the use of NMs for biological sensing purposes are described in this chapter. Various unique types of NMs, generally ranging from monomolecular nanomotors to considerably bigger nanocages, have been used in current breakthroughs in biosensing systems. NM-based biosensors are projected to replace traditional costly sensing systems in the coming years because of their quick, inexpensive, and simple operational processes. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors are thankful to the School of Biochemical Engineering, IIT (BHU) Varanasi, for providing technical support. This work was financially supported by the Department of Biotechnology, India, under the DBT JRF Ph.D. program, for providing fellowship to author Abhay Dev Tripathi during the tenure of this study. REFERENCE [1]

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[112] M.M. Zahran, Z. Khalifa, M. Zahran, and M.A. Azzem, Recent advances in silver nanoparticle-based electrochemical sensors for determining organic pollutants in water: A review. 7350-7365, 2021. [http://dx.doi.org/10.1039/D1MA00769F] [113] S. Iravani, H. Korbekandi, S.V. Mirmohammadi, and B. Zolfaghari, "Synthesis of silver nanoparticles: Chemical, physical and biological methods", Res. Pharm. Sci., vol. 9, no. 6, pp. 385-406, 2014. [PMID: 26339255] [114] Y.K. Mohanta, S.K. Panda, A.K. Bastia, and T.K. Mohanta, "Biosynthesis of silver nanoparticles from Protium serratum and investigation of their potential impacts on food safety and control", Front. Microbiol., vol. 8, p. 626, 2017. [http://dx.doi.org/10.3389/fmicb.2017.00626] [PMID: 28458659] [115] V. Kravets, Z. Almemar, K. Jiang, K. Culhane, R. Machado, G. Hagen, A. Kotko, I. Dmytruk, K. Spendier, and A. Pinchuk, "Imaging of biological cells using luminescent silver nanoparticles", Nanoscale Res. Lett., vol. 11, no. 1, p. 30, 2016. [http://dx.doi.org/10.1186/s11671-016-1243-x] [PMID: 26781288] [116] A. Kahru, and H.C. Dubourguier, "From ecotoxicology to nanoecotoxicology", Toxicology, vol. 269, no. 2-3, pp. 105-119, 2010. [http://dx.doi.org/10.1016/j.tox.2009.08.016] [PMID: 19732804] [117] M. Bundschuh, J. Filser, S. Lüderwald, M.S. McKee, G. Metreveli, G.E. Schaumann, R. Schulz, and S. Wagner, "Nanoparticles in the environment: Where do we come from, where do we go to?", Environ. Sci. Eur., vol. 30, no. 1, p. 6, 2018. [http://dx.doi.org/10.1186/s12302-018-0132-6] [PMID: 29456907] [118] R. Gupta, and H. Xie, "Nanoparticles in daily life: Applications, toxicity and regulations", In: Journal of Environmental Pathology, Toxicology and Oncology, 2018, p. 37. [119] A.M. Silva, H.L. Alvarado, G. Abrego, C. Martins-Gomes, M.L. Garduño-Ramirez, M.L. García, A.C. Calpena, and E.B. Souto, "In vitro cytotoxicity of oleanolic/ursolic acids-loaded inPLGA nanoparticles in different cell lines", Pharmaceutics, vol. 11, no. 8, p. 362. [http://dx.doi.org/10.3390/pharmaceutics11080362] [PMID: 31344882] [120] V.K. Chaturvedi, N. Yadav, N.K. Rai, R.A. Bohara, S.N. Rai, L. Aleya, and M.P. Singh, "Two birds with one stone: oyster mushroom mediated bimetallic Au-Pt nanoparticles for agro-waste management and anticancer activity", Environ. Sci. Pollut. Res. Int., vol. 28, no. 11, pp. 13761-13775, 2021. [http://dx.doi.org/10.1007/s11356-020-11435-2] [121] M. Hanauer, S. Pierrat, I. Zins, A. Lotz, and C. Sönnichsen, "Separation of nanoparticles by gel electrophoresis according to size and shape", Nano Lett., vol. 7, no. 9, pp. 2881-2885, 2007. [http://dx.doi.org/10.1021/nl071615y] [PMID: 17718532] [122] L. Zhang, B. Wang, G. Yin, J. Wang, M. He, Y. Yang, T. Wang, T. Tang, X.A. Yu, and J. Tian, "Rapid fluorescence sensor guided detection of urinary tract bacterial infections", Int. J. Nanomedicine, vol. 17, pp. 3723-3733, 2022. [http://dx.doi.org/10.2147/IJN.S377575] [PMID: 36061124] [123] W. Zhang, Z. Shen, Y. Wu, W. Zhang, T. Zhang, B.Y. Yu, X. Zheng, and J. Tian, "Renal-clearable and biodegradable black phosphorus quantum dots for photoacoustic imaging of kidney dysfunction", Anal. Chim. Acta, vol. 1204, p. 339737, 2022. [http://dx.doi.org/10.1016/j.aca.2022.339737] [PMID: 35397900] [124] Y. Zhang, X. Yu, Y. Hu, X. Bai, R. Zhang, M. Lu, J. Sun, J. Tian, and B.Y. Yu, "A polydopaminepolyethyleneimine/quantum dot sensor for instantaneous readout of cell surface charge to reflect cell states", Sens. Actuators B Chem., vol. 324, p. 128696, 2020. [http://dx.doi.org/10.1016/j.snb.2020.128696]

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CHAPTER 2

Carbon-Based Applications

Nanomaterials

for

Sensing

Rakesh Kumar Ameta1,* Department of Chemistry, Shri M. M. Patel Institute of Sciences & Research, Kadi Sarva Vishwavidyalaya, Kelavani Mandal, Gandhinagar, Gujarat 382023, India 1

Abstract: Recently, carbon-based nanomaterials (CBNM) have been widely used for chemical and biosensing applications due to their outstanding physicochemical properties, such as mechanical, thermal, optical, electrical and structural diversity. Such materials include carbon nanotubes, graphene oxide, graphene quantum dots and fullerene. As a consequence of inimitable features, these give superior strength, electrical conductivity, and flexibility toward numerous chemical and biological objects, which is valuable for chemical sensing and biosensing purposes. However, the specific intrinsic property makes graphene and carbon nanotubes (CNTs) most attractive among the various allotropes of carbon. Since the environmental contaminants in ppm level affect the people, therefore the use of CBNM for environmental sensing provides an accessible cache of data for modelling, which makes it easy to monitor environmental challenges. Thus, the biological, chemical, thermal, stress, optical, strain and flow sensors deliver a larger surface area, excellent electrical conductivity with chemical constancy, as well as mechanical difficulty with straightforward functionalization pathways of CNTs to improve old-style carbon electrode sensor platforms. Therefore, in this chapter, the CBNM for sensing purposes are focused in detail on their mechanism.

Keywords: Carbon electrode, CNT, Optical property, Physicochemical property, Sensors. INTRODUCTION Nowadays, due to the great demand for goods for a so-called better life, the production of such materials is being increased day by day, due to which global challenges have emerged, such as massive energy production and environmental pollution. To overcome this, new technologies or advanced materials are needed to improve the processes' efficiencies with an increase in productivity and reduce the generation of pollutants [1 - 8]. In this regard, the sensing technologies are coCorresponding author Rakesh Kumar Ameta: Department of Chemistry, Shri M. M. Patel Institute of Sciences & Research, Kadi Sarva Vishwavidyalaya, Kelavani Mandal, Gandhinagar, Gujarat 382023, India; Tel: +91 7923244690; E-mail: [email protected]

*

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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nsiderable. Recently, there has been a wide range of sensors for sensing heavy/toxic metal ions, humidity, gas and biomolecules, physicochemical parameters and others [9, 10]. Though, these have their own limits in detection, slow responses, little sensitivity/selectivity, and require pre-treatment and expansiveness. In this context, the nanomaterials offer a solution to overcome such limits of conventional sensors [10], improve parameters such as sensibility/ reliability, and shorten the response/ recovery times. These nanomaterials also make it a possibility to perform in situ analysis at a low cost. All these mentioned features are essential for producing effective sensor devices. Recently, nanotechnology, especially based on carbon, has had rapid development sympathetic to nanoscale phenomena. CBNMs, like CNT, fullerenes, graphene and others, are recently gaining considerable attention from scientific communities because of their specific physicochemical properties. The CBNMs have a wide range of applications, such as detecting or sensing heavy metal ions, food additives, gas molecules, toxic pesticides, antibodies, and bioimaging. Moreover, biomedical applications, energy production, information technology, environmental protection, agriculture, food, etc. Thus, much more scientific efforts are being devoted to the mass production of CBNMs with controlled surfaces. Therefore, CBNMs are being utilized in many fields as sensors, such as in the environmental field for water treatment, separation processes [11 - 14] and remediation [15 - 17]; in the electronics field for excellent electrical utility and optical properties [18 - 22]. With electrical/thermal conductivity having high mechanical strength [23 - 26], the CBNMs are reinforcing elements, and protective materials to prepare conductive polymers [27 - 34]. CBNMs also have been used in the biomedical field due to their sensing ability in controlled or targeted drug release [35 - 39]. (Fig. 1) summarises all the fields where CBNMs are used as sensors. CBNMs, especially CNT, graphene, fullerene, carbon dots, and nano-diamonds, have several applications as sensor, which are tabulated in Table 1. Table 1. CBNMs Applications. CBNMs

Applications/ Sensor

Graphene

Chemiresister, Optical, Strain, Mechanical, Electrochemical Electrical and piezoresistive, Biomolecule, DNA Immunosensor, Hemoglobin/ Myoglobin

Gfullerenes

Biochemical reactions, Electrochemical, Biomolecule X-ray and MRI contrast agent

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Rakesh Kumar Ameta

(Table ) cont.....

CBNMs

Applications/ Sensor Pharmaceuticals, Tumor cell, redox reaction, Immunosensing

CNT

Photoluminescence imaging, photoacoustic imaging Raman Shift imaging and detection Resonance frequency shift gas sensing Sorption, capacitance and ionization gas sensing Electrochemical sensors, detection of specific molecules pH sensor, Food quality sensor, Toxic molecule sensor

Nanodiamonds

MRI and fluorescence imaging, Photoacoustic imaging Multiphoton excitation imaging, Paramagnetic molecule sensing Temperature sensing, Electrochemical biomolecule sensing Gas sensing, Gene sensing

Carbon dots

Photoluminescence sensing, Chemosensing Electroluminescence, Electrochemical sensing, Bioimaging Immunosensing, Temperature sensing, Microfluidic marker

Fig. (1). CBNMs used as a sensor in various fields.

Due to more expansion of technology and automation, there is a need for advanced sensors having potential applications in various industries like electronics and automotive, biomedical, agricultural/ food, environmental monitoring, and defence.

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CBNMs As Environmental Sensors The unique and tunable features of CBNMs enable them to recognize and address environmental concerns. CBNMs have a wide range of environmental applications, such as high-flux membranes, sorbents, antimicrobial agents, depth filters, renewable energy technologies, pollution prevention strategies, and environmental sensors. In environmental science and engineering, CBNMs have been found to be applicable for transporting drugs through target cancerous cells, dense tissues, targeted delivery, removal of hazardous pollutants, and novel membrane for water filtration. These applications of CBNMs lead to improving public health, preventing environmental degradation, optimizing energy competence, wastewater reuse, remediation, and pollutant transformation. Environmental researchers have a challenging task in their work in that the contaminants are found in a range of parts per trillion, which are very difficult to analyse. This issue can be overcome by implementing the potential of nanotechnology. In this regard, environmental sensing is one of the applications of nanotechnology having the potential to link this range of scale. CNT-based nano sensors enable a number of benefits to current sensor platforms referring to new critical reviews related to the subject [40 - 45]. CNT-based sensors have enhanced the electrode's platform for stress, optical, strain, chemical, thermal, biological, pressure, and flow sensing ability, and these sensors show chemical stability, exceptional electrical conductivity, mechanical stiffness, and high surface area [46]. CNT with SiO2 substances works as anodes as ionization sensors for gas detection [47]. Such CNT scale sensors, work on the basis of electric field decomposition of the sample followed by cathode registration of a unique fingerprint for each gaseous sample, and contribute a key breakthrough in the field of sensor. The conductance of CNT is modified by the adsorption of species (charged) on the CNT’s surface, which establishes a correlation between current fluctuation and composition or concentration of sample. A gas sensor was developed by Kong et al. [48] in which the NO2 or NH3 at room temperature were detected even in part per million concentrations by observing the change in electrical resistance changed by 3 orders. The surface area of such sensors shows high sensitivity, low detection limits, and fast response time. Despite this, there is a lack of inherent affinity for CNT-based sensors to specify the chemical and biological samples [49]. The structural modification via functionalization of such sensors (covalently and supramolecular) enhances the sensing ability. The functionalization can be occurred by metals, chemical groups, enzymes, DNA molecules, antibodies, and any biological receptors. The CNT-based sensors are also being used for detecting microbial pathogens as a part of biosensor platform research [50]. Such detection of microbes using CBNMs enhances the response of microbial eruptions in drinking water systems as well as domestic security, and

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spreads the subsurface monitoring of biodegradation/ capturing evolution in microbial groups after environmental concern. CBNMS AS BIOSENSORS CNT Unique features of CNTs, like high aspect ratio/ conductivity/ chemical stability/ sensitivity/ fast electron-transfer rate [51], make them exceptionally appropriate for bio-sensing applications. The immobilization of biomolecules on the surface of CNT is the basic feature of CNT-based biosensors, which enhances the signal transduction process and recognition. On the basis of this, such biosensors are mostly considered electrochemical and electronic/ optical biosensors due to their promise to improve electron transfer. It enables them to unite electrochemical and electronic biosensors [52]. Many CNT-glucose biosensors, a combination of glucose oxidase and CNT biosensors, have been designed for sensing glucose from a glucose oxidase-impregnated polyvinyl alcohol solution [53]. Gaitan et al. reported the effect of surface chemistry and the structure of glucose oxidasecoated CNT for electrochemical sensing of glucose [54]. Similar sensors have been designed to detect NO (nitric oxide) and epinephrine [55]. The 20 distinct CNT corona phase biosensors have been established for detecting human blood proteins by Bisker et al. [56]. In this study, the specific corona phase was found to be capable of recognizing fibrinogen having high-selectivity estimated through fluorescence intensity. Landry et al., reported the detection of individual proteins of Escherichia coli (bacteria) and Pichia pastoris (yeast) with a label-free mechanism [57]. Similarly, a CNT-based biosensor has been developed to detect arginase-1 [58]. Graphene Oxide (GO) GO has the capacity to interact with the probe dynamically, and is used for the transduction of an exact response toward the target molecules where Raman scattering, fluorescence and electrochemical reaction are used to achieve this transduction process. With this concept, the GO is mostly used as biosensors [59], having a sense of single- and double-stranded DNA [60]. The electro-chemical detection of guanine, tyrosine, adenine and cytosine, bases of DNA, has been done by Reduced-Graphene-Nanowire-Biosensors by observing oxidation signals of the bases [61]. A label-free DNA highly sensitive biosensor has been developed by functionalization of GO with single-stranded DNA, which offered a wide analytical range [62]. Similarly, gold nanoparticle functionalized GO was reported for the detection of DNA with a detection limit of 1 nM and high specificity [63]. It was found that the DNA adsorption on GO surface is lengthdependent. Furthermore, a graphene deposited chip has been used for the

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detection of Mycobacterium tuberculosis DNA hybridization [64]. The GOglucose oxidase biosensors have been employed to exhibit superior selectivity and enhance glucose sensitivity having a detection limit of 0.5 mM [65]. A reduced graphene oxide with phenyl butyric acid as a linker to bind glucose was found to be capable of detecting glucose levels up to 1 and 4 mM [66]. Similarly, the highly stable and reusable graphene-bismuth composite device has been found to be capable of detecting glucose in the range of 1–12 mM [67]. Graphene Quantum Dots (GQD) Electrochemiluminescence, photoluminescence and electrochemical features of GQD enable them to use as biosensors for detecting bio-macromolecules such as nucleic acids, and proteins/ glucose with high selectivity/ sensitivity [68]. The DNA probe-functionalized reduced GQDs has also been used for the detection of DNA bases. Similarly, a Zr4+-based phosphorylated peptide-GQD hybrid is used for the detection of casein kinase II within the range of 0.1 to 1.0 ml−1 [69]. The pyrene-1-boronic acid functionalized GQD has been developed by Zhang et al. for sensing glucose where the sensitivity of glucose was dependent on the acid concentration [70]. With this, it was concluded that this functionalized GQD is a perfect probe to sense glucose with an increase in glucose concentration. Similarly, for the detection of hydrogen peroxide and glucose, the electrochemifluorescent polyvinyl alcohol-GQD nanofiber has been fabricated with high sensitivity/ selectivity [65, 71]. The Pd nanoparticles doped GQD are used for the detection of cancer cells in the early stage by electrochemical reduction of H2O2. CBNMs As Electrochemical Sensors For Toxic Metal Ions Non-biodegradable and hazardous heavy or toxic metal ions are considered environmental pollutants monitored by various spectroscopic techniques. But these techniques are not so effective as electrochemical sensors have portability, low cost and quick response. Recently, CBNMs have been used to modify these sensors to improve their sensitivity with high conductivity, larger surface area as well as working potential. Traditional carbon-based sensors include glassy carbon electrodes, carbon fibers and pyrolytic graphite. These CBNMs are deposited on the surface of the electrode through dip coating/ drop casting [15, 16]. Earlier, the electrochemical sensors used for the detection of metal ions, were toxic and less sensitive. To overcome this, the various eco-friendly CBNMs were explored for application in the electrochemical detection of metal ions, such as graphene and CNTs due to their redox electron transfer properties through voltammetry mechanism (Fig. 2).

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Fig. (2). Pictorial representation of electrochemical detection of metal ions using CBNMs.

For instance, Arsenic is detected using CBNMs modified electrode where the nanocomposite is prepared using gold-reduced GO in-situ reduction of GO in the presence of ultraviolet rays [72]. This nanocomposite fabricated sensor shows better sensitivity towards As(III) with a detection limit of 0.1 ppb. The stability of modified electrode was checked by storing it for more than fifteen days, then only a 9.6% appreciable decrease was noticed [73]. A highly sensitive electrochemical sensor for detecting As, was developed by coating the gold electrode in Nafion liquid containing L-leucine and GO, and it was found to be stable at 40C. Interestingly, it was found that this sensor was not influenced by the presence of other metal ions, such as Pb(II), Cd(II), Zn(II) and Hg(II), for detection of Arsenic [74]. Similarly, for the detection of Arsenic, Au nanoparticles and CNTs modified vibrating screen printed electrode having detection limit of 1.5 mg L-1 has been reported [75]. Due to the compatibility of Cu(II) ions with Au, this sensor was also tested for the detection of As(III) in the presence of Cu(II) where it showed sowed nice recovery up to 1.5 mg L-1 [76]. Tables 2 and 3 report the CBNMs used as electrodes for the detection of various toxic metal ions. Table 2. CBNMs used as electrodes for detecting Arsenic (As) and chromium (Cr) [77]. As

Cr

1

Au-Reduced Graphene Oxide nanocomposite-GCE

Bi/SWNTs-GCE

2

AgNPs/Graphene Oxide-GCE

Bis(2,4,4-trimethylpentyl) phosphinic acid/SWCNTs/Boron doped-Si wafers

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(Table ) cont.....

As

Cr

3

CNTs/glutamine/ Nafion-Pt electrode

Gold film coated carbon tape-ITO electrode

4

CNTs/Leucine/Nafion-Pt electrode

Au NPs/Graphene /Chitosan-Au electrode

5

L-leucine/Graphene oxide nanosheets-Au electrode

Fe3O4/Reduced Graphene Oxide-GCE

6

[Ru(bpy)3] 2+-Graphene Oxide nanocomposite-Au electrode

MWCNTs-GCE

7

CNTs/Polymeric resins/Graphite-CPE

MnOx/CNTs/chitosan-GCE

8

Reduced Graphene Oxide/Fe3O4-SPE

Ox-MWCNT-Aunano

9

Gr/MOF-GCE

Quercetin/MWCNTs-SPCE

10

Carbon black/AuNPs nanocomposite-SPE

Reduced Graphene Oxide-GCE

11

CNTs/Au NPs-SPE

MWCNTs-NR-AuNPs

12

Electroreduced Graphene oxide-AuNPs composite film-GCE

Polyaniline/Graphene quantum dots-SPCE

13

Buckypaper modified by GNP

MWCNTs/Nanosilica/Ionic Liquid/Eu Complex /Graphite-CPE

14

Thiacrown 1,4,7-trithiacyclononane and AuNPsGraphene paste electrode

AuNPs/PANI-co-PoT/GO

15

Graphene Oxide/PbO2 composite-GCE

-

16

Graphene/PtNPs-GCE

-

17

NH2-Reduced Graphene Oxide- Au microelectrodes

-

18

Reduced Graphene Oxide/Fe3O4-GCE

-

19

Reduced Graphene Oxide/MnO2-GCE

-

20

rGO-Aunano/GCE

-

21

DWCNTs/Gr/SPE

-

Table 3. CBNMs used as electrodes for detecting copper (Cu) and Thallium (Tl) [77]. Cu

Tl

1

Graphene Oxide terminated p-aminopheny-GCE

MWCNTs/BiF/SPCE

2

Aminophenyl film/SWCNTs/Gly-Gly-Hs-Silicon wafer

4-carboxybenzo-18-crown-6-SPCNFE

3

AuNPs/Graphene-GCE

Graphene oxide-GCE

4

DSP-AuNPs/PAMMAM /MWCNTs-GCE

MWCNTs/L2/RTIL-CPE

5

Hg film-carbon tip electrodes

Thallium imprinted polymer/MWCNTs-CPE

6

MPA/AuNPs/Cys-CFME

Au/MWCNT/DB18C6

7

Graphene/CeO2-GCE

Tri-aza dibenzosulfoxide macrocyclic/1-butyl1-methylpyrrolidinium bis(trifluoromethylsulfonyl) imide/TiO2 /MWCNTs/Graphite-CPE

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(Table ) cont.....

Cu

Tl

8

L-cys/AuNPs/ SWCNTs-GCE

Phosphorus ylide /OPFP(IL)/Graphene-CPE

9

PSS/CnP-PGE

SnO2 NPs/MWCNTs-GCE

10

N-CSs/MWCNTs-Nafion/GCE

-

11

SSA/MoS2/o-MWCNTs/GCE

-

12

Pyrene/Graphene-Au electrode

-

13

EGNs/hyxCNTs/Graphene-CPE

-

14

SnO2/Reduced Graphene Oxide-GCE

-

Chromium is sensed by modifying the electrode by CBNMs in electrochemical sensors especially glassy carbon electrodes with single-walled CNTs and bismuth film. The Bismuth film enables a faster electron transfer as well as larger stripping current/ good hydrophilicity, where Bi film coating is controllable. This sensor has shown good stability of up to 90% for three weeks [77]. Table 3 shows the CBNMs as electrodes for the detection of Cu and Tl. CONCLUSION This chapter mainly deals with the carbon based nanomaterials for the sensing applications. Such as graphene oxides, carbon nanotubes, carbon quantum dots and others are used for the same purpose. The modified surface of electrodes with CBNMs provide high sensitivity and selectivity as compared to conventional electrodes. CBNMs as sensors have applications in detection of toxic or heavy metal ions up to parts per trillion level. In this chapter, these CBNMs as sensor have been widely studied for the researcher working in the same area. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The author declares no conflict of interest, financial or otherwise. ACKNOWLEDGMENTS Author is highly thankful to Kadi Sarva Vishwavidhyalaya, Gandhinagar, Bharat/India, for providing infrastructure facilities.

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CHAPTER 3

Graphene-Based Nanomaterials and Their Sensing Application Vikash Kumar Vaishnav1,*, Khageshwar Prasad1, Rashmi Yadav1, Amitabh Aharwar2 and Bhupendra Nath Tiwary1 Department of Biotechtechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, C.G. 495009, India 2 Govt. College Harrai, Chhindwara, M.P, 480224, India 1

Abstract: Carbon-based materials (CBMs) like graphene, hybrid graphene compounds (HCOGs), graphene nanoplatelets (GNPs), graphene oxide (GO), reduced graphene oxide (RGO), and graphene quantum dots (GQDs), as well as their derivatives like graphane, graphone, graphyne, graphdiyne, and fluorographene, are the direct descendants of graphene-based nanomaterials (GBNs). GBNs are graphene derivatives with single and multilayered graphene products. Their doped versions have marked remarkable significance over the past decade in scientific fields for applications due to their physical as well as their chemical properties. Graphene has emerged as a promising application for sensing, gas separation, water purification, biotechnology, disease diagnosis, bioengineering, and biomedicine. Graphene nanomaterials also play an important role in surface engineering (bioconjugation), improving their performance in vitro/in vivo stability and elevating the functionality of graphene-based nanomaterials, which can enable single/multimodality image optical imaging, positron emission tomography, magnetic resonance imaging and therapy photothermal therapy, photodynamic therapy, and drug/ gene delivery in cancer. Graphene nanoparticles have the natural fluorescence properties of graphene, which helps to bioimage cancer cells. They are perspective drug carriers appropriate for their target selectivity, easy chemosensitization, functionalization, and excellent drug-loading capacity. Iron-based graphene composites are with other companionable materials of exploration to make novel hybrid complexes with preferred uniqueness for biointerfacing.

Keywords: Bioimaging, Cancer, Diagnosis, Graphene oxide, Nanomaterials. INTRODUCTION Graphene nanocrystals are entirely made up of carbon atoms. It is precisely described as a nanoscale, minute-sized, two-dimensional substance with an atomCorresponding author: Vikash Kumar Vaishnav, Department of Biotechtechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, C.G. 495009, India, Tel: +91 9340163169; Fax: +91-07752-260146; E-mail: [email protected]

*

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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wide linear surface. A hexagonal pattern formed by bonding carbon atoms produces a conjugated material with the pattern of a valuable honeycomb stone [1]. Graphene substances are made up of two concepts: GRAPHITE and -ENE into graphene: It has drawn a lot of emphasis on the form of graphene since Novoselov discovered crystal graphene in 2004 utilizing the scotch tape method (wherein a strip of tape is applied to peel graphene flakes off of a block of graphite) [2]. The density of graphene is represented by 0.335 nanometers as the marginal distance. The thinnest, most prevalent nanomaterial is 100–300 times stronger than steel [3 - 5]. The material was one atom thick, and exhibited 97.7% of optical transmittance and a substantial 3000 W·m−1·K−1 (watts-per-metre-kelvin) heat conductivity [6]. The Nobel Prize was awarded in 2010 for their achievements in physics. Currently, they are actively utilised in a variety of applications, including sensors, catalysts, healthcare, electronics, energy, and biology. The synthesis of graphene is usually done in one of two ways: bottom-up or top-down approach. In the bottom-up approach, graphite oxidised in aqueous media under extremely harsh conditions producing well-dispersed graphene oxide, a reduced version of graphene but graphene is not produced by the reduction process that is totally reduced because the chemical procedure produces graphene with certain flaws instead of being called graphene, it is called reduced graphene oxide. Chemical vapors are crystallized on an appropriate substrate to produce an individual layer of graphene on a top-down approach. However, this is incompatible with massproduction methods because of the benefits of manufacturing huge amounts of graphene in a reasonably easy procedure; many different types of exfoliation processes have been created. In it, the status of science was discussed, and the knowledge gaps for future study were noted. Graphene, graphene oxide (GO), reduced graphene oxide (RGO), graphene nanoplatelets (GNPs), graphene quantum dots (GQDs), and chemically modified graphene, all members of the large family of GBNs covered in this study (Functional groups covalently bonded to the surface of each graphite-like carbon layer). The versatile graphene-based nanomaterials (GBNs) are widely employed in physics, chemistry, biology, and medicine. They are easily created by different surface modifications [7 - 11]. HISTORY OF GRAPHENES First acknowledged between 1840 and 1958, graphene was the subject of study; in these time periods, Schafhaeutl, Hummers and others shaped graphene oxide.G. Ruess and F. Vogt have been descriptions of few-layer graphite published in 1948 that is reported to the TEM at the first time. In the year 1962, the chemical

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reduction of GO was observed by Boehm to discover rGO. In the time range of 1968 and 1969, a single layer of graphene stratum in the ground of Pt 100 is discovered by Morgan. A carbon surface and silicon carbide were arranged into monolayer graphite by Blakely and van Bommel, respectively, between 1970 and 1975; Boehm proposed the name “graphene “to describe a monolayer of graphene in 1986. In 1999, theoretically, one layer of graphene was described by Wallace P. R in 1947 and published his discovery in 1999. In 2004, they successfully produced, characterized, and extracted graphene for the first time from the graphite team led by Andre Geim and Konstantin Novoselov. The discovery of graphene has been recognized for its scientific importance and the potential for future innovation with the discovery 2010 Nobel Prize in Physics; when Geim and Novoselov isolated a single sheet of graphene before 2004, nothing was known about the material. Even though they give credit to Hanns Peter Boehm and a colleague for the initial exploratory finding of graphene in 1962 and subsequently, single graphene layers could only be seen using electron microscopy. Before 2004, intercalated graphite compounds were investigated using a transmission electron microscope (TEM). Before 2004, studies used multilayer graphene sheets that Ruoff had made by peeling graphite. Graphene and its plagiarism have recently emerged since exceptional biomaterials for use in biomedical treatment, drug design, bio-sensing, and cancer therapy due to its adjustable assembled unusual physicochemical properties, and outstanding biocompatibility [11 - 15] and developed a nanocomposite of graphene oxide (GO) for the delivery of drugs [11]. Since then, there has been a boom in the exploration of using graphene nanocomposites to treat illnesses and deliver a variety of medicinal chemicals [12]. For all foreseeable future devices and nanosystems, the explored properties or even uses of such a two-dimensional arrangement of the carbon structure have already offered unique, inventive potential [9]. CHARACTERIZATION OF GRAPHENE Blends of one and more layer graphemes, in addition to an atomically thin, twodimension (2D) sheet of sp2 carbon items synchronized in a bee hive pattern, usually make up the final output. It has been demonstrated to possess several favorable qualities, including strong mechanical strength [3], electrical conductivity [16], molecular barrier abilities [17], and other remarkable properties [18], as explained in the exfoliation and synthesis technique for graphene. Many graphene characterization approaches are aimed at distinguishing between those species because GO is reduced to rGO in the chemical synthesis technique; understanding the differences between the genus and the quantity of diminution is

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crucial [10]. GO and rGO can be identified using UV-visible spectroscopy GO was a feature of twinassimilation max (λMAX) between 234-299 nm. The aromatic C14C bonds' -* transition is responsible for the shorter MAX, whereas the C14O bonds' n-* transition is responsible for the longer MAX. In the instance of rGO, maxima arrive at 269 nm, which communicates to the aromatic C14C bonds going through a -* transition. When GO is reduced to rGO, the red shift of the -* transformation in the bioactive C14C bonds suggests additional p-orbital delocalization [19]. A good technique for differentiating between perfect graphite, GO, and rGO is spectroscopy. In pure graphite, a sharp Graphene band peak is produced at 1581 cm by the planar motion in the sp2 carbon atoms. When graphite deteriorates, the Graphene high point broadens to 1589 cm1 in a considerably wider mode, and the disordered architectural framework of GO is caused by oxidation and results in the formation of a D band at 1352 cm1 [20]. When GO is reduced to rGO, which is similar to the Grapheneband peak in pure graphite, the Graphene peak blue changes to 1582 cm1, or almost there. The others band peak strength between the D and G bands gauges the severity of the graphene flaw. FUNCTION OF GRAPHENE Graphene has a lot of prospective intended for uses in sensor systems, semiconductors, and other components, but it needs to be refined before it can be used in any practical way; there are certain challenges to be overcome, including zero's low deformability, band gap, and chemically inertness [21]. Many methods have been devised for improving graphene's real-world usability and functionalizing it. Bonding can be covalent or non-covalent to perform graphene functionalization [22]. The approach of functionalizing graphene by covalent bonding will be the subject of this review. Condensation, addition, and substitution reactions, which can be further classified into nucleophilic and electrophilic substitution reactions, can be used to process chemical reactions in organic chemistry to enable additional functionalization on graphene; thionyl chloride (SOCl2) chemistry is commonly utilized in condensation-type modification. GO is an excellent starting point for the functionalization process since it comprises a range of binding sites, including hydroxyl, epoxy, and carboxylic groups, which include oxygen. The reaction of a result between the carboxyl groups on GO and SOCl2, a -COCl unit that is labile to various nucleophiles, was created. An amide bond was created when alkylamine (RNH2) and -COCl interacted (-CONHR). The GO via amide bonds with the R functional group, allowing for facile dispersion in various solvents such as THF, carbon tetrachloride (CCl4), and dichloroethane [23]. Reacting isocyanate compound (RNCO) with carboxylic acid, amide bone (-CONHR) was created. The functionalization also makes graphene compatible with a variety of polymers,

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allowing for the creation of graphene polymer combination [24]. The additional step on graphene is an effective method for permitting graphene orientation chemical change, in contradiction to the abbreviation response, which is frequently carried out using GO. Based on this chemistry, diazonium salt functions effectively to clutch out graphene functionalization by generating free radicals when the diazonium molecule is heated. The addition reaction appears to affect the conductivity of the graphene when it reacts with the nitrophenyl diazonium molecule (BF-4 N+ 2- C4H4-NO2) to form the nitrophenyl group. This allowed for an improvement in the conductivity of graphene. Graphene's band gap was created when its properties were deliberately changed, enabling its usage as a semiconducting material [25, 26]. Substitution reactions involving several types of nucleophilic functionalities can occur at epoxy groups on GO. Primary amine groups are an excellent fit for this application which is to add alkyl groups to GO; amines with different lengths of alkyl groups (CnH2nNH2) were utilized. The chain length was (n¼, 2, 4, 8, and 12), the combustion was placed at ambient temperature. Nevertheless, if refluxed to complete needs to be a reaction as the alkyl chain was long (n ¼18) [5]. SYNTHESIS OF GRAPHENE A single layer, double layer, or many layers may be used in the production of graphene, and each of them has a unique set of uses in a variety of scientific and technological sectors, including, Catalysis, Sensors biotechnology, Biomedical application, Optoelectrical devices, Nanoelectronics, Energy technology, etc [7, 27]. Many researchers and scholars used multiple graphene synthesis techniques, particularly when a large quantity is required [9, 28]; there are various ways to exfoliate graphite [29]. It was possible to synthesize single-layer graphite [30], and several research into graphene have been published thus far (Fig. 1). On a single platinum (Pt) crystalline substrate, single, double addition multilayered carbon graphite formation was observed [3, 28, 31, 32]. Typically, the many processes in graphene production revolve around “Topdown” and “Bottom-up” techniques. As opposed to the bottom-up method, which focuses on separating precursor graphene (graphite) into atomic layers as, Mechanical exfoliation & Cleavage, Chemical exfoliation & Chemical reduction, Radiation based method, Electrochemical exfoliation, Intercalation of graphene, Solution based exfoliation from graphite oxide and graphene (Fig. 1) [10, 28, 33, 34]. Carbon molecules are used as building blocks in the bottom-up approach, primarily from conventional or non-conventional sources. The bottom-up method offers the chance to create massive amounts of graphene nanoribbons and graphene nanoflakes, even if high surface area graphene sheets may not be

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suitable for it [35]. They segregated into miscellaneous parts like chemical vapor deposition (CVD), thermal CVD, Plasma enhanced CVD, Pyrolysis/solvothermal, Epitaxial growth onto Sic, and Dry ice is produced by graphene synthesis methods (Fig. 1) [36 - 41].

Fig. (1). An approach to graphene synthesis.

Top-Down Granules play a key role in the raw graphite attack in this procedure. As a result, the attack would result in the collapse of one layer and the formation of a graphene region. For instance, the top-down approach interprets many of the stated strategies. Many different exfoliation procedures have been developed as a result of the advantages of producing substantial volumes of graphene using a fairly simple process [7, 9, 27, 42, 43]. Exfoliation techniques & Cleavage: (1) Mechanical exfoliation, (2) Chemical exfoliation, (3) Electrochemical exfoliation. Mechanical exfoliation is a bulk form of graphene that attack carbon–carbon atom through the Vander Waals force. In these exfoliation methods, the high-quality graphene sheet is exfoliated throughout scotch tape to form bulk graphene. From such a pure graphite sheet, graphene may be produced. Although primitive and inefficient, it nonetheless preserves the entirety of the primordial two-dimensional crystalline crystal structures of graphene, and many interesting electronic properties are easily observed. With the distinctive colour difference, this exfoliated graphite was

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applied on SiO2/ Si substrates using Scotch tape [10, 44 - 46]. The chemical process creates a colloidal suspension from graphite compounds to make graphene. To begin putting this theory into practice, separate pure graphite sheets using potassium metal and exfoliate them with ethanol to create a scattering of graphene mass. Emulsification and fracturing, then, are processes that employ mechanical or element power to weaken connections and divide unique graphene areas [2, 32, 43, 47, 48]. The electrochemical approach utilutilized in.1M H2SO4 electrolyte solution to exfoliate graphene from graphite. The cathode was platinum wires, and the anode was graphite flakes. The system is charged with a positive charge of around 10 volts, and graphite flakes dissolve quickly in the solution. The voltage reference is removed after 2 minutes, or the exfoliated graphitic material can be collected using vacuum filtering. The samples are also regularly rinsed with water to ensure that any residual acidity is eliminated. The obtained concentrate is disseminated in dimethylformamide (DMF), resulting in sheets of exfoliated graphite (EG) [9, 49]. Radiation Based Method Graphene can be made in a relatively short amount of time using radiation-based processes. Although this approach might produce high-quality graphene, the yield is modest. GO could also be subjected to electron beam irradiation and transformed into graphene sheets. A closed polypropylene package containing an aqueous GO and isopropyl alcohol dispersion was exposed to electromagnetic radiation for approximately 10 minutes, according to the recorded approach, under circumstances of 2 meV/10 mA. The decreased GO could be centrifuged, washed with alcohol numerous times, and dried beneath a vacuum at 60°C at some stage [50]. The laser synthesis method appears to be highly important [51]. Intercalation of Graphite Intercalation to graphene can further decrease graphite. To create a graphite study, and investigated the effects, different chemicals may insert graphite lamination. The distance to the graphite layers enhances as a result of these intercalants. As the increasing interlayer distance impacts the electromagnetic interaction between graphene layers, it also modifies the material's characteristics [52]. Chemical Reduction of Graphite Oxide A top-down way to manufacture a significant quantity of graphene is to chemically reduce the graphite oxide. Graphite oxide has always been synthesized by oxidizing graphite [53]. It is possible to generate graphene powder or nanoflakes with sizes ranging from one nanometer to several by the chemical method of graphite oxide. This graphene seems to be appropriate for sensor

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applications, polymer fillers, conductivity inks, coatings, ultracapacitors, rechargeable conductors, and other uses [54]. Bottom-Up Bottom-up strategies have been portrayed as simply producing graphene with carbon dioxide. The most common bottom-up processes are proceeding chemical vapor deposition (CVD), thermoelectric CVD, plasma-assisted CVD, Pyrolysis or solvothermal, Epitaxial growth onto Sic, Dry ice synthesis, etc., as illustrated and discussed below; (Fig. 1) [7, 9, 27, 47]. Chemical Vapor Deposition (CVD) Methods The chemical vapor procedures involve steam phase resurfacing. This method chemically divides graphene area from graphite without needing exfoliation. The first person to create graphene sheets with this approach was scientist Horiuchi. They applied the technique to transform regular graphite sheets into carbon nanofilms (CNFs). Various CVD techniques, including thermal, plasma-enhanced cold and hot wall, reactive, and others, can be employed, depending on the precursors available, like structure needed, quality material, and dimension. Thin graphene sheets were produced on copper or nickel and used as chemical vapor deposition [55]. Pyrolysis or Solvothermal Solvothermal synthesis is another unique method for generating SLG lm. in the ultra-rapid pyrolysis of sodium ethoxide is used by Ethanol and sodium. This is used as a precursor material of the hydrothermal technique which creates graphene sheets. Deep inside the vessel during the heating process, the molar ratio of sodium and ethanol (1:1) is established. Sonication is used to produce sodium ethoxide pluralization. This technology can easily improve the efficiency of graphene sheet detachment. As a result, the graphene sheets created can be measured back to 10μm [56, 57]. Dry Ice Synthesis The dry ice process can be used to make graphene by burning 3g Mg ribbon in one bowl of dry frost and smothering it with a building block of the alternate dry frost block. Mg has been entirely scorched in CO2 and the filtrate has been agitated during the night in 1M 100ml of HCl; Mg, like MgO, is a water-soluble element [58]. As a result, Filter the mixture and wash the residue with deionized until this pH restores to normal to eliminate the water content, followed by drying

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the residue at 100°C at 12/24 hour under vacuum, producing a graphene yield of 680 mg (92%) [58]. Epitaxial Growth Onto Sic One of the strategies for growing graphene onto surfaces is epitaxial growth. One of the most important graphene synthesis procedures is the thermal breakdown of silicon (Si) onto the normal plane of a solo 6H-SiC crystalline [59]. Graphene sheets are discovered to be just starting to develop when the 6H-SiC H2- etched surface is heated for a brief duration (1 to 20 minutes) at temperatures between 1250 and 1450°C. A SiC crystal may be heated or even cooled to finish the graphene synthesis procedure. Graphene seemed to have 1-3 layers epitaxially grown onto this surface; the number of layers varies depending on the temperature of the breakdown [60]. This technology is designed to used on a manufacturing level to generate graphene wafer-scale graphene with knowledge of the development process and interface influences, as well as the ability to professionally control the stratum amount [61]. Thermal CVD Technique Graphene production via thermal deposition (CVD) was a relatively new process. In 2006, the initial statement on planar just several graphene (PFLG) produced by CVD [62]. The synthesis of graphene on Ni foils in this work utilized camphor because it is a natural, environmentally benign, and low-cost precursor. Using argon as a carrier gas, camphor was first reprocessed at 700-850 degree centigrade in a separate compartment in a similar CVD oven after being originally vaporized at 180°C. FLG films were discovered on the Ni foils after spontaneously cooling at ambient temperature [63]. Plasma-Enhanced CVD Technique These are a technology used to support the thermal CVD method of producing graphene. PECVD is based on several ionization sources, including frequency band (RB), arc current source (CS), and microwave, which are used in the production of graphene. Since the graphene professes to have superiorness at lower temperatures, critical limitations of PECVD still need to be addressed [64]. Other Synthesis Techniques Thermal Decomposition of Ruthenium Crystal On a solo crystal organo-metallic surface, individual sheets of graphene are created at an amazingly vacuum. Graphene forms on a flat crystalline surface both

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controlled integration of carbon from the bulk of the substrate or heat breakdown of ethylene (which was before the crystalline area at ambient heat 1000K) can be employed to accomplish this [43, 65]. Thermal Decomposition of SIC The creation of graphene via thermoelectric breakdown of silicon on the reference flat surface of a crystalline structure of 6H SiC has recently come to the attention of researchers. It is more quickly accomplished and is now a typical method for producing graphene. Unzipping of CNTs The most current method for producing graphene starts with cross-carbon nanotubes (Multi-walled carbon nanotubes). 'CNT unzippings been the name given to the process thus far. As a CNT is a wrapped sheet of graphene, one can produce a “graphene nanoribbon,” or a thin, continuous stretch of graphene [66]. In addition to nanoribbons and partially opened MWCNTs, the products comprised graphene flakes. MWCNT's plasma etching produced graphene nanoribbons in prior studies, which were partially integrated into a polymer sheet [48, 67]. Organic Synthesis Technique Synthetic organic chemists tried yet another technique to process graphene with absolute controllability, claiming that most kinds of graphene layers can be manufactured by organic processes. In organic chemistry, polycyclic aromatic hydrocarbons are thought to be 2D graphene segments with all-sp2 carbons (Fig. 2) [68].

Fig (2). An approach to organic synthesis of graphene.

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Graphene to Graphene oxide (GO) A material formed from graphene called graphene oxide (GO) is produced when grapheme is oxidized. Acid-base healing of graphite oxide followed by sonication produces GO, single monomolecular layers of graphite oxide. The attacks of GO include several functional groups, including oxygen, epoxide groups, carbonyl groups (=CO), hydroxyl groups (-OH), and phenol groups [19, 28, 32, 69, 70]. The remarkable physicochemical characteristics of graphene oxide (GO), including its tiny size, high plane area, extraordinary potency in 2D construction, and intriguing visual and electrical capabilities, have been discovered. The primary distinction between graphene and GO is the existence of oxygen molecule that is linked to carbon atoms. GO is a hydrophilic derivative of graphene. Surface interactions are made easier by the presence of both aliphatic (sp3) and aromatic (sp2) domains in GO [8, 22, 41, 71, 72]. It is created using a variety of techniques, often using the Hummer's approach [73, 74]. It has oxygenated groups on the molecule plane, including the Staudenmaier method [75] and Brodie method [76]. These morphological and structural characteristics give a better understanding of GO formation even though there is no defined structure for GO. The release desquamate graphene from graphite is hydrophobic by the environment, which makes it difficult to disperse in water and makes functionalization more difficult. In contrast, GO oxidizes to become hydrophilic, which makes it water-soluble. For prospective biotechnological applications, GO achieves outstanding aqueous processability, amphiphilicity, flat surface role capacity; light emitted ability, etc. (Fig. 2) [77]. Reduced Graphene Oxide (RGO) As was previously indicated, numerous epoxide and hydroxyl structural features present in the GO layer are stacked to create a 3D structure called graphite oxide [8, 41]. It can be made using affordable graphite as the raw material by efficient chemical processes with a high yield. The fabrication of graphene from GO has recently become a very significant topic of study [78, 79]. The oxygen-containing groups have been reduced, and reduced graphene oxide (rGO) is more hydrophobic than GO and recovers some of the conductivity and absorbance of graphene [80] The three most often employed techniques for reducing GO to rGO are molecular reduction [81], electrodialysis [82], and heat reduction [83]because it simply requirements a high temperature and not chemicals, thermal reduction seems to be the most practical and ecologically benign of these techniques [84]. In addition to temperature, the reaction solution's alkalinity is claimed to play a substantial role in the degree to which rGO decreases. According to Hao etal., the conversion of GO into rGO is facilitated by alkaline conditions because they can balance the bicarbonate ions generated [85]. rGO has a structure that is more akin

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to graphene than GO, giving it greater mechanical strength, electrical conductivity, and photothermal effect. As is well known, the superb photoacoustic effect offers significant potential for heat-induced controlled medication release and photoacoustic treatment against cancer [86 - 88]. Graphene Nanoplatelets (GNPs) The recently created, less expensive substance known as graphene nanoplatelets (GNPs) is a short stack of individual graphite layers that commonly enhances the composite tensile modulus and may be used as nano-sized additions with enhanced thermal, electrical, and mechanical properties [89]. These nanoparticles are made up of tiny stacks of graphene that range in diameter from a few nanometers to 100 micrometers and range in thickness from 1 to 15 nanometers [90, 91]. Additionally, it As an anode component in lithium-ion batteries and supercapacitors, a current-conducting cathode material additive, a conductive component in specialized coatings or glues, as well as conductive ink, etc [92]. For conductivity in a thermoplastic matrix, GNP has a 1.9 wt.% relative permeability. Conductivity reaches considerable levels at concentrations of 2–5 wt% to provide electromagnetic shielding [93]. GNP can also be blended with synthetic fibers or even other matrix materials to get the required ionic properties for electrostatic coating or other applications. Contrary to carbon black, GnPenhances the mechanical characteristics of most composites, especially stiffness and tensile strength. Elastomeric materials with cGMP reinforcement have a longer lifespan and experience less surface wear. When used at densities of 3 weight percent or more, xGNP significantly improves the insulative properties of compounds due to its platelet structure [94]. Even though cGMP nanoparticles may be oriented with the help of a magnetic field, most extraction processes don't need alignment. For applications like gasoline lines or fuel tank linings, the resultant composites provide considerable cost reductions since xGnP imparts electrical conductivity at these densities [95]. Graphene Quantum Dots (GQDs) Graphene that has been broken up into a few layers with dimensions ranging from 20 nm to 100 nm is what is known as a graphene quantum dot (GQD) [10]. Despite the popularity of colloidal semiconductor quantum dots (SQDs), the more varied and extensive applications of GQDs are constrained by factors like their extremely small size, expense, non-toxicity, biocompatibility, photostability properties, tunable fluorescence, water solubility, improved surface grafting, and chemical modification. On the other hand, GQDs are regarded to be superior to SQDs in terms of these problems [96]. The spectrum range of GQD fluorescence

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emission can include UV, visible, and infrared. Given that it has been connected to quantum confinement effects, defect states, and functional states that may be influenced by the pH of the water in which the GQDs are spread, the source of GQD fluorescence emission is a matter of debate. The crystallographic orientation of the edges of GQDs affects their electrical structure; for instance, zigzag-edge GQDs with a diameter of 7-8 nm display metallic behavior [97, 98]. Their energy gap typically decreases and increase the number of graphene sheet or carbon atoms per layer. The optical characteristics of GQD syntheses are covered in this section. The thermally reduced GO to graphene, produced GQD, has a diameter of 5–13 nm in an aqueous environment. It included chemically oxidizing graphene, followed by hydrothermal reduction to GQD [99]. Electrochemical procedures have also been used to produce GQDs based on anode corrosion, anion complexation, and exfoliation of carbon anodes [100, 101]. The vast range of applications for semiconductor quantum dots (SQDs) in solar cells, LEDs, bioimaging, digital displays, and other semiconductor technology has attracted interest. GQDs are acknowledged as novel materials in the disciplines of biology, microelectronics, energy, and the environment [102]. APPLICATION OF GRAPHENE-BASED NANOMATERIAL Application of Graphene-based Nanomaterials For Catalysis Graphene and graphene-based nanoparticles are important for catalysis because of their exceptional properties, structural, optical, thermal, and electrical, as well as their large specific area, two-dimensional structure, and superficial ornament excessive adsorption competence, which were designed and implemented for catalysis. These substances were discovered to have fascinating and promising performance, the oxygen reduction reaction (ORR), water splits, Fischer-Tropsch synthesis (FTS), reduction of carbon, and other crucial processes, including selective hydroxylation, oxidized, and acetylene hydrochlorination are examples of reactions that help with energy conversion and environmental protection (Fig. 3) [103]. Energy-Related Reactions New applications for graphene-based nanomaterials in catalysis are the major rate-determining stages of ORRs, fixed cathode reactions, and polyelectrolyte membrane fuel cells (PEMFCs). Graphene's attractiveness to ORR is its superior resistance to carbon deterioration-throughout energy cell operation, high exterior area, and advanced electron conductive that serves as an excellent aid in the uniform distribution of catalytically active nanoparticles that includes graphite function [104]. Therefore, the function of graphene as a catalyst is associated with

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its non-public the maximum usually used platinum (Pt) and base metallic support [104, 105], and the heteroatom-doped catalyst substrate [106]. This DFT calculation confirmed that zigzag ridges with many defects were chemically active by using native graphene as a powerful ORR catalyst, predominantly based on total cleavage by micromechanical means increased zigzag aspect thickness and the ratio of aspectthe to bulk particle of graphene promotes ORR activity significantly. However, scheming the ratio of edging and bulk atoms remains a modern-day challenge, and the use of pure graphene in ORR can be confirmed due to its low reproducibility [103].

Fig. (3). - An application of graphene and their modified biological application.

Water Splitting The production of hydrogen by water splitting is an interesting method of supplying future electrical needs. The reaction includes the water depreciation or hydrogen evolution response (HER) as well as the freshwater oxidation or oxygen evolution response (OER). Both straight use of sunshine (photocatalysis) and power generated from sustainable resources are the most studied and lowest-cost routes. Ritual sacrifice reagents (like methanol) typically utilize the photocatalytic approach to decouple the reactions since it is still necessary to build green photocatalysts again for the overall reaction process [103]. Adjust the

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configuration of HER and OER catalytic for durability is necessary since the two reactions occur independently on the anode and the cathode in the electrocatalytic pathway [107]. Intensive research has been conducted throughout the past three decades, and every electrocatalytic and photocatalytic approach has due to the two approaches' very different catalyst needs, this session will concentrate on the usage of nanomaterials based principally on graphene for each one individually. Water Splitting With Photocatalysis Considering its use in the electrolysis of water since its establishment [108], the two fundamental difficulties for photocatalysis have been the quick rearrangement of two electrons and the discrepancy between the radiation from the sun's spectrum and the energy band gap. Graphene is more than just a high-quality support because of its large surface area and better carrier mobility; it is also more than just a circuit board for delaying such recombination. The role of graphene in photocatalytic hydrolysis is discussed in this section, which includes electron acceptors and transporters, cocatalysts, photocatalysts, and photosensitizers. The use of graphene as an electrophile and for transportation has received the greatest attention in the study of photocatalytic hydrogen generation augmentation. Its high intrinsic electron mobility (200,000 cm2 V1 s1) and high occupation purpose (4.42 eV). The former feature enables graphite to accept photogenerated electrons from the lowest unoccupied molecular orbital (LUMO) of dyes or the conduction band of the majority of electronics without a barrier, resulting in efficient recombination suppression. Cross that 2D plane to the H2 Evolution reaction site [109]. An NGQD / gC3N4 catalyst is created by combining nitrogen-doped graphene quantum dots (NGQD) with gC3N4, It increases the photocatalytic properties of gC3N4 by countering the high recombination of electrons of the photogenerated electrons and holes. The PL up-conversion characteristics produced short wavelength light in the 400 to 600 nm range after excitation with light at 600 to 800 nm. This emitted light, along with UV from the ambient light source, is adsorbed on gC3N4 and causes electrons and holes (h+) to form. Electrons were transmitted to the NGQDS surface, but holes reacted with sacrificial regions. Efficient electron dissociation, as a consequence, leads to strong H2-producing activity (2.18 mmol H 1 G1 evolution velocity) and absorption coefficients (5.5% at 420 nm) [103]. Applications of Graphene-based Nanomaterials For Sensing Biosensing is a complex feature regarding distinct homes, together with the accessibility of the interface, effectiveness of transmission, biochemical responsiveness, electron transport, and mechanical and electrical resilience. An electrochemical biosensor plays a crucial function in biological sciences. They

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were widely employed for detecting bimolecular including DNA, proteins, hormonal, sugars, essential nutrients, and toxins, and for studying how proteins interact with one another and with neural interfaces, among other things [109]. There are numerous difficulties encountered by using researchers at some point in particle sensing, and the majority of previous findings are comprehensively elaborated in the literature. A sensor is a device that measures the amount of an industrial, chemical, or metabolic supply that comes from either the human body or the outside environment. The analyte is defined as a substance that makes sense (such as a biomolecule or biochemical, such as protein, phenol, etc.). The sense tool's receptor is used to find, comprehend, and bind to produce a reaction. Additionally, it is known as a reputational receptor. The sensor, or body sensor, was used to measure a physiological variable and record data on the tool's side. Heating, moisture, sunlight, energy, electricity, intensity strength, bond lengths, stress, redox responses, cation or anion transfer, weight, pH extrude, biological reaction, shadow extrude, etc., are likely to be used as extrudes to evaluate physical limits (Figs. 3 and 4) [110].

Fig. (4). - Sensing application of graphene in the broad area for sensing biological molecules.

Graphene has gained a lot of awareness in the production of electrochemical sensors and electrodes because of its low electrical conductivity and atomic breadth. A graphene is an appealing option for capturing high-density edge defect points on the graph, which provide some active sites for electron transfer. Graphene is a great electrode material because of its conductivity and the benefits of SP2 electrochemistry [111]. Compared to oxygen reduction by specific

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biomolecules, it exhibits outstanding electrode catalytic performance and highspeed electron transmission (ET) kinetics. It's been suggested that the oxygencontaining molecules on the graphene sheets, which may speed up the electron transfer rate, are also what cause the electrochemical properties of graphene to different redox systems. GO and chemical-based biosensors based on reduced graphene oxides (rGO) have been suggested in the past [112]. Electrons for graphene have been discovered to follow a linear dispersion relation, allowing them to move ballistically through the graphene sheet without scattering at room temperature. Their mobility is very high, which is the foundation of graphene's exceptional electronic possessions. Graphene is a potential material to be utilized in the creation of sensitive electrodes due to its high electron mobility, ballistic dispersion, and 2D characteristics for ultrafast electronics and molecular biosensing nanotechnology [113]. Applications of Graphene-Based Nanomaterials In Healthcare Bioimaging Nanostructures made of graphene are more recently highly studied for exploring medical and biomedical applications. In this way, bioimaging is one of the most modern diagnostic methods. The main requirements for bioimaging are sensitivity, specificity, and non-toxicity [114, 115]. For instance, when a 658 nm laser was used to stimulate the poly (ethylene glycol), it functionalized as nanographene oxide (pegylated nGO) and was selectively recognized. However, their low quantum yield limits in invivo were studied later [115]. Direct application of dyes on GO/RGO was also examined for learning fluorescence emission behavior in addition to the covalent bond study. As for Ce6,2(1hexyloxyethyl) 2devinylpyropheophorbidalpha, a second-generation photosensitizer was loaded, and found significant fluorescence quenching in GO or RGO porphyrin. Graphene bind with the rings present in the structure of these photosensitizers, stacking, and fluorescence quenching [12, 116 - 118]. When single photons are exposed to GQDs it shows differences in the ability to penetrate deep into issues. Fluorescence imaging and TPFI are also used for bioimaging applications. It has also been explored for magnetic resonance imaging and radionuclide imaging (Fig. 4) [117, 118]. Phototheranostic formulation and sodium cynoporphyrin are used to improve pegylated GO fluorescent radiation [119]. Recently, GQD with a diameter of 2e6 nm has given a response in the deep red region (680 nm) [120]. Substances uptaken by tumor cells of xenografted mice were studied using pegylated nGO with Cy7 fluorescent dye [121]. GQDs are selectively labeled in the cytoplasm rather than the nucleus. In vivo bioimaging studies performed GQDs subcutaneous injection revealed a powerful PL injection site. Bioimaging technologies are constantly evolving with

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the change of surface properties of GQDs to achieve efficient radiative behavior in invivo use [122]. Recent advancements in two-photon fluorescence imaging have also been used and have become an advanced analytical tool due to their ability to analyze deep sediments in living tissues [122]. For laser cancer microsurgery, a transferrin-modified pegylated GO probe was employed as a three-dimensional two-photon fluorescence probe. Also used as two-photon fluorescence deep tissue imaging probes were N-doped GQDs (NGQDs). Drug Delivery In modern medical science, various life-saving medicines are available. The basic fundamental performance of a drug molecule, including typical tissue damage/off-target side effects and ineffectiveness under in vivo conditions, is associated with the success of transferrin-modified pegylated drugs [123]. Nanomaterials have been intensively investigated for drug delivery applications over the past 20 years [124]. New therapeutic platforms for the selective delivery of medicines, DNA, and proteins, among other things, have been made possible by graphene and graphene-based nanostructures [125]. A relatively high specific surface area of graphene (2630 m2/g) could make it useful for use biomolecule delivery [126]. The high surface area of the graphene is an important property, It has been shown that as the number of layers per graphene stack increases, the surface area decreases, decreasing the ability of the stack to transport drugs. Additionally, the filler becomes stiffer, making it easier for it to enter the membrane cell [127]. As a result, it is believed that the graphene's lateral dimension and number of layers significantly influence the efficacy of drug loading [128]. Since virgin graphene is hydrophobic and inert, it has essential features that have been used to investigate various ways to functionalize its surface [129]. It is reported that drug delivery covalent and non-bond formed between graphene-based nanomaterials and drugs [22]. It might boost the loading of the medication, increase cellular absorption of the drug and improve the water dispensability of the drug loading mechanism. It has also been extensively researched how graphene-based nanostructures can be used to transport genes [130]. The centered gene shipping device is a sophisticated scientific tool for dealing with cell issues like cancer. As a gene shipping vector for siRNA, the polyethyleneimine-GO nanocomposite has been investigated [131]. GO-polyethyleneimine hydrogel nanocomposites have been used to create an angiogenic gene delivery device. This hydrogel device delivered a significant healing effect by transfecting cardiac tissues [132]. Additionally, an RGOpolyethyleneiminee nanocomposite has been suggested for use in a photothermally controlled gene shipping device. The nanocomposites demonstrated green gene transfection after NIR irradiation. In addition,

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multifunctional transdermal drug delivery using chitosan-graphene nanocomposite microneedles has been developed [128, 132]. In a pH 7.4 neutral environment, the nanocomposite released 150% more medicine when RGO was used.) than it did in an acidic one (pH 4) [121]. The nanocomposite microneedles displayed considerably superior launch of a model large-molecular-weight drug using an external electrical stimulus, 95% as opposed to 86% in 24 hours [126, 133, 134]. By improving the polymer matrix's electrical conductivity, graphene made it possible to use iontophoresis in conjunction with transdermal medication delivery. Chitosan-GQD nanocomposite microneedles are used to differentiate between drug releases by iontophoresis and passive diffusion (standard) [126 135]. Due to the photo-luminescent and/or magnetic qualities of GQD and RGOIOQD, the magnetic focus, in addition to imaging (fluorescent and/or magnetic resonance), may also be added into those micro-needle arrays, offering multifunctional transdermal drug delivery platforms (Fig. 3). Photothermal Therapy Similar to photodynamic therapy, photothermal therapy (PTT) has been recognized as an effective biological weapon in the battle against cancer. As the PTT agents absorb light energy in this therapeutic technique, electrical stimulation and nonradiative relaxation take place. NIR is also recommended in this situation, much like PDT. Increasing kinetic energy, raising the cell medium's temperature to roughly 50 °C, triggering membrane rupture, and denaturing tumor cell proteins [135]. Gold nanorods [136], UCN [137], CNTs [138], graphene, and iron oxide and graphene nanoparticles have all been investigated for the use of the photothermal process [139]. Ru(II)-Polyethylene Glycol Complex-Decorated Graphene Oxide was used as a PTT agent [140]. The GO system is connected with quantum dots like CdSe or ZnS because of the poor fluorescence characteristic of GO. However, this method is ineffective since GO drastically reduced the QD fluorescence. In response, GO was swapped out for RGO in a later paper that demonstrated a reduction in the extinction effect [141]. The RGO/QD system also exhibits strong photothermal efficacy in warming the neighborhood following NIR absorption. After nine minutes of NIR exposure, using RGO/QD with a micro length of 260 nm decreased cellular viability to around 30%, and utilizing RGO/QD with an incredibly short length of 38 nm practically destroyed MCF-7 cells. In addition, this gadget is better suited for mobile internalization than GO [138]. Others have already mentioned the impact of nano-structured GOES on PTT effectiveness against most cancer cells [120].

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Treatment of Cancer Using Graphene Oxide Due to its unique physicochemical behavior, unusually high surface-to-volume ratio, and variable surface properties, graphene oxide has lately been recognized as an attractive nanomaterial [142 - 144]. Due to this, it is the best GO (GO (HPPH)-PEG-HK) coated with a photosensitizer and v6-targeting peptide (HKpeptide) (HPPH). By increasing the infiltration of cytotoxic CD8+ T lymphocytes within tumors, the GO (HPPH)-PEG-HK activated dendritic cells and significantly decreased tumor growth and lung metastasis, according to in vivo optical and single-photon emission computed tomography (SPECT)/CT imaging [144]. The Chen group developed the DOX-loaded reduced graphene oxide-gold nanorods vehicle for application in photothermal therapy and chemotherapy. There was a considerable release of DOX as a result of the NIR photothermal heating activity and the acidity of the tumor microenvironment [145]. The absorption peak was increased from 528 to 600 nm as a result of the close packing of Au NPS on GO. Au (30 nm)-GO (20 nm) demonstrated a maximum temperature increase of 23.2 oC under laser light (808 nm, 1.0 W/cm2) [146]. According to Cheon etal. assumption [147], functionalized graphene sheets loaded with DOX and functionalized bovine serum albumin (BSA) could be an effective tool for combining chemo and photothermal therapy of brain tumors. To treat breast cancer, the Chen group developed a DOX-folic acid-GO thermosensitive hydrogel that was grafted with hyaluronic acid-chitosan-g-poly (N-isopropyl acrylamide) (HACPN) [148, 149]. They developed a revolutionary material that contains two chemotherapy drugs loaded on sponge-like carbon material supported by lipid bilayers (lipo-GNS) customized with tumor-targeting protein on graphene nanosheets (graphene nanosponge). The well-constructed ultra-small lipo-GNS (40 nm), which showed significant accumulation in the tumor location, significantly inhibited the xenograft tumors in 16 days [149]. Shao et al. synthesized reduced graphene oxide (RGO) with polydopamine functionalization and modified it with hyaluronic acid (HA) and DOX loading. The effective chemo-photothermal agent RGO@MS (DOX)-HA was transformed by the pH-dependent, near-infrared-triggered DOX release [150]. In recent years, Dai et al. have created a smart material for the removal of tumors called TiO2-MnOx conjugated graphene composite [151]. Applications of Nanomaterials Based on Graphene in the Optical and Optoelectronic Fields Electrodes with Transparent Conductivity The transparent conductive electrode is one of the most important parts of modern optoelectronic devices, including solar cells and many types of displays

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(TCE).ITO is frequently utilized in these applications as TCE. ITO's brittleness, however, restricts its application in several circumstances. ITOs are also restricted by indium's limited supply, which contributes to its rising price. As a result, there has been a strong mandate to switch out ITO for other flexible, affordable materials. When producing thin film electrodes, CNTs and graphene have the benefits of being inexpensive and simple to process [152, 153]. Phototransistors and Photodetectors In modern optical communications, the photodetector is a key component. Due to its high charge carrier mobility and brief carrier lifetime, graphene could be used in high-frequency, ultrafast photodetectors. A 40 GHz radio is feasible. A photodetector built on single- and few-layer mechanically exfoliated graphene with possible internal luminescence has been presented for use over a 500 GHz bandwidth. Photo carriers are produced and delivered in a way that is very different from how regular media semiconductors are. The ultrafast photodetectors did not require bias because an intrinsic electric field already existed between the metals graphene and electrodes. The optical detector's responsiveness was 0.5 MA/W, but using heterogeneous electrodes allowed it to respond at 6.1 MA/W [154]. Environmental Applications Of Carbon-based Nanomaterials With the continued growth of the world's population, optimizing agricultural production on scarce arable land while minimizing environmental harm is a significant problem for the future. In this sense, contemporary nanotechnology might offer the following contributions: Boost plant productivity by utilizing 1. Nanomaterial-based fertilizers and growth-promoting agents for plants. 2. The use of non-material crop protection products that comprise pesticides and herbicides results in a general decrease in the number of pesticides utilized. 3. Pesticides and fertilizer with sustained release nanocapsules. 4. Nanotechnology that introduces precision agriculture and optimizes agricultural methods. Carbon-based nanomaterials and active chemicals as additives make up 40% of all nanotechnology contributions to agriculture. The majority of these applications are still in development, but the strategy presented in this section looks promising [155, 156].

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CONCLUSION This paper summarizes how GBNs, a kind of multifunctional nanomaterials, can be employed for environmental, bioimaging, drug administration, photothermal therapy, catalysis, energy-related activities, water splitting with photocatalysis, optical and optoelectronic, and cancer therapeutic applications. Furthermore, the drawbacks of GBNs in practical sensing applications are discussed, along with possible remedies. The top-down and bottom-up production of graphene, organic synthesis, various processes, oxidative stress, and physiochemical features have attracted much attention. We think that this substance has the potential to resolve current medical problems and improve the particular way that graphene interacts with a certain kind of bacteria. The possibility of using graphene as well as its derivatives for bioengineering, drug delivery, and the creation of faster computer processors, among other fields, has been investigated in an increasing number of research studies released in the past year. This approach might act as a manual for creating and modifying GBNs for use in the health context. CONSENT FOR PUBLICATON None Declared. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT None Declared. REFERENCES [1]

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CHAPTER 4

SPR-Based Biosensors in the Diagnostics and Therapeutics Anjali Bhargav1 and Neeraj Kumar Rai*, 1 1

Central University of South Bihar, Gaya, India Abstract: To analyze the physio-chemical measures of the cellular environment and display them in digital units, transducing methods are applied in biosensors. The labelfree biosensors employ biophysical characteristics such as spectroscopic methods, crystallization, and Surface plasmonic resonance (SPR) to determine the availability or concentration of substances. SPR is a method to elucidate interaction among biomolecules exhibiting affinity binding, structural changes, or alteration in pathological conditions. SPR methods are now employed in conjunction with a variety of transducer topologies, including optical fibers, nanoparticle-based SPR, immobilized or localized SPR (LSPR), long-range SPR, image SPR, immune-assay-based SPR, and phase sensing SPR biosensors' versatile configuration allows for the early detection of several illnesses, such as COVID-19, dengue, non-invasive cancer, biomarker-based fetuses identification, therapeutic antibody characterization, drug monitoring, etc. SPR system is leading in diagnostics and therapeutics with various advantages, such as their portable size, cost-effectiveness, quick result, and easy-to-handle method, but at extension, this technique needs development to ensure high sensitivity, averting background effect and evolution of label-free direct detector to quantify real sample. This chapter reviews the model’s instrumentation and bioassay of clinical samples from SPR and its associated biosensor.

Keywords: Biosensor, Diagnostics, Surface plasmonic resonance (SPR). INTRODUCTION Surface plasmon resonance (SPR) was first introduced by Liedberg et al ., in 1983; this technique has been utilized widely for the development of label-free and real-time biosensors [1]. SPR-based biosensors have been developed approaching various parameters (Affinity Binding, kinetics, Stoichiometry, Thermodynamics, and Analyte concentration) and interactions (Antibody–antigen, Ligand–receptor, Protein–DNA, Protein–protein, DNA–DNA, Protein–carbohydrate, Cell membrane interactions and Protein/DNA–virus interaction) upon various samples. * Corresponding author Neeraj Kumar Rai: Central University of South Bihar, Gaya, Bihar, India; Tel: +918507360084; E-mail: [email protected]

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.)

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The history of this technology started with the discovery of surface plasmon excitation (Table 1). Still, this technique continuously upgrades different parameters, such as instrument design, data analysis, and high-quality sensing. Table 1. History, discovery, and development of Surface Plasmon resonance. Year

Events

1902

Thin dark bands were observed by Wood through a diffraction grating [2]

1957

Ritchie predicted the elementary surface excitation value of SPP as a surface plasmon [2]

1968

The coupling of light with the surface plasmon by Otto which leads to the formulation of surface plasmon polariton (SPP) using attenuated total reflection (ATR) [3]

1971 Proposal of Kretschmann configuration of ATR coupling by Kretschmann, whose excitation method is followed in SPR biosensor [3] 1975

Term ‘Biosensor’ coined for the direct detection of biomolecules present at the surface using the transducer principle [4]

1983

SPR-based biosensor was first demonstrated by Liedberg et al . [4]

1988 Introduction of Surface plasmon microscopy by Rothenhäuslar and Knoll, which enables in imaging of interfacial structure through microscope [2] 1990

First SPR biosensor instrument was commercialized by Biacore [4]

1990

The carboxymethylated dextran labeled surface has been introduced for SPR application [4]

1996

Technique for phase interrogation was introduced by Nelson et al ., based on SPR sensing [2]

1998

First phase-resolved SPR imaging (SPRi) sensor was proposed by Nikitin et al . [2]

2012

Brian Kobilka and his coworkers win the Nobel prize in chemistry for application of Kretschmann configuration [2]

The basic principle of the SPR technique is based on the signal detection of altered refractive index developing at the surface of the sensor when the analyte flows around the channel (Fig. 1) and interacts with the immobilized ligands. As per the current estimate, a report has been published in ‘Future Insight Market’ that SPR global market will reach up to US$ 910.4 million in 2022 and US$ 1.5 billion by 2029 [5].

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Fig. (1). Representation of SPR sensor surface showing flow channel, metallic nanomaterial, and refraction.

Many new SPR technologies are revolutionized by collaborating with microscopy and spectroscopic methods to integrate their value. Some recent applications of SPR are surface plasmon resonance imaging (SPRI), SPR-Biolayer Interferometry (SPR-BLI) [6], and SPR-enhanced electro-chemical-luminescent (ECL) [7] (Fig. 2). In such a technique, a metallic surface consists of densely packed nanoparticles, where plasmonic interaction with metals such as silver and gold nanoparticles is utilized for medical sensing and the determination of biological and chemical analytes from a sample. Here, analyte separation and the refractive index at the surrounding medium are very sensitive aspects for their application. The change in the dielectric environment occurs due to the binding of a molecule, and altered refractive angle. Consequently, causing resonance shift that allows the determination of analytes such as biomolecules and chemicals. The fundamental aspect on which analyte separation and the refractive index at the surrounding medium depends is the characteristic of metal and the immobilized surface. Investigated chemicals are allowed over the surface of chips, and specific binding of analyte present in the sample, to the nanoparticles, will change local dielectric properties resulting in a noticeable shift in localized surface plasmonic resonance (LSPR) [8]. However, by using basic principles of functionalized nanoparticles, resonance angle, enhancement of interfacial means, and biomolecular interactions, continuous advances are used in SPR biosensors, which provide broad significance in diagnosis and therapeutics.

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Fig. (2). The summarized representation of targeted samples, major components (transducer and display unit), and applications of SPR. The transducer consists of electric devices such as nanowire array, nanoparticle, electrode, and field-effect transition devices to detect corresponding ligand-receptor binding. The signal processor directs the deviated surface reflective index to amplify and display as a response unit.

FUNDAMENTALS OF SPR TECHNIQUE Surface plasmon resonance (SPR) is a technique based on the optical incidence that comprises oscillation wave of charge density and dielectric metal upon interaction with polarized light. Due to the exponential decay of the metal and dielectric hybrid layers, the interface originating at the metal surface can be stimulated under the influence of a longitudinal electric field for a brief period. The surface plasmon waves have an electromagnetic intensity in the range of 200 - 400nm, which is highly sensitive to alter dielectric properties [9]. Metaldielectric interface could not excite with direct light; therefore, propagation of incident wave was enhanced through the dielectric means to extend the prolongation at surface plasmon. Three major methodologies that were worked for prolonged propagation of waves are diffraction grating at the surface [10], attenuated total reflection (ATR) in prism coupler, and optical waveguides. The coupling of surface plasmon with an electromagnetic field where wave does not propagate, momentum could be determined through the wavelength of incident light and dielectric constants of the metal layer present on the surface. The diffraction of light proved considerate in the amplification of momentum at the surface to compensate for the generated wave difference using metallic diffraction grating (Fig. 3).

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Fig. (3). Excitation of surface plasmon wave using metallic diffraction grating from incidence light in a dielectric medium.

Another method for prolonged wave propagation is attenuated total reflection (ATR) in a prism coupler, followed by the Kretschmann configuration. The highreflective index glass prism is applied to reflect incidence light at the metallic surface, and consequently, resonance occurs by the constant exposure of light [11]. The originated metallic-dielectric interface is implied widely on commercial SPR-based biosensors (Fig. 4). The defined SPR angle where resonance occurs upon constant light exposure, even minor alteration such as binding of the receptor to ligand can be observed as a reflective index of the sensing medium on a detector and plasmon cannot be formed. Moreover, quantification of surface concentration can also be done followed by inspecting the reflection of light intensity and shifts in resonance angle since the detection limit to 10 pg/mL.

Fig. (4). Excitation of surface plasmon wave using prism coupler via constant light exposure and metaldielectric interface.

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The waves whose amplitude become down with distance due to least propagation are excited at the interface of fiber and their border towards directed light wave upon optical fiber. It is also referred to as a surface plasmon wave at the corecladding interface. In case when clad piled up on a thin metal layer and incidence light wave could penetrate that metal layer, the surface plasmon wave gets excited consequently at the core-metal interface [12]. Hence, the directed light wave can be guided mode of wave (Fig. 5).

Fig. (5). Excitation of surface plasmon wave using optical waveguide via the constant core-cladding interface.

The ideal coupling between an incident light and surface Plasmon wave (surface plasmon resonance condition) is mainly influenced by the refractive index of the dielectric medium at the nearby surface of the metal layer. The dielectric medium represents a strong electromagnetic field which is why the SPR technique is known for its high sensitivity and surface-based analysis. The majority of commercialization and development of SPR is focused on alteration in optical features of surface plasmon waves and their interaction with light waves, such as intensity, phase, and interface generation. Therefore, the correlation of reflected light and the propagation constant of the surface plasmon wave is manipulated in designing SPR devices targeting various parameters such as intensity [13], angular [14], wavelength [15], phase or polarization [16] modulation-based device.

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APPLICATIONS OF SURFACE PLASMONIC RESONANCE Surface Enhanced Raman Scattering (SERS) The enhanced scattering of photons at nearby metal nano-materials is an important application of SPR, which is also implied as Surface Enhance Raman Scattering (SERS) that represents the inelastic scattering among a photon and an emitter, assisted by the vibrational or rotational mode of the molecule. The rise in scattering observed with environmental change and extended electromagnetic field occurs due to excitations of surface plasmon as well as filled electric field lines at the metal interface at the near-field of the metallic nanomaterial or a roughened metal surface. These are the advancement of the Raman cross section and recorded enhancements up to the date in order of 1014, which was raised on the roughened silver surface [17]. Fluorescence Enhancement The fluorescence of a molecule could also intensify as SERS in the presence of metal nanomaterial. Here, the incident field excites the molecule, which consequently enhances the fluorescence because of plasmon resonances at the metallic surface. Nanomaterials are used to prevent quenching of fluorescence from non-radiative processes or absorption that happens during surface plasmon resonance. The use of nanoparticles between two particles enhances the fluorescence intensity by 6 times and fastens the radiative decay rate up to 6–9 times based on the experiment. So, in such a way, the emission characteristic of the photon was conserved [18]. Few experiments explained the seriousness of distances when emitters are coupled with metal nanoparticles. Surface Plasmon Resonance imaging (SPRi) SPRi is a real-time optic-based biosensor used to determine the interaction among biomolecules. The imaging facility provides the visual spectrum of the refractive index at the surface of SPRi-Biochip [19]. This technique also correlates with mass variations which enable the determination of analyte concentration and the affinity of the interaction. Either in the case of binding or mass accumulation, a shift in resonance angle is featured due to alteration in refractive index. The variations in resonance angle (Resonance Unit) plot against the time duration concerning the kinetics of interacting biomolecules like ligands and receptors (Fig. 6). The plot represents four major steps that are following:

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Fig. (6). Representation for determination of molecular interaction (ligand-receptor) in sensorgram where resonance signal versus time plot showed kinetics of interaction.

Step 1: The immobilized ligands at the surface of the functional SPRi Biochip where no receptor bindings are allowed. In the plot, it implies a baseline as no interactions are there. Step 2: Analytes (receptors) are injected through the flow channel for binding to immobilized ligands, which induces a shift in resonance angle. Upon ligandreceptor binding, the association is measured with an increase in resonance units per second. Step 3: After maximum ligand-receptor binding, dissociation starts on sample ejection, which shows a decrease in resonance signal. Step 4: On complete dissociation, the plasmon curves and the kinetic curves return to the initial state. Hence, the resonance unit starts to fall down as the initial step. SPR - Electrogenerated Chemiluminescence (SPR-ECL) Surface plasmon resonance (SPR) and electrogenerated chemiluminescence (ECL) are two biosensors known for quantitative, specific, sensitive, and real-time analysis used for clinical purposes [7]. The coupling of ECL with SPR mainly assists in antibody detection from biofluids, overcoming an important concern of SPR, which is the adsorption of bio-analyte to the surface if the sample is fluid in nature, even though it gives real-time information. ECL lacks an adsorption approach like SPR, but it favors crude as well as fluid detection. Hence, the SPR -

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ECL instrument would be a better option for the determination of interfacial means employed in ECL and surface plasmons, as well as luminophores coupling will also provide enhanced chemiluminescence similar to the approach of metalenhanced fluorescence. The enhancement in order of factor six was observed when the luminophore was placed at least about 10 nm distance; otherwise, the transfer of energy from the luminophore to the metal surface caused quenching of ECL, and upon extension of distance than 10 nm, lower field caused diminished plasmon enhancement [20]. SPR - Biolayer Interferometry (SPR-BLI) The Biolayer Interferometry system is similar to SPR, it has an immobilized layer of recognizing molecules at the surface of the sensor, but in BLI tip is allowed to dip into the analyte where interaction occurs among the immobilized layer and corresponding molecule. Upon binding, disturbances arise at the interface in the pattern of white light which is recorded in biosensors. Here, a reflection of light is attempted first at the stationary surface and next at a molecular binding surface. This event introduces wavelength shift directly proportional to the optical depth of the binding surface. BLI has an advantage over SPR in the way of dipping biosensors than using flow channels in SPR, which is cost-effective as well as a high throughput system regarding the kinetics of interaction, the binding affinity of ligand-receptor and molecular specificity [21]. In SPR, the binding of immobilized ligand to analyte molecule gives an increase in signal intensity due to alteration of refractive index at the metallic surface, but in BLI, this has been recorded based on altered optical depth due to molecular binding at the tip surface. So, the SPR provides more sensitivity for an analyte, and enhancement at the interface gives an opportunity to couple with other approaches, such as fluorescence and chemiluminescence. To the date, both technologies are well-developed as well as widely accepted for their possible replication, less error with the human sample, real-time detection, and label-free assay. Unless the measure of enthalpic changes occurring while the interaction was not required for viral detection. As matrix dilution may be ascendent in resulting the total enthalpy output because of different binding competitors, the binding event may affect a single binding component in the immobilized surface. Hence, regeneration of the surfaces is required so that binding would not affect the structural orientation of the molecule, which is possible with SPR biosensor and to carry over dipping of sensor surface in analyte sample with various dilutions with an optimized buffer, which also provides structural affirmation to immobilized molecules can be done by coupling of SPRBLI [6]. This SPR-BLI coupled technique needs advancement in surface

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development to be robust for viral detection or such sample where various optimized buffers are required for dilution for specific binding without affecting the structural orientation of interacting molecules in the analyte. SPR IN DIAGNOSTICS AND DISEASE DETECTION SPR in Viral Disease Detection Surface plasmon resonance and coupled SPR techniques are known for real-time and label-free analysis based on quantification of biomolecular interaction and wide concentration range, which could also provide kinetics of binding. This technique has been employed to develop a device that can show featured virusligand interactions and determine a viral subunit during ligand interaction. Some technologies used in virus–ligand and virus-like particle–ligand binding is shortly discussed in the given column, developed by using various immobilized surface, buffer and nanoparticles (Table 2). Table 2. SPR devices associated with the detection of viral infection. Virus

Immobilized Surface; Ligand

Buffer; Metallic Layer

Year; Reference

Cytomegalovirus (CMV)

CMV specific micro-RNA; poly(A)-Au

PBS; MagneticNanoparticle

2021 [22];

H5N2 virus

Streptavidin biosensor, biotinylated aptamers

PBS; Gold film

2019 [23];

Potato virus Y(PVY)

CM5 sensor chip, amine coupling of mAbs; Anti-PVYN antibodies

HEPES; Gold Surface

2018 [24];

Norovirus (NoV)VLPs

CM5 sensor chip, amine coupling of rabbit anti-mouse IgG. Followed by mAbs; NoV mAbs

HEPES; Gold surface

2015 [25];

H5N1, H5N8, and H5N2 viruses

Biotin-labeled H5Nx-specific aptamers; Streptavidin biosensor, biotinylated aptamers

PBS; Gold film

2016 [26];

Bovine viral diarrhea virus Streptavidin biosensor, biotinylated (BVDV) type 1 aptamer; Aptamers, for sandwich assays

PBS; Gold film

2014 [27];

Porcine reproductive and respiratory syndrome virus (PRRSV) type 2

Streptavidin biosensor, biotinylated aptamer; Single-stranded aptamer

PBS; Gold film

2013 [28];

Feline calicivirus (FCV)

CM3 dextran sensor chip, amine coupling of Abs; Anti-FCV Abs

HEPES; Gold Film

2013 [29];

Cytomegalovirus (CMV)

CM3 sensor chip, amine coupling of CMV virons; CMV glycoprotein B antiantibodies

PBS, Gold film

2011 [30];

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An SPR biosensor was designed in multiplex format to detect the active virus in a patient with respiratory issues, which was targeted to the detection of nine different viruses that are H1N1, influenza A and B, respiratory syncytial virus (RSV), adenovirus, severe acute respiratory syndrome (SARS) coronavirus, and parainfluenza viruses 1–3 (PIV1, 2, 3). For the accuracy of the sample, a throat swab is considered as a specimen. The working principle of this technique is first, all nine virus-specific oligonucleotides were intact as an immobilized surface of SPR chip. Biotin-labelled primer is used for strong signal and high sensitivity upon amplification [21]. Further quantification is done, followed by streptavidin addition and hybridization. This device shows better output and promising for the application of detecting common respiratory viruses in future. Later, another biosensor has been developed for the detection of human immunodeficiency virus (HIV) and human papillomavirus (HPV) and mumps virus using SPR. Synthetic polymeric receptors have also been used in SPR to determine waterborne viruses and endotoxins such as MS2 phage, adenovirus, and E. coli endotoxin. SPR in Molecular Sensing SPR is one of the highly sensitive techniques which enables the detection of limited sample quantity. In terms of sensing molecules, especially protein, SPR combats various biochemical analysis steps, such as reagent preparation. SPRi provides the advantage of determining multiple approaches in an instance, such as the binding affinity, kinetics, analytes and their coated targets through biomolecular interactions. Enzyme-Linked Immuno-Assay (ELISA) is also utilized for the determination of molecular interaction, and it is more advance than conventional biochemistry, but it needs labelled ligands as well as multi-steps to come on output. The introduction of label-free SPRi shows efficiency in various aspects such as time, label-free, specificity and sensitivity [31]. The 2D spectral SPRi works on the phase interrogation principle and provides real-time ultrasensitive molecular sensing with a detection limit of 125 pico-mole, experienced on the anti-bovine serum albumin (anti-BSA) to the BSA antigen interaction and goat anti-rabbit IgG to rabbit IgG antigen–antibody interaction [2]. There are various applications of SPR that are utilized for molecule sensing in terms of drug screening and biomarker detection and many more, few of them are the following: a. In the case of analyzing cancer cells, an apoptosis marker, cytochrome c, was used to detect to differentiate cancerous cells in a sample with both spectral and conventional SPR [32].

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b. Quantification of antibody-secreting from hybridoma cells using SPRi [33]. c. Binding of oligonucleotides or primers with marker stretch of nucleic acid is also a well-performed way to determine nucleic acid where surface-coated probes are allowed to bind target DNA or RNA. The detection of short nucleotides is sensitive as well as effective at such a low concentration of 100 pM, using SPRi, which is 100 times improved than conventional SPR [34]. d. Aptamer is a single-stranded DNA or RNA that can acquire 3D configuration and target specific stretch. The binding of aptamer in real-time SPRi provides a kinetic profile with possible targets, which is highly sensitive as well as specific and supports as low as six SELEX cycles along with negative selection [35]. The optimization of buffer and possible washes up to elution is required in case of affinity-based separation because salinity and pH may vary with various recognition element-target. For example, the development, production and purification of recombinant ligands such as humanized gene, recombinant insulin and recognition elements. This concept and principle have been used while determining antigenic structure of herpes simplex virus, calorimetric assay of protein interactions, quantitative measures of in-epitope binding to develop subunit vaccine. e. Utilizing SPRi, qualitative as well as a quantitative study of the biomolecule interactions has been done already to understand the post-translational and transcriptional modifications of histones in DNA and RNA, which is key to discovering the epigenetic regulation in particular. SPR in the study of Live Cell Investigation of cell-surface interactions usually needs fluorescence-label cells to observe using microscopy. SPRi provides high-resolution imaging and sensing for the study of surface interaction; otherwise, limited detection sensitivity, quenching and fluorescence stain toxicity causing the short lifespan of a cell are various drawbacks of conventional fluorescence-based analysis. The procedure of live cell imaging through SPRi involves the attachment of cells on the sensing surface, having an inert metallic surface such as gold. Then the image resolution was enhanced by interfacial enhancement using random nanodot arrays format. Finally, time-lapse scanning surface plasmon microscopy has been employed to adherent living cells or bacterial biofilms to study [2]. The different applications of the given approach are the following: a. The distance between cell and substrate has been analyzed in human aortic endothelial cell (HAEC) culture at 40–60 nm using SPRi. The detailed features of the cell have also been studied, such as the width of the accumulated cellular protein layer as a measure of the effect of the induced drug with a variable time duration that was 20 ng/cm2 [36]. This technique enables the

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understanding of cells to fibronectin (FN), an extracellular matrix protein interaction with a resolution of 2 µm. Expression of FN has been noticed during cell adhesion, growth, migration, differentiation, wound healing and embryonic development. SPRi also enables the study of cell surface antigens through pre-coated antibodies which work as a tool for cell identification and blood group typing [2]. Real-time analysis of cellular pathways within the live cell, such as tracking G protein-coupled receptor signaling. Few related mechanisms have also been explored simultaneously, like PKC translocation upon ligand interaction with mGluR1 and A1R-mediated regulation in mGluR1-mediated PKC translocation in HEK293 cell line cells via SPRi [2, 37]. SPRi sensing surface was also employed to understand cerebellar motor learning on a cellular basis. Diagnosis of secretory defects in the pancreas has been analyzed in a diabetic patient using SPRi surface sensing. Studies showed islets of Langerhans cells as an ideal site for detecting multiple islet’s secretion products belonging to paracrine secretion via an array format of SPR targeted to hormones and pathways in secretory defects [2].

SPR in Healthcare Testing To rapid the process of investigation in the disease condition on the basis of symptoms, nucleic acid and protein markers used to ensure target infection, DNA probing using SPR array is common for nucleic acid biosensing. Earlier, failure was associated with the investigation of minute nucleic acid stretches due to smaller size, less concentration and low sample size, such as human microRNAs. Then, the coupling of reverse transcription polymerase chain reaction (RTPCR) provides sufficient sample size because of amplification, but this method was time-consuming. Therefore, SPRi is a better option as it is both fast and has a good amplification range of signal for reverse transcribed RNA and bound targetspecific RNA-DNA hybrid [2]. Protein determination using a particular biomarker, usually antigen–antibody interactions, is preferred for rapid confirmation of infectious disease, mainly in allergic sensitization, blood transfusion and viral infections. To confirm the peanut sensitization, SPRi was used to quantify the level of Immunoglobulin E (IgE) antibodies corresponding to four targeted peanut epitopes and anti-IgE. Now, the determination of viral surface protein as well as group-specific antibodies, has been reported for SPR nano-arrays [38].

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Transfusion of mismatched red blood cells (RBCs) shows adverse response and complicates future transfusions. However, the gold standard kit for blood type determination with the agglutination-based ABO and Rh blood type. Development of SPRi provides anti-A, B and O specific antibodies along with Rh-D, C, c, E, e, and Kell antigen-specific [39] antibodies with 100% agreement in cross-match comparison with Sanquin National Screening laboratory typed with classical serology. This high-throughput identification facilitates the identification of multiple blood group antigens in an instance with 946 donor samples, which is impossible with the conventional method [2]. Diagnostic wings prefer the development of portable on-site screening devices while visiting remote areas and disease eradication programs. So, Mobile-based SPRi devices have been designed coupled with computing programming and smartphones, which enables storage of large analysis data such as insulin detecting devices, handheld devices for telemonitoring of geriatric cancer patients, fast spectral imaging devices for tumor margin mapping, and so on. SPR in Cancer Diagnosis To date, many SPR biosensors have been designed for the purpose of diagnosing several tumors and cancer diagnosis. It has been reported that SPR-based biosensor enables the detection of cancer biomarkers in serum samples through sensing technology, such as carcinoembryonic antigen against colorectal and lung cancers, prostate-specific antigen (PSA) against prostate cancer and so on. Microcontact imprinting coupled SPR biosensors use clinical samples to highly sensitive as well as a specific result where the stable and regenerative sensor has been accommodated. Some devices used to quantify tumor markers in the early phase, such as human chorionic gonadotropin and activated leukocyte cell adhesion molecules from blood plasma [40]. The nanoparticle-enhanced SPR biosensor was developed for the investigation of breast and oral cancers by coupling nanoparticles and immunoassay that detects tumor necrosis factor-alpha (TNF-α) antigen at a very low concentration that is in femtomolar quantity. It became possible because of the enhancement of the plasmonic field originating from the gold rod to increase sensitivity. The antibody-functionalized biosensor, which is already conjugated with gold nanoparticle rods, has been designed for ultrasensitive sandwich immunoassay and is 40 times more sensitive than the conventional SPR technique. This technique is employed on cancer-related diagnosis with a detection limit (of 0.03 pM) which is proficient in detecting minute variations of TNF-α to discover novel cancer biomarkers.

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The amplification of SPR imaging in RNA-aptamer microarray format enables the detection of picomolar concentrations for enzymatically active protein biomarkers of cancer. Here, the adsorption of proteins forms a surface aptamer–protein–antibody complex over RNA microarray, and then SPR imaging signals amplify it followed by localized precipitation reaction in the presence of horseradish peroxidase. This technique has been used first time for human thrombin at a concentration of 500fM. Further, a biomarker, vascular endothelial growth factor (VEGF) was examined against lung, breast, colorectal, and rheumatoid arthritis and is age-related muscular degeneration [1]. Another approach of SPR scattering and absorption spectra was demonstrated for oral cancer detection by conjugating gold nanoparticles to monoclonal antiepidermal growth factor receptor (anti-EGFR) antibodies. Upon incubation of one non-malignant and two malignant cell line together, specific binding was imaged on the cancerous cell surface with an affinity of 600% more compared to normal cells. This specific binding induces a sharper SPR absorption band with a red shift in wavelength than added to the normal cells [41]. Hence, SPR scattering imaging or coupled absorption spectra resulting from antibody-conjugated gold nanoparticles shows efficient cancer investigation in vivo and in vitro oral epithelial study. SPR in Detection of Infectious Disease Microscopy, culture, immunoassays, and nucleic acid amplification are a few pathological investigation methods that are frequently used to confirm infectious conditions. According to reports, poor diagnosis, laborious analysis, and postponed treatment account for approximately 95% of infectious disease-related mortality. The development of techniques like SPR-based bioanalyzers can facilitate a wide array of diagnoses for bacterial, viral, fungal, and parasitic infections. The SPR biosensors enable detection at a limit of 103CFUmL−1 with low sample concentration and no secondary labels to image whole Escherichia coli, Methicillin-resistant Staphylococcus, Salmonella, and Lactobacillus [1]. Although, some controversy is found related to the whole bacterial diagnosis through SPR, such as low sensitivity and limited penetration of bacteria in the electromagnetic field because of undifferentiated refractive index resulting from bacterial cytoplasm and aqueous medium. Otherwise, using the DNA sensing mechanism of SPR biosensor enables Mycobacterium tuberculosis detection. CONCLUSION SPR biosensor technology is featured with measures of binding among immobilized and analyte allowed in flow chamber utilizing the principle of light reflection. The implementation of specific biomarkers and coupling with other

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approaches leads to advancement in the diagnosis and detection of diseases, such as cancer, viral diseases, allergic reactions, and enzymatic or protein-related disorders. Employment of advanced technologies in the microelectronics and nanotechnology industry integrated with SPR-based sensing devices has upgraded the analysis, affirmative output, high throughput, and data storage of these systems. Some of the recently developed SPR sensors are designed to analyze around 7000 molecular interactions per day, which have a high significance in drug discovery, studying signaling pathways, mimicking protein folding, targeting novel therapeutic molecules against cancer as well as performing multiplex detection assays [42]. The major advantage of employing SPR biosensors in diagnostics for the molecular level of investigation is their Label-free and realtime kinetic properties. The development of more specific and stable ligands, along with the computation of receptor and target biomarker-based interaction, needs computational research to succeed in the field of sensing technology, surface design, and metallic nanostructure designing in health care. There are a few reported limitations in the case of SPR-based sensing that optimization is required for surface regeneration in terms of buffer and chemicals. Another drawback is the occurrence of nonspecific binding in clinical samples of humans, a smaller number of immobilized partners, and limited penetration of the sensor in some cases. SPR-based sensing technology has put forward a great future in the diagnostic and discovery of new therapeutic candidates as well-accepted devices in the field of biosensors. CONSENT FOR PUBLICATON Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGMENT Declared None REFERENCES [1]

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CHAPTER 5

Implication of Biosensors For Cancer Diagnosis And Therapeutics Shubha Gupta1, Navitra Suman2 and Neeraj Kumar Rai2,* College of Medical Technology and Allied Health Sciences Sanjay Gandhi Post Graduate Institute of Medical Sciences, India 2 Department of Biotechnology Central University of South Bihar Gaya, India 1

Abstract: “Caution is the parent of Safety”. Early-stage diagnosis of Cancer can provide better medicinal therapeutic responses. Currently, a majority of cancer is diagnosed after having metastasized throughout the body. This led to the urgent requirement for potent and precise cancer detection methods for clinical diagnosis. Over the last several decades, the majority of researchers have concentrated their efforts on developing a potential rapid detection technique based on Biosensor technology for a variety of frightening human health-related disorders, such as cardiovascular disease, cancer, diabetes, and others. Significant advances were made in a wide range of fields attributed to the designed techniques having enhanced sensitivity, specificity, and repeatability. The development of diagnostic treatments in medicine was aided by noteworthy advancements in other scientific fields, including genetics, chemistry, micro-electrical engineering, and computational biology. As a result, efficient, accurate, rapid, and steady sensing platforms have been successfully developed for specific and ultrasensitive biomarker-based disease diagnostics. Biosensors are analytical devices designed to detect biological analytes by converting biological entities’ responses (DNA, RNA, Protein) into potent electrical signals. The biosensor device combines a biological component with a physiochemical detector for sensing an analyte (biological samples). The discovery of the Biosensor boosted the potential clinical diagnosis of cancer at a large scale. Biosensors can be designed to detect emerging cancer biomarkers and determine drug efficacy at various target sites. Biosensor technology has the potential to be used as a diagnostic tool for accurate and impressive cancer cell imaging, tracking cancer cell angiogenesis and metastasis, and evaluating the efficacy of treatment for the disease. This chapter will provide a quick overview of the challenges facing the early diagnosis of cancer, get through the depth of how biosensor technology may be used as a reliable diagnostic tool, and highlight potential uses for biosensor technology in the future.

Corresponding author Neeraj Kumar Rai: Department Of Biotechnology Central University of South Bihar Gaya; E-mail: [email protected]

*

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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Keywords: Biosensors, Cancer detection, Early-stage diagnosis, Nanotechnology, Oncogene.

INTRODUCTION Cancer is a significant health problem affecting people worldwide; additionally, it is one of India's leading causes of death. In 2018, 18.1 million new cancer cases (17.0 million excluding non-melanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding non-melanoma skin cancer) were predicted by Globacon. As per ICMR data published in May 2016, the new instances of cancer in India had increased to 14.5 lacs per year, with the number expected to rise to 17 lacs by 2020 (http://icmr.nic.in/ncrp/pbcr2012-14/index.htm), owing in part to lifestyle changes and economic advancements in the country. Lung, prostate, breast, ovarian, hematologic, skin, and colon cancers, as well as leukemia, can take over 200 different forms, and both environmental comprising tobacco smoke, alcohol, radiation, and chemicals and genetic factors, i.e., inherited mutations and autoimmune dysfunction linked to a higher chance of getting cancer. Additionally, there is a strong correlation between the development of several cancers involving bacterial and viral diseases comprising stomach cancers and cervical cancer, respectively. Even though cancer is more usually identified in older age (The majority of instances 77%, are found in adults 55 and over), Children ages 0 to 14 will receive diagnoses for 11,000 instances. According to the American Cancer Society (ACS), the worldwide cancer survival rate estimated for 5 years increased to 67 percent between 2010 and 2016, up from 50 percent between 1975 and 1977. This rise in survival can be ascribed to the biomedical advancements that have resulted in better treatment and earlier detection. The application of developing biosensor technology could help with the early-stage diagnosis of cancer and thus more effective therapies, increasing the likelihood of overall survival and improving patient quality of life. Cancer is a group of specific genetic and epigenetic abnormalities, which can be either environmental or inherited and result in uncontrolled cell development. Uncontrolled cell proliferation creates cancer cells that develop immunity to regular checking and balancing within the homeostasis over time. Tumors develop immunity to apoptosis and other anti-growth mechanisms in the body [1]. As cancer spreads to other body organ systems, the tumor keeps expanding past its original location, at which time it is essentially incurable. The two primary routes for carcinogenesis are oncogene activation and tumor suppressor gene (TSG) inactivation [2 - 5]. When a typical gene (a proto-oncogene) involved in cell formation, multiplication, and/or diversification is altered or duplicated, oncogenes are activated. This usually leads to excessive production of a typical gene product or unregulated stimulation, which causes cell growth to be disrupted, cell division to rise, and tumor formation to occur. As potential cancer indicators, growth factor

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receptors have been studied, more than any other type of oncogene. In 33 percent of all breast tumors, for example, the human epidermal growth factor receptor Her-2 is amplified, and tumors having amplified Her-2 develop and spread more aggressively. As a result, knowing of Her-2 condition is crucially important for developing the best therapeutic approach. Trastuzumab, a transgenic humanized monoclonal antibody aimed towards Her-2, is now the mainstay palliative therapy for individuals with this level of elevated transcriptional [6, 7]. By slowing or preventing mitosis, TSGs help control unregulated cell cycle progression by delaying or inhibiting mitosis. Retinoblastoma protein (Rb), BRCA1/2, and p53 were indeed a few of such TSGs in cancer that have undergone the most investigations [3]. Rb is said to be a master regulator of cell division, and Rb mutations are linked to a variety of malignancies. The far more typical reasons for Rb1 gene silencing are point mutations and deletions [8 - 10]. BRCA1 is the DNA repair enzyme that checks to validate the newly replicated DNA for fidelity and mutations. Normally, DNA repair enzymes eliminate replication defects before a cell multiplies. About 50% of hereditary breast cancers and 80%-90% of hereditary breast and ovarian cancers are caused by BCRA1 gene abnormalities [11, 12]. Eventually, the p53 protein controls apoptosis or programmed cell death. Brain, breast, colon, lung, hepatocellular carcinomas, and leukemia have all been shown to have p53 mutations. The potential for p53 dysfunction to serve as a mechanism for chemotherapy chemoresistance is another significant danger [4, 5, 13]. The creation of biosensors that are capable of spotting p53 mutations, Rb, and BRCA1 genes is critical for better-determining cancer risk and developing more effective cancer treatments. Biomarkers of Cancer “A biological molecule present in the blood, other body fluids, or tissues that is a symptom of a normal or aberrant process, or of a condition or disease; a biomarker can be used to determine how effectively the body reacts to an illness or condition's therapy.” according to the National Cancer Institute (NCI) [14]. DNA (particular mutation, translocation, amplification, and loss of heterozygosity), RNA, and protein can all be used as biomarkers (i.e., hormone, antibody, oncogene, or tumor suppressor). Cancer biomarkers have the potential to be the most beneficial tools for detecting cancer initially, accurately staging it before surgery, figuring out how it responds to chemotherapy, and monitoring the course of the disease [15, 16]. Biomarkers are commonly found in physiological fluids, including blood, serum, urine, and CSF; however, they are also present in or on tumor cells [17]. Table 1 contains a fragmented list of tumor biomarkers. On the other hand, the bulk of these biomarkers hasn’t yet demonstrated enough sensitivity and specificity for regular clinical use or suitable treatment. Biosensor technology may be useful in this particular situation.

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Table 1. Common biomarkers utilized for cancer detection [17, 18, 21]. Types of Cancer

Biomarkers

Breast

BRCA1, BRCA2, CA 15-3, CA 125, CA 27.29, CEA, NY-BR-1, ING-1, HER2/NEU, ER/PR

Colon

CEA, EGF, p53

Esophageal

SCC

Liver

AFP, CEA

Lung

CEA, CA 19-9, SCC, NSE, NY-ESO-1

Melanoma

Tyrosinase, NY-ESO-1

Ovarian

CA 125, HCG, p53, CEA, CA 549, CASA, CA 19-9, CA 15-3, MCA, MOV-1, TAG72

Prostate

PSA

Biosensors and Cancer A biosensor is a tool that detects a biological analyte, whether they are from the environment or within the human body. A signal coming from an electric source can be magnified, displayed, and evaluated to determine whether or not the analyte is present and at what amount. Proteins (antigen, antibody, and enzyme) are examples of analytes, as well as nucleic acid and other biological or metabolic components (such as glucose). Biosensors may be used to determine viruses, diagnose and monitor cancer, and check diabetics' blood glucose levels. Locating harmful pesticides or germs in food, water, or the air is one of the many environmental applications of biosensors (i.e., during food preparation). The military is very interested in the creation of biosensors as counter-bioterrorism tools that can spot the presence of chemical and biological weapons to avoid contamination or disease. Biosensors can be implanted into the human body to monitor vital signs, correct irregularities, or even signal a cry for help in an emergency, according to the futuristic vision. Biosensors have an almost infinite number of uses in theory. A tumor biomarker is an analyte recognized by the biosensor in terms of malignancy. By detecting quantities of certain biomarker proteins produced and/or released by tumor cells, biosensors can assess the presence of a tumor, whether it is benign or malignant, and whether therapy has successfully reduced or eliminated harmful cells. Most types of cancer involve numerous biomarkers, and biosensors that can detect multiple analytes may be particularly valuable in cancer diagnosis and monitoring. The capacity of a biosensor to screen for numerous markers at the same time aids diagnosis while also saving time and money [17]. A biosensor has three parts: a recognition device, a signal transducer, and a signal processor that transmits and displays the information. To produce electricity, the transducer transforms the biological

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signal, once the molecular identification component identifies a 'signal' from the environment in the form of an analyte. Biosensor recognition elements The biosensor's recognition element is a crucial component. Early biosensors relied on purified recognition elements extracted from biological or environmental systems. Thanks to advances in synthetic chemistry and technology, many biosensor recognition components can now be produced in the lab, increasing the reproducibility and stability of biosensor functions. Recognition factors include elements like receptor proteins, antigens, antibodies, enzymes, and nucleic acids. Components of receptor recognition Cell surface receptors are drug delivery targets, which can be used to track the efficacy of cancer therapies. Different signaling events within a cell are triggered by the activation or deactivation of receptor molecules. Changes in membrane permeability, activation of adenyl cyclase and second messengers, and activation of small G proteins, kinases, phosphatases, and transcription factors can all occur when the function of a receptor is altered. Receptor proteins would be beneficial as biosensor recognition components even though that receptor function governs a multitude of aspects of cell life, making their application in biosensors hard. Since receptors require a bilayer lipid membrane to function properly, obtaining stable and active pure receptor proteins in high yield is challenging [19]. Recognition elements based on antigens and antibodies are among the fastest detecting techniques. Important benefits of this kind of element include the inherent exclusivity of antibodyantigen interactions and the lack of a requirement for target molecule purification before identification. An anti-PSA antibody serves as a detection component for PSA biosensors, which are extensively utilized biosensors in clinical applications for the diagnosis of prostate cancer. Surface plasmon resonance-based sensors and micro cantilever-based transducers were linked with anti-PSA recognition components to detect PSA by monitoring changes in vibrational frequency brought on by antigen binding to an antibody [20, 21]. Enzymes As recognition elements, allosteric enzymes have a lot of promise. Most of the time, the regulatory subunit serves as the recognition element, while the catalytic site serves as the transducer [22]. One of the most sophisticated sensors in this class is the glucose sensing device (Glucometer), which employs glucose oxidase as an identifying component. Glucose oxidase catalyzes the conversion of glucose to gluconolactone and hydrogen peroxide in the presence of oxygen. The rate of oxygen removal or hydrogen peroxide formation is often measured by an amperometric transducer and converted to a glucose value [19].

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Nucleic Acids Aptamers are oligonucleotides with extremely high binding affinities for their targets chosen from a pool of thousands of distinct sequences. As a progressive outcome, they are quickly gaining popularity as biosensor recognition components. To produce nucleic acid ligands from a library of DNA and RNA oligonucleotides, researchers developed the combinatorial chemistry-based method called SELEX (orderly evolution of ligands by exponential enrichment). The applications of SELEX are practically limitless due to a large number of possible ligands and the selection of molecules for high-affinity binding to a target ligand. Biosensors based on this approach have proven to be effective in the development of new biomarkers that are crucial for early cancer detection. SELEX technology has been used to find cancer biomarkers such as NY-BR-1 and ING-1, and CT antigens CAGE-1 and NY-ESO-1 [23, 24]. Additionally, Aptamers are utilized to identify cancer proteins in small sensor arrays. The second feature of aptamers is that they have allosteric characteristics. Allosteric aptamers include RNAzymes and DNAzymes. These chemicals are excellent for disease monitoring and have displayed potential in the treatment of Alzheimer's and diabetes [19]. Biosensor Transducer A molecular recognition element can work with a variety of signal transducers. The chemical signal is converted by the transducer into an electric or digital signal that may be evaluated, projected, and studied. Electrochemical (i.e., amperometric and potentiometric), optical (i.e., colorimetric, fluorescent, luminescent, and interferometric), mass-based (i.e., piezoelectric and acoustic wave), and calorimetric (temperature-based) transducers are the four types of transducer biosensors that use electricity. The most popular type of biosensor employed today is an electrochemical biosensor, which is portable, inexpensive, compact, and simple to operate. As point-of-care (POC) devices, electrochemical biosensors are utilized at home or the doctor's office. As previously stated, the glucose sensor is an electrochemical biosensor [17], revolutionizing the methods used to measure and record blood glucose levels. The two highly popular forms of electrochemical biosensors are potentiometric and amperometric biosensors. Ionselective electrodes are used in potentiometric biosensors to look for an electrical response in specific ion dissolved in a solution mixture [25]. Although not yet in clinical use, a light-addressable potentiometric sensor (LAPS) connected to a phage recognition element exhibits tremendous promise in the field of cancer diagnosis [26]. The MDA/MB231 breast cancer cell line and the cancer biomarker hPRL-3 were both very sensitively detected by the phage-LAPS. This brand-new potentiometric-based biosensor has been suggested for use in clinic medication

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evaluation and cancer identification. When a potential is applied between two electrodes, amperometric transducers measure the current that is created. A current is produced by oxidation or reduction reactions, which can subsequently be measured [27]. The use of sequence-specific DNA as the recognition element in amperometric-based biosensors for cancer detection hexane is tremendously effective in cancer diagnosis [28, 29]. These detectors recognize and hybridize particular DNA sequences present in the chromosomes of malignant cells, allowing them to identify the presence of gene alterations linked to cancer. Wang and Kawde [30] made a breakthrough utilizing this technology when they discovered that BRCA1 and BRCA2 mutations are linked to hereditary breast cancer using chronopotentiometric transduction biosensors. The GlucoWatchTM is a glucose sensor designed to provide noninvasive, uninterrupted blood glucose monitoring in diabetic patients. The GlucoWatchTM is a wristwatch that measures blood glucose levels by reverse iontophoresis, a procedure in which a small electrical impulse drives glucose applied directly to the skin to be measured. An amperometric transducer converts glucose readings into an electrical signal. Patients can use this device to maintain their blood glucose levels without the agony of regular injections. The GlucoWatchTM also contains an alarm that sounds when blood glucose levels fall outside of the usual range, as well as a feature that allows the patient to record several glucose readings [31, 32]. Deformed DNA and the carcinogens that produced the damage can be detected using electrochemical biosensors [27]. In addition to immunoassays and protein arrays, electrochemical transducer technology is widely used. Cancer biomarkers have also been measured using immunosensors, which consist of an antibody connected to an electrochemical transducer. A significant advancement in biosensor technology is the development of multiplex biosensors that can identify numerous CAs, allowing for more accurate assessment and management. Multiple transducers must be used in this sort of biosensor, each of which is tuned to specific proteins or antigens for detection. Due to the technology's dependability, low cost, and simplicity in scaling down with the use of semiconductor materials, electrochemical-based biosensors have played an important role in the field of multiplex biosensors. Multifunctional antibody arrays based on ELISA technology are the most popular multiplex devices being used for carcinoma protein analysis [17]. The practicality of a cell-based electrochemical biosensor that tracks modifications in cell impedance in answer to the analyte was proven by

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Asphahani and Zhang [33]. These cytosensors, using living cells as a biological sensing component to keep track of changes generated by diverse stimuli, are usually referred to as cell-based biosensors. In cancer treatment, this kind of sensor can be used to assess how anticancer medications affect their target analytes. The majority of anticancer medicines act by inducing p53-mediated apoptosis in cancer cells. The cell's membrane integrity, ion channel permeability, and general shape all alter dramatically during apoptosis. Cytosensors would be able to detect such cellular changes more quickly and effectively than a sensor that uses a pure component (ie, receptor or enzyme), allowing for a more accurate assessment of the anticancer agent's pharmacological efficacy. Optical Biosensors Optical biosensors are light-based sensors that detect variations in certain light wavelengths. A luminescence, fluorescence, colorimetric, or interferometric transducer can be used. Wavelength alterations or SPR in reaction to analyte identification are converted into a digital and electrical interface using optical transducers [17]. Photonic crystal biosensors, which use an optical transducer, are a new type of biosensor. The photonic crystal sensor captures light from very small areas or volumes, allowing for higher measurement sensitivity, and then transmits it into a strong electromagnetic field for display. This approach detects when and where cells or molecules connect to or are released from the crystal surface by measuring the light reflected by the crystal. Chan and colleagues used this form of the biosensor to track modifications in proliferation and apoptosis in breast cancer cells exposed to doxorubicin, as well as calculate the IC50 of doxorubicin [34]. This type of biosensor technology could be used to screen effective doses before therapy to ensure that efficacy and toxicity are both balanced. The esophageal laser fluorescence-based optical biosensor for the detection and monitoring of malignancies of the throat is another fascinating example of how this type of technology might be used to detect cancer. The gadget sends a laser beam emitting a certain wavelength of light onto the surface of the esophagus after being eaten by the patient. Depending on whether the tissue includes malignant or normal cells, the esophagus wall reflects light at very precise wavelengths. Optical fibre sensor detecting carcinogen benzo(a)pyrene (BaP) has been tested on more than 200 individuals, and it has been found to accurately identify cancer 98% of the time. [35]. Surgical biopsies, as well as the discomfort, could have their related recuperation time eliminated with the use of this sort of biosensor. Mass-Based Biosensors The mass-based biosensors category includes piezoelectric and acoustic wave

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biosensors. Piezoelectric biosensors are more widely used when it comes to cancer detection. The mass of quartz crystals varies when potential energy is given, which is how piezoelectric sensors work. This mass change produces a frequency, which can be turned into a signal. Cancer biomarkers have been identified using piezoelectric immunosensors and microcantilever sensors [17]. Dell'Atti and colleagues [36] used a piezoelectric biosensor in combination with PCR amplification to identify point mutations in the human p53 gene, that are implicated practically in every kind of cancer. As p53 mutations are so important for cancer formation and therapy success, there has been a lot of work put into developing quick, affordable, and efficient techniques to identify p53 alterations. Calorimetric Biosensors Calorimetric biosensors are a little more frequent in cancer diagnostics than other types of biosensors, however, the advent of nanotechnology in the field of biosensors has broadened the variety of applications for these sensors. Exothermic processes are monitored using calorimetric biosensors. Many enzymatic reactions produce heat, which can be used to determine analyte concentration by measuring variations in heat. Enthalpy variations are measured to monitor the reaction, revealing information about the substrate concentration in an indirect manner [25]. Although calorimetric biosensors are not widely employed for cancer diagnosis and prognosis, they have been shown to have some cancer-detecting capabilities. Medley and colleagues [37] recently published a study that showed the usage of an aptamer-based gold nanoparticle calorimetric biosensor for cancer identification. Using gold nanoparticles, the researchers managed to distinguish between two types of cells: acute leukemia cells and Burkitt's lymphoma cells. This study shows how aptamer-based identification elements can be used with a calorimetric transducer to identify cancer cells [37] and possibly differentiate between benign and malignant cells. Biosensors and Nanotechnology Nanotechnology is a fast-developing science having a significant effect on biosensors and, as a result, on cancer detection, prognosis, and monitoring. The majority of cancers are discovered after they have spread, making them far more dangerous and difficult to cure. Approximately 60% of cancer cases are discovered after spreading to other parts of the body. The use of nanotechnology in biosensor creation increases the likelihood of identifying cancer early, resulting in better patient survival rates. One example is the use of magnetic resonance imaging (MRI) for cancer diagnosis and monitoring, which is one of the most widely used imaging technologies today. The fact that MRI can't identify objects smaller than a few millimeters is a significant disadvantage. Nanomaterials can be

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used as imaging tools to provide more acute and efficient measurements of malignant tissues. Nanomaterials such as liposomes, dendrimers, buckyballs, and carbon nanotubes have been employed to improve cancer imaging [38]. Nanotechnology also translates to smaller sensors, which means improved exposure to and diagnosis of cancer indicators, and more potent and targeted signal improvements, lower costs, and high bandwidth detection [1]. Nanoparticles are described as particles with a diameter of 1–100 nm. Nanoparticles' small size guarantees a higher surface-to-volume ratio. This enhanced ratio enables better diagnosis, scanning, and sensing procedures, as well as improved medicine delivery to previously inaccessible tumor locations. Structures such as nanocantilevers, nanowires, and nanochannels have been used to detect cancer-specific molecular processes and improve signal transmission [39]. Zhang and colleagues [40] created a microRNA detection biosensor based on nanowires (miRNAs). MiRNAs are key gene regulators that have been linked to the development of cancer. Northern blot analysis, for example, is a timeconsuming and expensive way of detecting miRNA. The creation of a sensitive, low-cost, and simple biosensor for finding miRNAs associated with cancer is a significant step forward in miRNAs' usage as cancer biomarkers. Single-walled carbon nanotubes (SWCNTs) have substantially improved the electrochemical biosensors' screening characteristics detection, increasing enzyme reaction sensitivity. SWCNTs show higher activity toward hydrogen peroxide and NADH [41] and are employed to improve signal identification and transduction in nucleic acid-based sensors and immunosensors for cancer biomarkers [42, 43]. Surfaceenhanced Raman scattering is a type of optical biosensor that has been made possible by nanotechnology (SERS). SERS allows for a larger extent of duplication than current approaches. SERS can evaluate up to 20 biomarkers at once without interfering with the results [44]. A famous illustration of how nanotechnology might improve medical care is the creation of laboratory-ona-chip (LOC) microfluidic devices. LOC technology simplifies a laboratory's intricacy into affordable, user-friendly, lifting devices that clinicians or patients may utilize. The ability of LOC techniques that include immunoassays and DNA hybridization arrays to examine people to determine those who may have a greater likelihood of developing cancer [39]. Quantum dots are another important application of nanotechnology. Quantum dots are luminous nanocrystals with capabilities similar to optical biosensors [17]. Quantum dots may produce light with a variety of wavelengths, intensities, and spectrum widths, enabling the identification and detection of a variety of molecular constituents [38]. They can track chemicals and the motion of whole cells and substances in their surroundings. As a result, they could be particularly useful in watching cancer cell motility, spreading, and medication therapy efficacy is useful in observing the course of cancer. Quantum dots are appealing because of their high stability,

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multimodality, and compact size. (for biological applications, 50–100 units in diameter). Quantum dots can transport therapeutic compounds to specific target areas, enhancing pharmacological efficacy while reducing negative effects [45]. Dendrimers have also been used as medication delivery systems for efficient targeting methods as a result of advances in nanotechnology [46]. CONCLUSION Biomarkers for cancer are key predictors of tumor progression. They are used to anticipate therapy outcomes as well as detect and track disease. POC cancer diagnosis is the fundamental purpose of biosensor technology. Point-of-care testing (POCT), or on-site diagnostic testing, is an area where biosensors could have a big influence, allowing patients and doctors to acquire findings quickly and conveniently. POCT enables more rapid diagnosis and has the potential to save money [47]. However, multitarget detection of many biomarkers is required to progress biosensors toward POC devices. Furthermore, while bringing biosensor technology to the patient's bedside, POCT and multibiosensors must maintain the laboratory's accuracy and dependability [27]. LOC biosensors are a promising new technique in this field. Nanomaterials, particularly quantum dots, have had a big impact on biosensor development since they can not only help diagnose and track cancer cells but also deliver medications to specific places with accuracy and allow for more sensitive imaging systems that diagnose cancer at an initial stage. Nanotechnology will undoubtedly revolutionize cancer diagnosis and treatment in the next 5–10 years. We can identify disease early, enhance cancer imaging, help with diagnosis/prognosis, and increase drug delivery while avoiding side responses by combining nanomaterials with biosensors. Cancer creates a micro-environment inside the cell thus, the treatments involving drug-loaded nanomaterials could easily be endocytosed into the cell, obstructing the cellular signaling of the cancer cell and leading to the retarded cell growth. CONSENT FOR PUBLICATON Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared None

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CHAPTER 6

Recent Advances in the Application of NanoBiosensor in Tissue Engineering Soumya Katiyar1, Shikha Kumari1, Ritika Singh2, Abhay Dev Tripathi1, Divakar Singh1, Pradeep K. Srivastava1 and Abha Mishra1,* School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, India 2 School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi-221005, India. 1

Abstract: Nanotechnology has a profound influence on environmental research, infrastructure, energy, food standards, information technology, and medicine. In biomedicine, nanotechnology primarily aims to provide solutions for preventive care, diagnosis, and therapy. Biosensors have significantly revolutionized the medical sector by offering on-site diagnostic capabilities. Since 1962, the combination of biosensors with nanotechnology has made a significant contribution to therapeutics and tissue engineering. Biosensors are diagnostic devices that monitor biochemical interactions and translate them into measurable electrical, optical, or mechanical signals. The tissue-engineered technology has gained popularity in the postmodern era to confront the shortcomings of biomedical applications, graft rejection, challenges in the recuperation of functional tissue, and specificities in the tissue regeneration site. The multitude of techniques for evaluating cell counts, growth, metabolic activity, and viability across the scaffolding of regenerated organs is reportedly labor-intensive and time-consuming. Biosensors have been rapidly advancing and influencing the field of tissue engineering in the last several decades. Recent developments in nanomedicine and biomaterial science have enabled them to overcome long-standing challenges. Biosensors used in tissue engineering and regenerative medicine (TERM), unlike the other biological systems, must comply with the requirements mentioned above: (i) biocompatible, causing no or little response to foreign materials; (ii) non-invasive while probing the whole three-dimensional structure for targeted biomarkers; and (iii) should offer long-term monitoring (days to weeks). This chapter offers a comprehensive set of biosensors as well as their implementations in the field of tissue engineering and regenerative medicine (TERM). This chapter reviews current breakthroughs in nanobiosensors, their implementations in tissue engineering, and their promise for diagnostic purposes. Corresponding author Abha Mishra: Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India; E-mail: [email protected] *

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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Keywords: Biosensors, Nanotechnology, Tissue engineering and regenerative medicine (TERM). INTRODUCTION The damage or malfunction of organs and tissues as a consequence of an accident and other such sorts of trauma is a serious health and safety concern. The conventional approach for treating these individuals is tissue or organ transplantation; however, donor availability is highly curtailed. Alternative treatments, such as surgical treatments, therapeutic interventions, artificially synthesized prostheses, and biomedical gadgets, are not supply-limited; however, they have drawbacks. The emergence of novel nanomaterials and potential alternative therapies has resulted from efforts to solve these issues and limits. Tissue engineering has been identified as a potential alternative to conventional therapy for managing tissue, organ loss, or dysfunction. The fundamental goal of this fast-emerging emerging field of study and technology is to use tissue engineering to replace dysfunctional internal organs with the ability to heal and regenerate [1]. In the last decade, advances in nanotechnology and nanotherapeutic devices have given tissue engineers' conventional methodologies a new perspective on life [2]. Ongoing advancements in the discipline of tissue engineering and regeneration need the deployment of authentic, non-invasive, and non-destructive diagnostic technologies for evaluating the validity and properties of the interaction of cultured cells with biocompatible scaffolds and tissue regeneration. Since the emergence of the very first biosensor by researcher Leland C. Clark in 1962, investigation on bioanalytical chemistry and biosensors has achieved tremendous progress and drawn significant prominence [3]. The sensors are systems that generate measurable signals in response to various physical and chemical inputs. Generally, the biosensor's key purpose is to analyze and examine instant, efficient, and specific real-time biological reactions of analytes. Most such sophisticated biosensors potentially trace particular molecules in minimal amounts and are thought to be a valuable tool for detecting disorders at a preliminary phase and initiating therapy. However, only low amounts of biomolecules are needed, but still, their purity may be critical to accuracy. Conventionally, a biosensor is a diagnostic technique that combines a biological or biologically derived specific element and a particular analyte with a transducer to identify and transform a biological input into an electrical output and the detector that shows the signal values. The basic schematic representation of a biosensor is shown in Fig. (1).

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Fig. (1). Schematic representation of the working principle of biosensors.

A biosensor typically consists of four major components: Bioanalytes A substance of concern whose components are indeed being characterized or recognized (such as glucose, DNA, proteins, lipids, etc.) Bioanalyte receptor system This system functions as a receptor for a specific analyte (material to be recognized or quantified) and aids in determining the amount, interaction, and existence of these target analytes in a sample. Commonly used biomolecules as sensing elements involve enzymes, aptamers, cells (animal or plant), peptides, antibodies, and so on. The accessibility and accessibility of a huge range of biological receptors capable of detecting multiple kinds of analytes make biosensors a desirable device that could be employed in a wide range of study fields. Transducer These components recognize the signal produced by the analyte's engagement with the biological recognition component and convert it into measurable output. In most advanced biosensors, many types of transducers, such as electrical, optic-

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al, electrochemical, gravimetric, thermal, and piezoelectrical, are employed; biosensors are often categorized according to their transducer nature [4]. Signal Processing Unit This can analyze and intensify the electronic signals and output them in a suitable format, such as digital readout, visual changes, or readable format. Diagnostic tests that are quick, accurate, and convenient to use can considerably enhance the early identification of therapeutic targets of disorders with high morbidity and mortality, such as heart disease, tumors, chronic kidney diseases, diabetes, and many others [5]. Existing traditional monitoring approaches are mostly histological in nature, need tagging, and include invasive methodologies to analyze cellular activities. Biosensing devices have clearly proven incredibly significant for use in diagnostic imaging and other sectors such as medicinal, food, water remediation, environmental, industrial, agricultural, and other bioengineering sectors. New biosensor approaches and devices are emerging to revolutionize the ever-changing horizon of preventative healthcare, permitting many biomarkers to be detected in vitro and in vivo on relatively small systems [6]. Scaling down the basic and clinical investigation to the nanomolecular levels allows researchers to make use of the features of nanoscale biomaterials to produce more economically efficient medications and therapeutic drug delivery platforms. Nanomaterials such as carbon nanotubes/graphene, quantum dots, nanoparticles, and others are increasingly being used in biosensing applications as a consequence of technological advances in nano-engineering. Recent technological improvements in nano-engineering substantially increased the employment of nanostructured materials in biosensing devices. Nanobiosensor, which is fundamentally an interdisciplinary field, has made exceptional progress in the past half-century, but this still deserves particular emphasis from the scientific and technical society in order to conceivably fulfill the analytical needs of the overall population while also advancing scientific knowledge. Incorporating nanostructured materials as transducers in sensing applications has laid the foundation for remarkable advancements in the field. It tends to contribute to stable and sustainable sensing probes, amplified tracking sensory information in limited sample amounts, miniaturized tools, and multiplex monitoring devices. The evidence for enhanced biosensor applications using NMs is primarily owing to a profound knowledge of molecular mechanics structure dynamics, in which surface atoms and molecules play an important role in reducing the activation energy. Biosensors used in tissue regeneration, unlike all other biosystems, must meet the following characteristics: (a) they should be biocompatible or nonimmunogenic, causing almost no immunogenic reactions, (b) should be nonintrusive and inert in nature while probing the entire three-dimensional structural

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framework for associated proteins; (c) should offer careful and consistent monitoring over an extended length of time and (d) should be inexpensive, easily accessible, and wearable. In recent decades, researchers have investigated a number of novel ways for miniaturizing these devices such that they may be employed as an active component of tissue regeneration systems and transplanted in vivo. This chapter focuses on the therapeutic applications of nanobiosensors as well as their future possibilities in the domain of tissue engineering. We tried to emphasize the concepts of nanobiosensors and their importance in tissue engineering and regenerative medicine. We further discussed many nanobiosensors for monitoring highly bioavailable molecules, such as blood samples, cell cultures, urine samples, and so on. The outcomes of these approaches demonstrate the potential benefits and drawbacks of employing nanobiosensors and how future breakthroughs in this field can radically impact biological diagnostics and therapies. NEED FOR NANOBIOSENSORS ENGINEERING

IN

THE

FIELD

OF

TISSUE

TE is the use of biological and technical concepts to create artificial tissue constructs that can restore or conserve lost functionalities in injured tissues [7]. Tissue engineering offers the amalgamation of intriguing interactions between cellular and physical entities to develop better integration between cells and materials [8]. For this purpose, biosensors were discovered to examine the cellular aspects, including cell behavior and responses. The introduction of microfluidic platforms in tissue engineering and biosensors has become increasingly famous due to their specific properties for biomacromolecules sensing and sensing cell behavior with tiny scaffolds [9]. A nanobiosensor (NBS) is composed of 4 parts: a bioreceptor molecule, a transducer, a signal processor for translating electronic signals into desired signals, and a display interface [10]. NBS is used to analyze a range of specimens, including eateries specimens, fluids from the body, and tissue culture [11]. Due to the exceeding requirement for quick and reliable stimulus detection, biosensing is gaining traction. Regarding processing speed, qualified labor, and detection accuracy, biological moieties sensing has surpassed traditional diagnostics. These NBS provide precise real-time information about the tissue constructs through different biosensing systems, including photosensitive, impedance-based, and electrochemical or electrical sensors [4]. Biosensors used for cellular applications are of two types: the first one is based on cell polarity. These polarity-based biosensors can be used to study biochemical

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activities that occur at the membrane or subcellular level [12]. In one of the research studies, cell- apoptosis was detected using live-cell data by applying a polarity-sensitive annexin-based NBS with different fluorescence phases [13]. This biosensor was used to understand the in vitro and in vivo alterations occurring during the relapse of neurons. In contrast, the second one is based on cell behaviors like metabolism and stem cell proliferation/differentiation. The behavior of cells and their signal evaluation, illness modeling, and drug toxicity or biomolecular valuation are all areas where biosensors for cellular applications are used. As a result, numerous methodologies for cellular signal transduction are used, including cell metabolic assessment, and intracellular and extracellular potential determination [12]. Microelectrode arrays (MEA) are the best choice for determining the electrical and physical characteristics of heart and nerve cells which is the prerequisite for tissue engineering [14]. Biosensor-based systems provide a simple method for detecting the diverse tissue-mediated response, which can help in disease prognosis [15]. There are several advantages of the MEA approach, which include non-intruding observation of neurons' electrical and physical activity, recording at multiple sites, and highly efficient diagnosis of any disease. In particular, the NBS and biomimetic chip-based biosensing systems can easily determine the stem cells' real-time proliferation, differentiation, and neural network formation. They can also rapidly record the electrical and physiological responses of the stem cells. On the other hand, bioelectrical activity is a crucial cardiac function that can easily affect cardiac health. It is produced by cardiomyocytes, which are driven by a little change in the membrane potential of a specific cell location; by this coordinated electrical propagation, the heart is induced to have a synchronized pumping pattern. Therefore, the heart-on-a-chip NBS serves as an in vitro model (disease) for studying the effects of low oxygen levels in the heart tissue. Other tissue models, such as the lung and the liver, are created along with incorporated nanobiosensors to monitor live tissue constructs' physiological responses. Mitochondrial malfunction (MM), for example, plays a vital role in the occurrence of any toxic chemical or pharmacological response. Liver organoids that were composed of Hep G2 were employed as a disease model by Balvi et al., who cultivated the organoids in a microfluidic system [12]. It serves as a nanobiosensor that can simply trace the MM dynamics by recording the metabolic activity of the liver organoids in real-time [12, 16]. Studies on cancer have been conducted for various years. In general practice, cancer research has focused on treating cancer disorders, and developing numerous new effective therapeutic strategies. However, people with cancer disorders are sometimes diagnosed at late stages, causing them to miss the optimal

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opportunity for treatment [17]. As a result, in identifying or prognosing cancer disorders precisely recently, a lot of research has been done on this topic. To date, several cancer disease models have been fabricated for studying cancer cell production, spread, mutation, and other mechanisms.Several researchers also developed cancer-based chip models obtained from heart cancer cells, microfluidic chips, and liver cancer cells [18]. The impact of medications in the blood flow on the liver cancer cells' migration and proliferation may be evaluated using this co-culture paradigm. Label-free biosensors were frequently employed for early detection since they are a quick and easy way to make flexible cancer biosensors. Similarly, several biosensors were developed to study cancer on-chip. The ultimate requirement of biosensors for TERM is discussed in Fig. (2). Because of the complexity inherent in translating in vitro systems into in vivo systems, nanosensors are now an important aspect of research. Because many parameters are linked to one another, the system's impact on the analyte's expression necessitates systematic and realtime monitoring.

Fig. (2). Need for nanobiosensors in TE.

NANOMATERIALS USED FOR BIOSENSING APPLICATIONS IN TE Nanomaterials have recently gained immense importance in the field of biosensors. Nanomaterials are materials that exist in extremely tiny sizes that possess an external diameter or internal radii of 100 nanometers(nm) or lesser.

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These nanoparticles exhibit significant surface area that allows various surface modifications, which helps in enhancing their physiochemical interaction with the target molecules [19]. After Richard Feynman coined the term nanotechnology in an annual meeting of the American Physical Society; thereafter, fifteen years in 1974, Japanese scientist Norio Taniguchi brought the term nanotechnology, which focused on the processing of materials by a singular atom or molecule. Afterward, scientists like Chad Mirkin and others worked on nanomaterials-based biosensors that included optical biosensors, electrochemical biosensors, resonant biosensors, thermal biosensors, and ion-sensitive biosensors were applied to detecting molecular biomarkers with maximum sensitivity [20 - 22]. Due to the exquisite properties of these nanomaterials (such as nanoparticles, nanowires, and nanotubes), they are being widely explored for smart biosensors that can detect the concentration of the analyte even at a nanoscale level and are further classified as organic and inorganic NMs as shown in Fig. (3) [23]. They are usually applied as transducer materials, important components in developing biosensors. Nanomaterials are also used for in vitro detection of several biomarkers of different disorders like infectious diseases, cancer, neurodegenerative disorders, etc., where they detect the disease progression by interacting with the bodily fluids being released. They are also utilized for contrast imaging purposes in order to outline the in-vivo disposition of biomolecule markers when joined to an imaging paradigm like MRI (Magnetic resonance imaging) or CT (Computed tomography) scan [24]. Therefore, these nanomaterials are predicted to be the future of biomolecular sensing devices with high sensitivity and detection limits. The incorporation of nanomaterials is best suited in transduction responses or moieties for supporting the detection of a biosensor. For instance, in detecting glucose from a specimen, conventionally, glucose oxidase is used alone. But the detection limit can be enhanced tremendously if it is functionalized with other nanomaterials like graphene sheets or carbon nanotubes. Similarly, quantum dots, nanowires, and metallic nanoparticles can also be utilized to replace the transducers in the biosensing devices for a more stimuli-responsive mechanism. These attributes of nanomaterials are quite tunable through external perturbation, and therefore only the slightest modification can alter the normal response efficiently [25]. Nanomaterials that are applied as biosensing moieties possess several salient aspects, including their high surface area and multiple binding sites, their size and shape, which corresponds to high surface energy, and their vigorous preparation mechanism, which allows different permutations and combinations in developing desired nanomaterials. These properties can be achieved by applying different approaches that help in the development of such nanomaterials. Like modification with avidin-biotin interaction, modification with

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thiol group compounds, modification through π-π stacking interaction, and functionalization with EDC-NHS chemistry. All these methods have been used in the past to attain specific properties in the synthesized nanomaterials. For example, in real-time, silver nanoparticles were used in conjugation with EDCNHS for analyzing the interferon-gamma (IFN-γ), a noted TB marker. In this study, interferon γ was coupled with an antibody in the silver nanoparticles solution that was capped with citrate molecules in the presence of (75 mM) Ethyl DiamineCarbidamide and (15 mM)N-Hydroxysuccinate [26]. Nearly all nanomaterials possess certain functionality after proper functionalization with polymers without affecting their existing attributes depending on their chemical composition [27]. This functionalization helps to improve the biocompatibility of NMs by consistent ligation of bioreceptor units. The invention of electron microscopes made it feasible to examine nanoscale topographies and morphologies with distinct resolutions, which led to the application of nanostructured materials for biosensing.

Fig. (3). Commonly used nanomaterials for biosensing applications.

Micromachining technologies employing scanning probe microscope (SPM) variants offered information on these entities' enhanced surface area (SA) to volume ratios. These conclusions also lay the groundwork for surfaces of nanomaterials and their quantum simulations, along with progressive advancements in techniques such as microwave treatment and spontaneous emulsification with lower energy processing [28]. Because of their biocompatible

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surface functionalizations, metallic nanoparticle biosensing system potential is enhanced at this time. In this context, the utilization of gold nanoparticles has become very popular because of their suitability as both absolute involvements and as linkers and monodispersed enabling moieties. In addition, gold, silver, and iron oxide nanoparticles are also presently synthesized and conjugated with the sensing probe. Following nanoparticles, carbon nanotubes (CNT), graphene-based nanomaterials, fullerenes, and polymeric nano-composites, collectively known as carbon-based nanomaterials, are the next main nanomaterial drawing interest for biosensing [29]. Although few toxicity issues exist with fullerenes and CNT, the resilience of surface modification engineering has substantially increased their biological probe importance. CNT, at the very least, is enormously popular for its properties embodiment in both regimes, including covalent and non-covalent at this time. Carbon-Based Nanomaterials Carbon nanostructures have attained immense attraction in the field of biosensing applications in the past few years. Carbon-based nanomaterials like carbon nanotubes and graphene possess brilliant properties of both nanowire morphology, biocompatibility, and mechanical and electronic properties [29]. This makes them the most suitable option for biosensing applications for TERM. Its unique structure or inevitable characteristics collectively help in the formation of miniature probes with high-quality performance and low power requirements. They also possess a high strength-to-weight ratio along with high electron mobilities, which imparts better thermal stability and flexibility to these moieties [30]. The exemplary vast applications of carbon nanomaterials in biological sensing owe to the tetravalent bonding in carbon and catenation that provides the extended binding ability to the ligand molecules. Carbon nanotubes (CNT) display enhanced sites for the reaction of redox enzyme, and thus it leads to better wiring with the major electrode. Their complex three-dimensional structure and organic functionalization impart more specific docking sites for the biomolecular interaction in the bioelectrochemical reactions [31]. The 3D structure of CNT films delivers a higher surface area for enhanced anchoring of a higher amount of bioreceptor units that ultimately result in higher sensitivities [32, 33]. CNT is composed of hexagonally arranged C atoms in a ring shape and is one of the most well-known nanomaterials. These rings connect to form a graphene sheet, which then aligns to make a smooth cylindrical tube. Single-walled carbon nanotubes (SWCNT) have only one graphene sheet wrapped up, but multi-walled carbon nanotubes (MWCNT) have numerous rolled graphene sheets overriding them [34, 35]. SWCNT possess excellent mechanical and electrical properties, and due to these physicochemical properties, they are widely used in biosensing

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applications for tissue engineering. It is found to facilitate electrical conductivity and biosensors' signal response, making its applications more interesting in the field of biological reactions. SWCNT has been utilized with other polymeric composites in order to overcome some of its limitations, like insolubility issues. But its combination with other electrically conductive polymers as fillers also helps in overcoming these limitations. MWCNT is made up of multiple layers of single-walled graphene cylinders that are linked with Van der Waals forces. They possess an interspacing of 3.4 Å [36]. And they possess a sidewall structure similar to the graphite basal plane.MWCNT, with great conductivity and electrocatalytic characteristics, has also been applied as a modified scaffold on the electrode. In contrast, metallic CNT possesses higher electrical conductivity due to two properties that include minimal imperfections that scatter electrons and their excellent tenability at increased temperatures (in the air up to 300°Celsius and in vacuum1500 °Celsius). As a result, better ballistic transport is discovered [37]. Overall, it is completely clear that with the seamless longitudinal structure, tunable surface properties, and high aspect ratios, CNT displays significant immobilization potential for application in biosensing probes. They could speed up their activity and minimize reaction duration by attaining a higher aspect ratio and the capacity to vary electronic responses due to different doping. This will further enhance the ultimate sensitivity for low stimuli responses. Graphene-Based Biosensors After Carbon nanotubes, graphene is the most promising biosensing moiety applied in tissue engineering and regenerative medicine. The high motility, temperature conductivity, surface area, and electric potential of graphene are due to its constitution, which is a singular sheet of sp2 hybridized C atoms arranged in a 2-D grid [38]. Graphene exhibits numerous unique properties like high thermal conductivity, ambipolar diffusion, and resistance quantization that are imparted due to its conjugated e-distribution and higher surface area [39]. Several improved graphene-based nanomaterials are produced to improve their properties for application in electro-chemical nanobiosensors and planar graphene structures. These modified graphene nanostructures include graphene nanoribbons, thin strips of nanocarbon with 100nm or lesser width, and graphenenanowalls [40, 41]. The graphene nanowalls are also called carbon nanowalls, and they are mainly formed in a parallel or vertical manner with exposed sharp edges. Manipulation of the layer number and native stacking order can easily alter graphene sheets' surface area and stacking intent. Physisorption is a key feature of graphene that contributes to its interactions with many proteins. Graphene

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oxide(GO), reduced graphene oxide(RGO), and graphene quantum dots are a few most commonly employed graphene derivatives in biosensing applications [42, 43]. The graphene nanomaterials can be functionalized by physisorption via nonpolar interactions, electrostatic or covalent interactions through functional groups of oxygenated graphene oxide or reduced graphene oxide, or non-covalent binding through cleavable linker molecules using biorecognition constituents such as nucleotides, aptamers, or proteins [44]. In summary, graphene biosensors are widely employed in DNA biosensing, protein biomarkers biosensing, metabolites biosensing, and pathogen biosensing for higher specificity and sensitivity. Their exceptional electrochemical properties make them an ideal platform for making highly efficient, sensitive, and reliable biosensors for tissue engineering and regenerative medicine. Quantum Dots Quantum dots(QD), luminous semiconducting nanocrystals, are another type of nanomaterials utilized in bioanalytics. The most well-studied colloidal QDs based on Cd chalcogenides are Sulphur, Selenium, and Tellurium, which have a broad absorption wavelength and a size-reliable restricted emission wavelength. It is due to the band gaps in between the semiconductor materials that result in distinct emission wavelengths from the e- hole excitation recombination. The accessibility of various absorption and emission spectra from different sizes of QD permits efficient multiplexed analysis with conventional light-based transport [45]. A limitation to the above procedure might occur due to the non-radiative relaxation that can serve if structural problems exist inside the crystal lattice plane. Coreshell composites with semiconductor material and a large band gap (often ZnS) were discovered to address this issue. They helped overcome these surface imperfections and improve the quantum yields and optical stability. Core-shell QD has turned out to be a promising alternative to natural fluorophores due to its better optic and chemical stability. Quantum dots are now accessible with inert or biologically compatible coatings to furnish essential functional groups for functionalizing receptor molecules or treating possible toxicity issues [12]. As a result, practically any macromolecule can attach to a small nanocrystal as long as it is smaller in size. Varying wavelengths of fluorescence can be generated by QD having similar constitutions yet varying sizes. Highly efficient, multifunctional, and sensitive bioassays are made possible by remarkable optoelectronic characteristics [46, 47]. QD is well explored in target analytes' detection and quantitative analysis by applying fluorophores in combination with these biomolecules [48]. In comparison to standard dyes, QD provides a number of advantages as a

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fluorescence reporter. In the last two decades, these benefits have boosted their use in fluorescence-based biological sensing, ranging from in vitro determination of the biomolecule to in vivo imaging. Quantum Dots-based fluorescent biosensing has recently gained more attraction in biological research as the biocompatibility of freshly emerging QD has improved. Combining QD-based fluorescent imaging with PET, CT, and MRI diagnosis can turn into a robust approach for research in the field of biomedical applications. Overall, quantum dots proved their suitability in bioanalytics either as optical labels or as parts of the biosensor(transducers). Hence, soon QD-based biosensors can become the most reliable biological sensing equipment [27]. Likewise, the mentioned principles and techniques, along with their examples, suggest the bioanalytical applications of QD in combination with various nano-objects. This can be done without losing their novel characteristics; hence, it can be a futuristic approach with a conventional and highly effective transduction mechanism. Metallic Nanomaterials Besides carbon nanomaterials and magnetic nanoparticles, metallic and metallic oxide nanoparticles have also gained great attention due to their chemical characteristics and functional properties. With their biocompatibility, optical and electrical characteristics, relative ease of fabrication, and surface functionalization, gold nanoparticles (AuNp) are widely applied to noble metallic nanomaterials for NBS [27, 49]. The optical behavior of gold surfaces is very well-acknowledged, which contributes to its excellent biocompatible properties. Due to their ease of manufacturing, chemical stability, excellent biocompatibility, and various optical properties, gold nanoparticles are among the most studied nanotechnological tools for optical biosensing and bioimaging. Many optical features of gold nanoparticles can be tuned by modifying their form and size, such as the ratio between light absorption and emission coefficients, localized surface plasmon resonance (LSPR), fluorescence, and so on. Nanoforms of spheres, rods, shells, prisms, pyramids, cages, rings, disks, etc., also exist. The unique optical properties of gold nanostructures enable or accelerate recent developments in optical biosensing and bioimaging techniques [50]. Gold nanoparticles have also been shown to be effective in bioanalysis when used with SPR transduction. Analyte detection can be measured by various methods, including changes in the reflected light's angle, intensity, or phase. Gold nanoparticles are suited for in-vivo imaging and can be directly employed for 2-photon and multiplexed-photon imaging. Gold nanoparticles' excellent qualities make them an interesting candidate for bioanalytics for a variety of other study domains. Characteristics of AuNp of this type can be tweaked and modified. Using the appropriate synthesis technique, practically any required shape or size can be created, regardless of the desired application.

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Similarly, like gold (Au), silver (Ag) is also a metallic element of the periodic table and has a number of chemical features in common. In fact, following AuNP, AgNP is the next best candidate suitable for nano-biological sensing abilities due to their absorption (LSPR), which will cost less than Au NP. Furthermore, comparable to AuNP, AgNp has properties that can be controlled by causing changes in morphology, size, and aggregation behavior [51]. These properties include the metals' electrical, optical, and catalytic behavior. Furthermore, AgNPs can also be utilized for colorimetric analyte detection due to their absorption band at 380 nm, a visible light wavelength in the electromagnetic spectrum. This little change in LSPR band can be achieved by constant modifications in the shape, composition, size, and dielectric constant [51, 52]. AgNP is perfect for coating purposes as they provide non-toxic protective shells with tunable size and dispersibility. Silver nanoparticles are synthesized by biological, physical, or chemical processes. Electrostatic interaction and physicochemical attractions have all been used to immobilize or functionalize the biomolecules over the nanoparticles [53]. In gest, Surface plasmon resonance (SPR), Raman spectroscopy (RS), ELISA, and several electrochemical detections all use silver nanoparticles compounded biomolecules that possess exceptional sensitivity and stability for the target molecular validation [54]. Magnetic Nanomaterials Magnetic nanomaterials have recently gained lots of importance in the field of nanobiosensors against nanoscale size bio-interactive stimuli through modified ligand-receptor moieties. In biosensor devices, magnetic nanoparticles (MNPs) are the best-suited alternative for fluorescent labeling because of their higher sensitivity in comparison to bulk nanomaterials [55]. Due to decreased magnetic domains, MNPs possess distinct magnetic behaviors than their major material, resulting in super-paramagnetic, ferromagnetic, and paramagnetic behavior [56]. It can be inferred that directions can be switched via magnetic stimulation in a short period. Hence, magnetization appears to be zero on average when a magnetic field (MF) is not present. This thermally responsive process is eliminated by matching the magnetic moments with an outer MF. While the effect appears identical to the typical paramagnetic materials, the superparamagnets possess a far higher magnetic susceptibility. On the other hand, their magnetic moments rise in response to the applied MF strength, slowly reaching a hike. Since produced magnetization is minimal when MF is not present, magnetic nanoparticles offer huge signals for detecting a variety of bioentities at high magnetization. These characteristics allow them to modulate their blood flow without being subjected to outer MF, allowing for more specific bonding with the target cells. They are usually synthesized using co-

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precipitation, thermal decomposition, microemulsion, and hydrothermal analysis. Their size and homogeneity play an essential role in biosensing applications for tissue engineering. Surface functionalization is key in reducing their toxicity and integrating the magnetic traits in the desired biosensor. These nanoparticles have the tendency to bond with nucleophilic functional groups like OH-, COO-, NH2, PO4-, etc., due to their electron-deficient nature. These functional groups serve as linkers between biomolecules, allowing them to be attached via different kinds of bondings and chemical interactions. Therefore the magnetic labels exhibit excellent properties for biosensing applications due to the bio-moieties that don't display any magnetic nature. Hence ultimately, no such aberrations or noises are captured or expected during the transduction and capturing of the signal. Because of their large surface area, better electrocatalytic property, optical characteristics, e-transfer kinetics, strong absorption tunable properties, and low-cost manufacturing, they are considered appropriate materials for developing biosensors. INTRODUCTION OF NANOBIOSENSORS A sensing device measures the amount of analyte (diagnostic molecule) in a specimen. Preferably, such an implementation is capable of a continuous and reversal reaction, with the added benefit of not damaging the sample. The typical structure of biosensors is a combination of biological components (such as an enzyme, DNA strand, antibody, and whole cell) used to attach to the analyte in the sample and a transducer. Nano-biosensing devices generally incorporate nanostructured materials, which are often used to monitor pollutants, biological molecules, chemical compounds, temperature, and so on, into their design [57]. The integration of NMs in the construction of nanobiosensors raises the unit's sensitivity and operating performance simultaneously. Nanoparticles, nanowires, nanotubes, nanopores, nanorods, and nano-composites with biomolecules are all elements of nanostructured materials [58]. Nanomaterials possess physicochemical and biological features from their nanoscale structure that distinguish them from huge-size materials. NMs tend to bind biological macromolecules to their outer surface tightly. They serve a vital role in supporting biomolecules at the nanobiosensor surfaces due to their huge surface area-to-volume ratio. In particular, spontaneous surface adsorption of biomolecules to the exposed exterior of bulk materials results in the reduction or loss of bioactivity. Due to the obvious biocompatibility and non-toxicity of the NMs, anchoring such biomolecules onto the target surface of the nanomaterials may sustain their biological functions [59]. As a result, the conjunction of nanoscale structures and biological macromolecules paves the framework for

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expanding a biomaterial–nanostructure interfaces with attractive properties and importance. The “Nanobiosensors” category refers to numerous biosensors that portray nanostructures' role and have been created for medical, pharmacological, agricultural, and other purposes [57, 60]. Classification of Biosensors Based on Biosensing Element Nanobiosensors may be classified based on their biosensing components and transducer type, as shown in Fig. (4). As previously noted, biosensing elements are sufficient to perform certain group reactions or bind with specific groups of substances to produce a measurable signal that is processed and translated by transducers. The two main types of biological sensing components are often used: catalytic (cells/tissues/organelles/enzymes) and affinity (receptors/NAs/ antibodies), as summarized in Table 1. Table 1. Biosensing component-based biosensors. Biosensing Component

Description

Merits

Applications

Reference

Cellular activity studies, cancer diagnostics, cell surface investigations, food analysis, and environmental pollutant monitoring.

[61, 62]

Catalytic-type Biosensing Elements 1. Cells/ tissues

Cells/tissues have the potential to change in response to their surroundings, allowing them to be employed as a biosensor component. These biosensors use complete cells as core transmitters to create signals, which would then be transformed by the central transducer to monitor, which is often an electrical signal.

Ease to handle, rapid proliferation, high availability, good sensitivity, enhanced selectivity, and helps in drug screening and allows organic contaminants detection.

2. Organelles

Each organelle performs a distinct function within the cell and may thus be used in biosensing the relevant analyte.

Easy to handle, Detection of specific availability, higher ions, biomedical sensitivity, selectivity, studies, water and also helps to detect pollutant detection. ions (e.g. mitochondria may sense calcium levels owing to their ability to accumulate calcium).

[63, 64]

3. Enzymes

An enzyme-based biosensor's operation is based on the catalyzed reaction mechanism and binding properties for specific analyte monitoring.

Extremely sensitive, higher stability and efficacy, ease to handle, ease of enzyme extraction, and availability.

[65, 66]

Medical applicability and commonly used to detect glucose and urea.

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(Table ) cont.....

Biosensing Component

Description

Merits

Applications

Reference

Catalytic-type Biosensing Elements Affinity type Biosensing Elements 4. Aptamers

These short ssDNA or ssRNA receptors may be created to bind to amino acids, hormones, proteins, and other compounds.

Easy to synthesize and functionalize, highly sensitive to a specific analyte, and allows efficient discrimination among closely related molecules, FDA approved.

Monitoring specific proteins, cancer cells, infectious agents, and various therapeutic purposes.

[67 - 69]

5. Nucleic acids (NAs)

The emergence of Easy to use, good Screening at the nanobiosensors to diagnose specificity, reusable, point of care for particular DNA has the ability highly accurate common diseases, to affect fundamental results,label-free and infectious agents, biomedical studies as well as ultrasensitive technique. metabolic disorders, disease-related genetic cancer, and heritable assessment. The detection diseases. algorithm based on DNA biosensors primarily depends on the immobilization of ssDNA on the nanostructured materials surface of a sensor, allowing coupling of sequencespecific DNA and identification of similar target DNA.

[70, 71]

6. Antibody

Human and other mammalian More precise and rapid Lable-free detection immune systems make methods are extensively of diseases and antibodies, which are proteins used in the detection of inherited disorders. and are an important contagious diseases, realcomponent of immunosensors. time detection, and are These immunosensors operate highly sensitive. on the basis of a highly potent and selective antigen-antibody (Ag-Ab) interaction. The antibodies bind with an analyte, allowing alteration of the functional groups linked to the interface of the transducer for identification and estimation.

[72 - 74]

Classification Of Biosensors Based On Transducers Transducers are the parts of the biosensor that recognize the signals produced by

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the bioanalyte's engagement with the biological recognition element and convert them into a measurable signal. Transducers are further classified into electrochemical, optical (e.g., fluorescence, surface plasmon resonance (SPR), chemiluminescence), electronic, piezoelectric/gravimetric, thermal, and other categories based on their functioning principles, as shown in Fig. (4) and some of the commonly used transducers used for biosensing applications are described in Table 2 given below. There are still multiple transducer-based biosensors that use the principles of acoustic, magnetoelastic, and bioluminescence but are not extensively used in clinical diagnostics. Table 2. Transducer-based biosensors. Biosensing Component 1. Electrochemical

2. Optical

Description

Merits

It is a well-researched transducer Highly sensitive that measures the electrochemical and specific, signals that occur on the detecting simple to use, surface of electrodes when they and costcontact the specific analyte. These effective. transducers are further categorized based on electric signals as potentiometers (a variation in voltage level), amperometric (a difference in recorded current at a specific voltage), and conductometric measurements (an alteration in the detecting material's capacity to transmit charge).

Applications

Reference

Detection of nucleic acids (DNA or RNA), membrane proteins, cancer detection, therapeutic applications, and field monitoring.

[75, 76]

Optical biosensors are diagnostic Highly selective Most extensively devices that include a biological and sensitive, researched for recognition element in an optic easy to use, and medical transducer setup. An optical requires a short diagnostics, biosensor's operating concept is to response time. monitoring of create signals corresponding to biomolecules, and analyte content and to allow labelenvironmental and free enabling real-time simultaneous food quality. monitoring. The most popular optical-based biosensors include fluorescence-, chemiluminescence-, SPR-, and optical fiber-based optical biosensors.

[20, 77, 78]

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(Table ) cont.....

Biosensing Component 3. Thermal

Description

Merits

Applications

Thermal transducer-based biosensors Highly Widely used to make use of the fundamental sensitive, low assess enzymeproperties of biological processes cost, lesser time based reactions, (exothermic or endothermic), namely and power pesticides, the detection of heat energy received consumption. infectious diseases, or emitted during the interaction. It and serum monitors the variation in heat, which cholesterol is immediately analyzed in order to detection. assess the amount of the reactions (for catalysts) or the structural analysis of biological molecules in the soluble form.

4. Gravimetric These are mass-based biosensors that or piezoelectric produce quantifiable signals in response to a slight variation in the weight of binding surface material, including biomolecules (such as proteins or antibodies). It involves piezoelectric quartz crystals, which vibrate at a precise frequency based on the supplied current and the weight of the identified substance.

Low cost, extended lifetime, compact size, and inert.

Fig. (4). Classification of biosensors based onBioreceptor and Transducer.

These transducers are widely applied in the biomedical field to detect infections and antigens via strong binding interactions.

Reference [79 - 81]

[79, 82]

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Types Of Nanobiosensors And Their Application In TE Quantum-Dot Based Nano-Biosensors QDs are inorganic nanostructures that usually belong to the 0-Dimension NMs family. They provide superior inherent optical features such as vast excitation, strong photocatalytic persistence, narrow size output bandwidth spectrum, and low photo-bleaching [83]. QDs are nanometer-scale semiconductors that operate on the fluorescence transmission mechanism [84]. They have indeed been widely employed in the development of sensing applications to analyze chemical substances, pharmacological samples, and biological macromolecules, including oligonucleotides, peptides, amino acids, catalysts, and so on. They are most often used to help diagnose cancer and other chronic diseases in vivo [85]. Due to their excellent susceptibility, specificity, compact design, inexpensive, size-dependent wavelength range, and quick sample monitoring are ideal prospects for numerous optical biosensing applications [85]. Cui et al. suggested an effective electrochemical biosensor for Cu (II) based on Graphene-QDs (GQDs) and graphene. The coupling of GQDs alongside graphene enhances the efficiency while maintaining a lowlimit of detection (LOD) [86]. The utilization of graphene-based QDs as the energy supplier and AuNPs as the energy receiver in the creation of fluorescence biosensing for the sensitive and specific analysis of specific cell lung cancer biological markers [87]. A magnetized fluorescence biosensor relying on GQDs, Fe3O4, and molybdenum disulfide (MoS2) nanosheets has been designed to quickly and efficiently isolate and detect migrating tumor cells [88]. Carbon Nanotubes-Based Nano-Biosensors Carbon nanotubes (CNTs) are tubular assemblies of the covered graphene sheet. CNT-based wearable nanobiosensors are being used mostly for biomedical applications because of graphene's remarkable physiochemical properties. Due to the existence of atomic bonds, these nanotubes can survive extremely high temperatures and function as good thermal and electrical conductors. Antibodies or specific probes on these nanostructures detect antigens like viral pathogens, nucleic acids, enzymes, etc. These biosensors operate on the basis of a variable electrical conductance proportional to the proximity between the targeted sample and the particular probe, which is detectable by an electrical analyzer. Nanotubes can also be used in conjunction with electrochemical biosensors to improve the susceptibility, sensitivity, and efficacy of enzyme sensors, immunosensors, and NA-based biosensing systems. It is readily folded and compressed owing to its exceptional tensile properties and flexible tendency. CNTs have also gained much importance for their potential use with oligonucleotide and enzyme-based

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biosensing. CNTs are anomalous because they have both benefits and drawbacks for biological applications. Furthermore, because of its high flexibility and mechanical characteristics, it is likely to be used as a bone implant or as a calcium chip related to bone structural system; however, due to its small size and biocompatibility, it could be used as a transplant in an artificial limb without causing host rejection. As CNTs are nanosized, they may efficiently penetrate the cell membrane and engage with proteins or genes that are highly expressed in cancerous cells. The fundamental limitation is the biosynthesis of CNTs in their pure state without compromising most of their distinguishing characteristics. They are somewhat soluble in aqueous media, and their pharmacokinetics are affected by factors like structure, size, chemical properties, and coagulation capacity; it's still unknown. Small-sized NPs less than 100 nm can easily penetrate the cell membrane via phagocytosis and the inflammatory processes and can be redistributed from their initial location [89 - 91]. Microfluidic Based Nanobiosensors These are quantitative biosensors in which the bioactive molecules or bioreceptor are immobilized with an electrical transducer to identify specific analytes in a viscous fluid solution. This method identifies changes in the surface mass of dielectric characteristics in the presence of a tumor diagnostic marker or infection. These systems are distinguished by their high specific surface area-to-volume ratios. The current flow in these fluidic nanobiosensor devices can be caused by pressure, electro-kinetic characteristics, or electro-osmotic features. The technology is compatible with electrochemical, biomechanical, as well as optical transduction methods [91]. Lab-on-a-Chip Lab-on-a-chip is a compact device with a high diagnostic accuracy value coupled with a single microchip capable of automatically detecting one or more analytes, including NAs (DNA or RNA). Microfluidics and molecular bioengineering are the primary technologies influencing the development and advancement of labon-a-chip [92]. These devices are assembled with numerous microscopic channels fixed with biological components, enabling several biochemical reactions from a meager blood sample [93]. Polydimethylsiloxane (PDMS), thermoplastic polymers, silicon, glass, and paper-based innovative technologies are commonly employed to construct lab-on-a-chip biosensors. However, PDMS and paperbased lab-on-a-chip nanobiosensing devices, on the other hand, are more extensively employed due to their cost-effectiveness and ease of fabrication. Labon-a-chip sensors accelerate PCR operations by performing high-speed micro-

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scale temperature changes. It has a DNA microarray that allows for thousands of times quicker genomic analysis and sequencing. These devices also have the capacity to accommodate all stages of proteomics, beginning with protein sample preparation, isolation, purification, mass spectroscopy, and crystallization. This nanobiosensing device is capable of dealing with a huge cell count. Nonetheless, it can identify and assess cells at the single-cell scale at the same time. The benefits of lab-on-a-chip nanobiosensors include their low prices, increased sensitivity to traditional diagnostic tests, simplicity, rapid results, portability owing to their small size, small volume samples required, and, most crucially, real-time surveillance [91, 94]. Nanowire (NW)-Based Biosensors The NWs are ideal for developing durable, accurate, and efficient electronic biosensors of biological interaction processes. The optical and electronic properties of the NWs are highly repeatable. Total current flow in almost any 1-D network, including NWs and NTs, is acutely susceptible because minute differences in such system applications are difficult to detect since flow is so near the surface [95]. NW provides great transduction signal generation, which eventually reaches macroscopic equipment. The combination of NWs' customizable conductive capabilities and potential to adhere samples on their surface results in a fast, direct, tag-free electric signal [96]. These nanobiosensors operate on the ion-selective FET principle, focusing on the interplay of external charges with carriers in a surrounding semiconducting material to improve selectivity and sensitivity at lower pH. Park et al. constructed an optical fiber sensor for an ultrasensitive plasmon biosensing system employing Zinc-Oxide NWs and AuNPs [97]. Priolo et al. developed a tag-free and PCR-free optical nanobiosensor device based on silicon NWs for immediate genomic identification. They found that the artificial genome had a diagnostic capacity of 2 copies per experiment, and the human genetic material derived from human blood had a diagnostic capacity of 20 copies per response [98]. A silicon NW-based sensor system with new molecular controllability for electrical sensing was utilized to identify Dengue virus (DENV) genetic material. The sophisticated sensor featured a LOD of 2.0 fM concentration and sensitivity of around 45.0 A [99]. Nanorods-Based Biosensors Nanorods are often fabricated as a simple electrochemical modifier to facilitate a highly specific process. They are usually a build-up of gold, manganese, graphene, zinc, iron oxide, or a combination of these materials [100, 101]. Its most common applications are to recognize nucleic acid and the detection of basic

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biochemical markers such as glucose and hydrogen peroxide. A new device based on the assembly of CDs/Au NR-based FRET sensor prepared for detecting lead ions [102]. Zhu et al. developed a ZnO NRs-based FET nano-biosensor for continuous glucose monitoring based on AC frequency mixing.GNRs and graphene oxide (GO) based nano-biosensor has been used by Sun et al. to enhance the sensitivity of a wavelength modulation SPR nano-biosensor to effectively detect bovine IgG [103]. Hahn et al. assembled a vertically grown ZnO NRs-based FET nano-biosensor to sense phosphate with high sensitivity [104]. Gold Nanoparticle-Based Nano-Biosensors AuNPs, which belong to the superior metal NPs family, are widely exploited and utilized due to their distinctive optical, biological, electrical, and physicochemical characteristics. These NPs are widely employed in biological and medicinal research because of the numerous benefits: simple production methods, simpler manufacturing procedures, increased chemical integrity, wide electrochemical stability spectrum, strong catalytic properties, and reliable nano-composite forms [49, 105]. Wu et al. used an AuNP-based electrochemical sensing system to measure uranyl in natural water in a specific and efficient manner [106]. Luo et al. developed a new “turn–on” fluorescence-based sensing system for sensing Pb2+ by combining two NMs: graphene quantum dots (GQDs) and AuNPs [107]. An innovative non-enzymatic glucose sensor has been developed using gold-nickel bimetallic NPs doped alumina silicate frameworks generated from agricultural residues, which demonstrated a broad linear response for glucose (1–1900 M) and a LOD for its monitoring (0.063 M) [108]. Silver Nanoparticles (AgNPs)-Based Nano-Biosensors AgNPs have piqued the involvement of researchers in the biomedical field because of their superior surface-enhanced Raman scattering (SERS), boosted electrochemical signals, cytocompatibility, high electrical conductivity, and catalytic performance [109 - 111]. Rivero et al. employed Ag NPs to construct an optical fiber sensor that uses both localized surface plasmon resonance (LSPR) and lossy-mode resonance (LMR). The devices exhibited high sensitivity, a large versatile range, and a fast response time. This device could be implemented for monitoring human breath [112]. Metal Oxide-Based Nanoparticles Metal oxide-based NMs have been utilized in a wide range of studies in past years, including electrochemical processes, catalysis, magnetism, and biosensor manufacturing, due to their broad range of electrical, chemical, and

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physicochemical properties. These metal oxide-based nanomaterials may be employed as an efficient electrocatalyst for diagnosing a wide variety of samples in the domains of biomedical diagnostics and therapeutics due to their strong electrocatalytic performance, relatively inexpensive, and high organic usage capacity. The most commonly used metal oxide NPs include nickel oxide (NiO), cobalt oxide (Co3O4), iron oxide (Fe2O3), copper oxide (CuO), manganese oxide (MnO2), zinc oxide (ZnO), and many others [113]. NiO NPs exhibit excellent electrical, optical, electromagnetic, thermal, catalytic, and biomechanical properties [114]. Kamyabi et al. developed new electroluminescence (ECL) glucose nanobiosensor based on immobilized glucose oxidase in a nickel foam cavity coupled with NiON.P.s. The predicted ECL biosensor system demonstrated improved performance and efficiency in terms of glucose level in phosphate-buffered saline and its LOD [115]. Co3O4 NPS are gaining popularity due to their superior optical, physiological, magnetic, electrical, and chemical attributes. They may be used as catalysts, solar-specific absorbers, gas sensing units, supercapacitors, lithium-ion batteries, photocatalysis, magnetic materials, and so forth [116]. Wazir et al. fabricated a robust urea biosensor developed on glass filter paper through the immobilization of urease enzyme onto a cobalt oxide-chitosan nano-composite system [117]. Ge et al. constructed a photo-electrochemical (PEC) sensor based on Co3O4-Au polyhedrons for the identification of miRNA-141 [117]. Due to the high electron transfer efficiency and bioanalytical processes, iron oxide (Fe2O3) and manganese oxide (MnO2)-based NPs are among the most well-known magnetic NMs. They are also considered important and deserving nanomaterials for electrochemical biosensors [118, 119]. THE MAJOR CHALLENGES OF NANOBIOSENSORS AND FUTURE DIRECTIONS In tissue engineering (TE) application areas, nanobiosensors assist in precise, sensitive, and quick disease diagnostic tools. Nanobiosensors, as contrasted to typical ELISA analytical techniques, provide a method for real-time and accurate monitoring of biological signals through the use of a fusion of biological, biochemical, and physiological approaches. Furthermore, nanobiosensors have advanced significantly over the years, but many issues still need to be addressed. One of the numerous hurdles in nanobiosensor construction is the development of a transducer capable of effective and productive in collecting signals from a specific process. In this circumstance, additional specific biological components labeled for optical, electrical, or thermal transduction must be applied. The scalable approach and the long-term integrity of commercial devices are the key

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problems of nanobiosensors. Existing nanobiosensors are typically shown as concepts at research laboratories. As a result, as industrial goods, scalable systems are critical for swiftly mass-producing biosensors with excellent reliability and quality from the research laboratories to the industrial sector. However, integrating research insights into an economically viable industry procedure is challenging, costlier, labor-intensive, time and resource-consuming. Additionally, from the industrial to the retail level, commercialized nanobiosensors often involve an extended period before they are supplied to a consumer, which may impact their overall stability and performance. Even though nanobiosensors have a vast range of economic and operational uses, they are still only suitable in a few sectors due to cost constraints and technological hurdles. Biosensors encounter several constraints in order to perform properly in vivo. This would include immunogenicity, wherein the sensing device must be noncytotoxic, not disrupt the system's homeostasis equilibrium, and preferably be non-invasive and painless; additional problems include sustaining long-term durability, combinatorial, and retaining high temporal and spatial accuracy. Therefore, to address the challenges mentioned above, the integration of interdisciplinary approaches is required to build more sensitive and elevated reactive components for the production of nanosensing devices. Furthermore, while numerous in vitro cell-based sensing devices exhibit continuous and active monitoring features, compact and lighter-weight biosensors, including paperbased biosensors, offers a simple technique for immediately observing the findings that resolve complicated operating concerns. As a result, the ongoing nanobiosensor paradigm in tissue engineering and regenerative medicine is the fabrication of compact, small, lightweight, and flexible biosensors. This form of sensor device opens up a new avenue for incorporating biosensors into wearable technology. Moreover, wearable nanobiosensors linked with applications and smart devices provide a novel perspective for developing succeeding biosensors for real-time, active monitoring, detecting, or prognosing illnesses. Further study is needed in this domain, and researchers anticipate that continuing research studies will be translated into economically feasible designs by industry in the coming years. CONCLUSION Tremendous achievements have already been claimed for the constant monitoring of specific analytes, specifically markers important for tissue engineering. Throughout the initial form of tissue regeneration, the overall objective is an offthe-shelf platform in which tissues/organs may be rejuvenated with sensors continually assessing transplant vitality throughout the course of the regrowth,

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without any need for interactions with patients. Further, with the application of nanomaterials (NMs) in biosensors, researchers have seen a fast expansion in advanced biosensing technologies over the last decade. This would be due to the application of novel biological recognition components and transducers, improvements in simplification, designing, and fabrication of nanoscale devices at the micro-level, and novel NM production processes, which together combine scientific methods, and innovative technologies. Nanobiosenensor technology has become far more diversified, robust, adaptive, and flexible with the emergence of nanostructured materials. The biological signaling process in nanobiosensors has indeed been greatly enhanced (including heightened susceptibility, quicker recognition, reduced processing speed, and reliability) by employing various nanomaterials, including metallic nanoparticles, carbon-based materials (e.g., graphene or carbon nanotubes), quantum dots, and many more and each seems to have unique attributes inside nanobiosensing devices. Due to the increased number of various NMs, each with their own unique set of features, only a few instances could be given here while accentuating the main benefits of such materials. Although there has been significant progress with the use of nanoscale materials in biosensing devices in tissue engineering, some challenges restrict these implementations from progressing to further technical levels. For example, the insufficiency of sensitivity and selectivity continues to be a barrier to the use of many nanoscale materials (such as carbon-based biosensors, etc.). Such a barrier, nevertheless, can be circumvented by combining these nanostructures with some other materials. Durability, biocompatibility, toxicity, flexibility, manufacturing cost, and complex production procedures are among the main challenges with these biosensors. These concerns should be researched and resolved when novel nanomaterials are developed for biosensors. With the exception of glucose sensors and pregnancy test kits, only a few biosensing devices have achieved massive commercial success on a worldwide scale. There seems to be a demand for lowcost nanostructure-based biosensors that provide accurate data instantly and are simple to use. Additional research towards nano biosensors advancement could contribute to the discovery of innovative, more successful, and efficient methods that might open the way for a much more efficient cure for infectious and lethal chronic diseases in the coming decades. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

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ACKNOWLEDGMENTS The authors are thankful to the School of Biochemical Engineering, IIT (BHU) Varanasi, for providing technical support. This work was financially supported by the CSIR JRF/SRF, India, under the CSIR NET/JRF Ph.D. program, for providing fellowship to author Soumya Katiyar during this study's tenure. REFERENCES [1]

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CHAPTER 7

DNA Biosensors: Effective Tool in Biotechnology Arpita Mishra1, Avanish Kumar Shrivastav2,* and Vivek Kumar Chaturvedi3 Department of Life Sciences, Kristu Jayanti College, Bengaluru-560077, India Department of Biotechnology, Delhi Technological University, Delhi-110042, India 3 Department of Gastroenterology, Banaras Hindu University, Varansi-221005, India 1 2

Abstract: A biosensor is a device that converts a biological response into a detectable electrical signal. In recent years, biosensors have gained significant interest due to a plethora of applications in the field of disease diagnosis, detection of various environmental pollutants, food quality analysis, and pharmaceutical drug research. Among various types of biosensors, (such as enzyme-based, immunosensors, DNA biosensors, thermal and piezoelectric biosensors) DNA biosensors are being widely employed because of superior biocompatibility, thermal stability and alternative functionalization. DNA biosensors introduced in recent years include an aptamer-based sensor, molecular beacon-based biosensors, fluorescence-based sensors, hybridizationbased sensors and electrochemical-based DNA biosensors. This chapter highlights the fundamental knowledge and recent advances in the field of DNA-based biosensors. This chapter also focuses on the significance and wide application of DNAbased biosensors in the diverse areas of biotechnology and allied fields.

Keywords: Aptamers, Biosensor, Diagnosis, DNA-based, Environment, Fluorescence-based. INTRODUCTION Biosensors are devices that employ biological reaction to detect target analytes [1 - 3]. It entails the combination of biological receptors with a physical transducer that converts biorecognition into usable electrical impulses [4]. The signal generated is proportional to the analyte concentration [5 - 10]. The bioreceptor, transducer and the detection system are the three essential components of a biosensor (Fig. 1) [11]. Bioreceptors viz enzymes, cells, aptamers, deoxyribonucleic acid (DNA or RNA), and antibodies recognizes the analyte to produce detectable signals during the interaction. The transducer associated with the sensor converts the biorecognition event into a measurable signal to be displayed. Based on the receptors involved, biosensors can be categoCorresponding author Avanish Kumar Shrivastav: Department of Biotechnology, Delhi technological university, Delhi; E-mail: [email protected]

*

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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rised into immuno biosensors, DNA biosensors, enzyme biosensors, whole-cell biosensors, and phage biosensors [12]. Transducers may be amperometric (current measurement at constant potential) [13], potentiometric (potential measurement at constant current) [14], piezoelectric (measurement of changes in mass [15], thermal (measurement of changes in temperature) [16] or optical (detect changes in transmission of light) [17]. Among these several biosensors DNA biosensors, utilizing DNA as a probe, hold great potential in the field of biosensing. The present review throws light on recent applications of DNA-based biosensors.

Fig. (1). Biosensors, types and applications.

Types of DNA-Based Biosensors Aptamer Based Aptamers are synthetic single-stranded DNA or RNA with 15–80 nucleotides capable of binding to the target. It can be chemically synthesized and are structurally and functionally stable over a wide range of temperatures and storage conditions. The first aptamer was acquired in 1990 by Ellington et al. [4, 18]. Aptamers can be isolated from oligonucleotide libraries by an In vitro selection mechanism, SELEX (Systematic Evolution of Ligands by Exponential enrichment) [19, 20]. It can bind to a large number of targets (e.g., proteins, drugs, cell, amino acids, natural and inorganic particles) by folding into three-layered structures with high fondness and particularity [12, 21 - 24]. These molecules can be amplified by polymerase chain reaction (PCR), which increases the sensitivity of aptasensors [5, 25], LAMP [26], and RCA [27 - 29]. Aptamers possess several advantages over traditional bio probes and are thus regarded as promising alternatives for antibodies in bioassay areas. They are stable even in drastic environmental conditions and does not require special transport or storage conditions. DNA aptamers are steady to incredibly high temperatures, pH values,

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and high ionic fixations. Beside this, modifications of functional groups can be done without losing the biological activity. It can be prepared on a large scale by simple chemical synthesis with inexpensive nucleotides [30]. When it detects and captures a target, the aptamers roll into a three-dimensional alignment. Since the essential atomic design of aptamers is poor in strength and stability, some unbound nucleobase interacts to form basic themes to choose from. The interaction of these themes leads to more complex designs for higher education such as coaxial stacking and G-quadruplexes. Approaches involving nanoparticles (NPs) in electrochemical aptamer sensors, eno sensors, and immunosensors have been developed [31]. The construction of nanoscale electrical biosensors using aptamers as molecular recognition elements are reported [32]. A sensitive ratiometric fluorescence aptasensor for the determination of ochratoxin A (OTA), a small molecular mycotoxin produced by Aspergillus and Penicillium strains, has been successfully constructed. Leng et al., 2016 studied the framework for the development of aptamer-based biosensors and bioassay techniques [33]. Sefah and the participants discussed the use of aptamers in biosensor development by classifying them into three standard levels: structural exchanges, chemical based, and aptazyme-based biosensors. The most commonly used method of DNA aptamer detection is to make the DNA aptamer work with report particles, such as ferrocene or methylene blue and static particles, such as alkane thiol, alkane amino, streptavidin or hydrazoate at the end of the 5 'and 3' DNA strand, respectively. An electrochemical sensor in the light of 34-mer IFN-γ-retricing aptamer interferon-gamma (IFN-γ) was developed by Liu et al. [13]. In their review, the proposed DNA aptamer was concentrated in the outer layer of the cathode using a combined reaction of gold and alkyl mercaptan. Without any specific purpose, the DNA aptamer was shown to fold down to form a circle, making the particles that are exposed affect the end of the sensor. Limiting the target and the DNA aptamer alters the adaptation to the aptamer, extending the distance between the detailed particles and the storage area. This results in differences in the technology of electronic exchange between the declining atoms and the storage areas. The detection limit (LOD) reached 0.06 nM, and the direct detection range was found to be 10 nM. The DNA aptamer can also be activated by synthetic polymers, which are commonly used as report labels in fluorescent and colored biosensors due to their excellent optical properties [34]. The DNA aptamer can penetrate polymers formed by electrostatic forces [35]. While limiting biotarget, modification of the aptamer DNA sequence will trigger the modification of the polymer structure, which will affect the simulation and output frequency of the formed polymers [36]. This strategy has been effectively used to distinguish human α-thrombin, with a LOD of 2 × 10−15 M [37]. Although biosensors for active DNA aptamers show many benefits, the ineffectiveness of aptamers against the nervous system is a challenge. Graphene

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oxide (GO), which exhibits amazing photoelectric properties and transport capacity, is a commonly used 2D to enhance the cycle [14, 38 - 40]. Aptamers with a wide range of acquired features can be integrated to achieve broader recognition, and this approach makes sense in the area of a few diseases [41] and inflammatory biomarkers [42]. In any case, due to the excessive unchanged reaction of the sensor, the response of this type of biosensor will decrease. Electrochemical Based The electrochemical biosensor is one of the most widely used sensing devices based on transducing the biochemical events to electrical signals. It includes an electrode as a key component used as a solid support for the immobilization of biomolecules and electron movement. These biosensors are being used extensively due to their high sensitivity and rapid response. Electrochemical devices are very useful for DNA diagnostics. An important rule of electrochemical DNA biosensor is that the natural reaction between the bioreceptor and the target can create or consume particles or electrons, altering the flow of electricity, energy, or other electrical components of a system. The natural signal can be converted into a visible electrical signal associated with the focus of the transducer and displayed on a PC [12]. Electrochemical recognition of DNA hybridization, as a rule, involves looking at current energy. The performance of nucleic corrosion testing in the transducer area plays an important role in the introduction of DNA biosensors and quality chips [43 - 45]. The most common transducers are gold electrodes (GE) [46 - 48], glassy carbon electrodes (GCE) [44], pencil graphite electrodes (PGE) [48] and screen-printed electrodes (SPE) [45], and carbon ionic liquid electrode (CILE) [10]. The reaction between the bioreceptor and target is performed on the electrode surface. When considering a real transducer, various techniques can be used to combine DNA tests in a solid environment. The sensory features of electrochemical DNA including responsiveness, transparency and integrity - are linked to the movement of bioreceptors in the outer layer of the anode. Later, it is important that the prevention strategy does not destroy the organic bioreceptor action or affect the link between the bioreceptor and the target. Among the various techniques of DNA immobilization, adsorption is very simple, and does not require synthetic reagents and DNA modification. DNA being negatively charged can be immobilized by modifying positively charged substances like chitosan, cationic polymeric films, etc., on the electrode surface [49]. An electrochemical DNA biosensor was developed to detect Bacilluscereus DNA [50]. The location of the gold terminal was modified with polypyrrole (PPy) to stabilize DNA, followed by about 0.8 V of 600 s to improve production and reliability of immobilization. Apart from that, covalent binding is another widely used method for DNA

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immobilization on electrode surfaces due to the high efficiency of DNA immobilization and hybridization. Also, self-assembly is one of the most common ways to integrate DNA immobilization into the cathode area. DNA testing is used as self-assembling monolayers (SEM) in gold transducers by integrated coupling in the gold field using alkanethiol-based monolayers. Researchers promoted an electrochemical DNA biosensor to detect Bacillus cereus milk and baby recipe (Izadi et al., 2016). Before becoming acquainted with DNA and biosensor, they cut 5′dissolved ssDNA to block ssDNA in the PGE area, converted to gold nanoparticles by Au-S bonds. One of the most important mechanisms for strong DNA inhibition in cathode is selective limitation. Biotinylated DNA testing is used for the interaction of biotin-avidin bonds in storage [49, 51 - 53]. This method is dependent on the specific affinity between avidin and biotin. However, the LOD of the electrochemical DNA biosensor laid out by this technique is low. For instance, an electrochemical DNA biosensor was created by polypyrrolepolyvinyl sulfonate (PPy-PVS) coated in the Pt circle terminal [49]. DNA testing was poorly performed on the anode by biotin-avidin (roundabout immobilization) or carbodiimide coupling (direct immobilization). Compared to circuitous immobilization, the detection was progressively more effective in preventing further expansion of the test, and the response increased several times. A number of experiments have been compiled in order to improve the quality of DNA. For example [51], stimulated the electrochemical DNA biosensor to detect E. coli. Avidin was formulated as -COOH and subsequently added to polyaniline (PANI) - modified Pt plate with a strong boundary between COOH and - NH / NH2 for PANI. Therefore, biotin-based adhesion tests have not been able to move to the terminal area at will. Finally, a sound detection limit for E was found, coli genomic DNA (0.01 ng / µL). Hybridization Based Hybridization biosensors are associated with the integration of the DNA base of the environmental recognition cycle. In these biosensors, in short, 20-40 base pairs are deeply directed at the stranded single-stranded DNA fragments in the cathode area. DNA strands do not move with the ultimate goal of maintaining their integrity, regeneration, and availability of targeted analysis. At the point where the target DNA is linked to a catch-related sequence or test DNA in a cycle called hybridization, an electrical signal is formed. Ferrocenyl naphthalene diimide (FND) is an electrochemical marker that is specifically linked to DNA duplexes, resulting in electrochemical marking. Horseradish Peroxidase and soluble phosphatase are some of the composite markers used as part of hybridization. Colloidal gold has also been used as a symbol of hybridization. Like other complex organic macromolecules, experimental conditions, such as

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temperature, ionic energy, and time that are considered to be hybrids, must be controlled to achieve higher selection and awareness. Fluorescent Based Biosensors Fluorescent biosensors are widely used in the field of biology, medicine, and several other fields. Fast response, a simple instrument, high sensitivity, and good selectivity are the features owing to its wide application [27, 54 - 57]. In most fluorescent biosensors, the fluorescence power is recorded as the readout signal for the analytes. A brighter fluorescent tag and signal amplification technology are usually applied to improve the fluorescence signals of biosensors during construction. Among numerous variations, cyclic signal intensification (CSA) innovation is one of the most valuable procedures because of its straightforward, minimal expense and adaptable plan standards. CSA innovation uses the hybridization of nucleic acids or chemicals for nucleic acids to deliver the analyte, which is reused for additional increments in the fluorescence results of the biosensors. Therefore, after the CSA, the fluorescence mark can be strengthened by multi-fold to achieve a particularly critical limit for the detection of biomolecules. The most widely used CSA strategies include rolling circle development (RCA), strand development response (SDR) and enzyme-assisted amplification (EAA), etc [41, 52, 58]. Xu et al., (2011) [59] improve the mercury (II) heart rate by detecting the fluorescence detection system “sub-atomic reference point” with 5-color 6-carboxyuorescein (FAM) and 3-terminal marking quencher 4- (4- dimethylaminophenylazo) benzoic corrosive (DABCYL), and the maximum was 2.5 [59]. RCA contains circular DNA and a linear complementary primer (Zhang et al., 2020). In the RCA process, circular DNA is used as a template to which primer is hybridized, which then forms a single strand of DNA that contains a large amount of repeated sequence by polymerization, resulting in an increase in fluorescencesignal through amplification. Application of DNA Sensors Food Quality Analysis Due to its properties, such as low detection limit, wide linear dynamic range, and good repeatability, the Electrochemical DNA biosensor is frequently utilised as an alternative to traditional methods for detecting food-borne diseases [50]. Apart from that, aptamer-based biosensors have been successfully created for the detection of numerous mycotoxins with good sensitivity and selectivity when compared to standard instrumental methods and immunological approaches, owing to their simple, quick, and low-cost properties. Ochratoxins, a type of

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mycotoxin generated by a fungus such as Aspergillus ochraceus and Penicillium verrucosum, have been detected using Aptamer [60]. The maximum affinity for OTA is found in the first aptamer, which is the smallest of the examined sequences. 200 nM is the dissociation constant [61]. To detect S. Typhimurium in apple juice, researchers developed a label-free impedimetric biosensor. Before immobilisation on the electrode surface, the amino group at the 5' end of the aptamer is modified. The developed biosensor's LOD was 3 CFU/mL, resulting in a satisfactory detection result. A rapid and simple fluorescence biosensor using a bioenzyme (acetylcholinesterase and choline oxidase) system, quantum dots, and acetylcholine as substrate was proposed for the detection of dichlorvos in actual samples such as apples (Eivazzadeh-Keihan et al., 2018) [27]. In the construction of electrochemical DNA biosensors for the detection of food-borne bacteria, three main detection techniques are widely used [1]: Direct binding mechanism, in which an aptamer immobilised on the electrode surface attaches directly to the target, causing the aptamer's conformation to change and the current signal to alter [2]. Mechanism of target-induced dissociation (TID) [43] in which the aptamer hybridises with its complementary sequence in the absence of a target. While the addition of the target causes the complementary sequence to dissociate and be replaced by the aptamer, allowing the complementary sequence to become free again and modifying the electrochemical signal [3]. In the design of sandwichtype aptasensors, a dual aptamer detecting mechanism is used. The first aptamer is immobilised on the sensing interface as a capture probe to bond with the target, whereas the second aptamer serves as a signal probe in this situation. Monitoring of antibiotic residues in food remains crucial for food safety and human health. Biosensors detecting antibiotics in food have been designed. A sensitive, labeland enzyme-free fluorescence aptamer sensor for the detection of trace kanamycin in milk samples was developed [61]. Detection of Environmental Contaminants Various chromatographic techniques, such as gas chromatography and highperformance liquid chromatography combined with capillary electrophoresis or mass spectrometry, are used to monitor pollutants in the environment, but there are several drawbacks, including expensive reagents, time-consuming sample pretreatment, and expensive equipment [32, 33]. Advanced biosensing devices were developed in response to the need for fast, selective, sensitive, accurate, and realtime sensors for detecting and screening contaminants. Biosensors such as immunosensors, aptasensors, genosensors, and enzymatic biosensors, which use antibodies, aptamers, nucleic acids, and enzymes as recognition elements, have been reported for the detection and monitoring of various environmental

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pollutants [62]. Disposable amperometric enzymatic (acetylcholinesterase) biosensors using a cysteamine self-assembled monolayer on gold screen-printed electrodes were proposed for the detection of organophosphorous insecticides using paraoxon as the model analyte [63]. The disposable biosensors have a linear range of up to 40 ppb, a sensitivity of 113 µA mM cm−2, and a limit of detection of 2 ppb. A sensitive and selective enzymatic biosensor using hydrolase and a uniform nanocomposite based on magnetic Fe3O4 (average diameter of 120 nm) and gold nanoparticles (diameter=13 nm), was used to determine another insecticide, methyl parathion. The disposable biosensors exhibited a linear range of up to 40 ppb with a limit [64]. With sensors based on quantum dots, the detection of soluble particles, ClO-for example, in water has been achieved with ultra-low limits and ultra-high sensitivity [64]. Pathogens in environmental matrices, particularly in water compartments, constitute a severe threat to human health, and certain biosensors have recently been proposed for detecting them in the environment. For example, for the detection of metabolically active Legionella pneumophila in complicated environmental water samples, quick and selective optical biosensors based on surface plasmon resonance have been proposed [65, 66]. The principle of detection in one study was based on the RNA detector probe mounted on the biochip gold surface recognising bacterial RNA [66]. For signal amplification, streptavidin-conjugated quantum dots were used, and the detection period was roughly three hours, indicating that the biosensing system is capable of detecting bacteria in the 104–108 CFU mL-1 range [66]. A self-assembled monolayer of protein A and an antibody solution against L. pneumophila used to functionalize the gold substrate in another study [65]. Enzymatic biosensors were also employed to detect pirimicarb, a carbamate pesticide, utilising enzymatic biosensors (acetylcholinesterase and laccase) [67, 68]. MWCNT on composite carbon paste electrode was employed in an enzymatic biosensor based on laccase enzyme to detect pirimicarb with a limit of detection of43 µg mL−1. Heavy metals are highly hazardous and widespread contaminants in the environment [11]. They can pollute natural water environments, posing serious health risks, therefore, portable, low cost, and quick heavy metal assessments are a top priority worldwide. Mercury ions (Hg22+) were employed as a model target for evaluating a DNA optical biosensor for heavy metal ion detection. Toxins, such as brevetoxins and microcystins, are created by cyanobacteria blooms caused by the eutrophication of aquatic systems, and accurate and cost-effective technologies for the early detection of such toxins are required. Using gold electrodes functionalized with cysteamine self-assembled monolayers, a sensitive electrochemical aptasensor was used to detect brevetoxin-2, a marine neurotoxin [69]. A limit of detection of 106 pg mL/1 was achieved, with good

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selectivity for brevetoxin-2 over other toxins from various categories, such as okadaic acid and microcystins [69]. Pharmaceutical Applications Many of the sensors mentioned above are also appropriate for screening purposes in order to find novel drugs. Such systems should provide information either about compounds with known bioactive substances or about the bioactivity of samples with identified or unidentified chemical configuration. As transducer elements of biosensors, electrical devices such as electrodes and semiconductors, optical components, e.g., fibre optics, and quartz microbalances are frequently utilized. To create chip-based sensory systems, several of them have been shrunk. These methods, in particular, may win out in drug screening since they allow for a large throughput of samples while using common experimental equipment [70]. The first amperometric biosensor was a glucose sensor with an oxygenconsuming enzyme (e.g., glucose oxidase, phenolase) mounted on a platinum electrode, with oxygen reduction at the electrode resulting in a current that is inversely proportional to the amount of oxygen consumed. The penicillin biosensor, which is based on semiconductor structures, is another well-studied biosensors system for medicinal applications. As a physical transducer, a pHsensitive electrolyte-insulator-semiconductor (EIS) was developed, which immobilised the enzyme penicillinase on its active surface [71, 72]. The biosensor that resulted was sensitive to penicillin G, ampicillin, and amoxicillin. The detection limit of the sensor was around 0.1 mM penicillin G. The detection of cysteine sulfoxides (amino acid derivatives present in onions and garlic) using biosensors has also been extensively researched [70, 73, 74]. An ammonia-gas electrode, a modified pH-sensitive glass electrode, and the enzyme alliinase make up the cysteine–sulfoxide biosensor. Alliinase is an enzyme that breaks down cysteine sulfoxides into allylsulfenic acid, pyruvic acid, and ammonia. The electrode detects the latter substrate particularly. The sensor had a detection limit of 0.5 M alliin, a common cysteine sulfoxide, and could be utilised for real-time measurements for 400 hours. Over a period of 250 days, the enzyme was shown to be stable. SPR-based screening approaches, which include various tactics and a competitive screening format in addition to amperometric sensors, appear to be the most promising way ahead for an HTS of novel medications. If the ligand is a high-molecular-weight chemical, interactions between ligands and proteins can only be evaluated at low doses in a direct binding test. As the detection limit is highly dependent on the sensor type used, particularly its surface qualities, affinity to the immobilised binding partner, and ligand molecular weight, a precise detection limit cannot be specified. However, only the affinity between interacting biomolecules can be assessed, with no evidence of intrinsic binding partner

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activity. As a result, distinguishing between agonists and antagonists necessitates elaborate experimental setups. A human deltaopioid receptor was used as a model protein and reconstituted in an artificial lipid layer to successfully establish such a distinction between agonists and antagonists [75]. SPR observed particular mass movements of the surrounding lipid bilayer generated by interactions of the receptor with an agonist and antagonist [76, 77]. Identification of pathogen is significant for the diagnosis and treatment of clinical patients. A fluorescence sensor was reported to guide the detection of urinary tract bacterial infections rapidly. The Ami-AuNPs-DNAs sensor that discriminates five main urinary tract pathogenic bacteria was reported and sufficiently sensitive to determine individual bacteria with a detection limit of 1×107 cfu/mL [78, 79]. CONCLUSION DNA biosensors are being utilized as one of the most promising alternatives to established detection methods. Despite being extensively applied in numerous fields, issues like lethal toxicity, stability and complexity in fabrication are the areas needed to be explored more. Besides, the cost of detection, however, remains high, restricting its widespread use, particularly in developing nations. Future research should focus on standardising biosensors based on nanomaterials which hold the potential to develop a new generation of biosensors. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 8

Biosensors for the Diagnosis and Therapeutics of Cardiovascular Diseases Avanish Kumar Shrivastav1, Dhitri Borah2,* and Sudeshna Mandal3 Department of Biotechnology, Delhi Technological University, Delhi-110 042, India Department of Zoology, Biswanath College, Biswanath Chariali, Assam-784176, India 3 Department of Zoology, Visva-Bharati, West Bengal-731235, India 1 2

Abstract: Biomedical diagnostic research is becoming increasingly important in the modern medical profession. Infectious disease inspection, initial detection, chronic disease treatment, clinical services and well-being hunt down are the various applications of biosensors. Advanced biosensor technology permits the identification of the disease and the examination of the patient’s responses to medication. Sensor technology is crucial for a broad range of low-cost and practicable developed medical appliances. Biosensors offer many possibilities because they are unambiguous, ascendable and capable of synthesizing procedures. Cardiovascular disease(CVD) is now recognized as the leading cause of death. It is estimated that the number of people dying from heart disease and stroke will approach 20 million by 2015. The risk event of unexpected death associated with it can be minimized by recognizing the challenges involved in its beginning, symptoms, and early detection. Therefore, this chapter aims to provide an idea for the diagnosis and therapeutics of CVD. Biosensors, created to be utilized as quick screening instruments to detect disease biomarkers early on and classify the condition, are revolutionizing CVD diagnosis and prognosis. Biosensors have become faster, more accurate, portable, and environmentally friendly diagnostic equipment as a result of advances in interdisciplinary study domains.

Keywords: Bio-element, Biosensors, Biomarker, Cardiovascular disease, Healthcare service, Immunosensor. INTRODUCTION Cardiovascular disease (CVD) is the leading cause of death in the globe, causing the deaths of nearly 17 million people each year [1]. It was estimated that 17.7 million people died from cardiovascular disease till 2015, reporting for 31% of all deaths planetary; also, coronary heart disease and stroke took away the lives of 7.4 million and 6.7 million people [2]. A person with CVD needs early identificaCorresponding author Dhitri Borah: Department of Zoology, Biswanath College, Biswanath Chariali, Assam784176; E-mail: [email protected]

*

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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tion and care, both medically and psychologically. The current method for detecting CVD is based on a traditional procedure that involves tests that might take many hours or even days to complete, including either costly imaging techniques like the ultrafast computerized tomography (CT) or magnetic resonance imaging (MRI) or hazardous invasive techniques like cerebrovascular or coronary angiography. Such invasive diagnostic procedures are risky and not good for mass screening [3]. The patients must meet up the following conditions to undergo CVD therapy, conditions like alterations in electrocardiogram (ECG), biochemical markers rising in blood tests and distinguishable pain in chest. An indispensable tool to regulate CVD treatment embodied ECG, although it is a poor diagnostic tool for CVD since 50% of CVD patients have a normal cardiogram, making it more difficult to detect CVD [4]. Biosensors with biomarkers are playing a critical role in the diagnostic revolution of cardiovascular illnesses. For the precise diagnosis of cardiac disorders, the design and development of highly sensitive and specific biosensors using practical surface chemistries and non-materials is imperative. Biosensors are made up of a biocatalyst that can detect a biological element and a transducer that can turn the biocatalyst and biological element's combined event into a detectable parameter. Biomolecules such as metabolites, enzymes, cells, DNA, RNA, and oligonucleotides can act as biocatalysts, and transducers can be acoustic, electrochemical, piezoelectric, optical, or calorimetric. Biosensors based on immobilised cells, enzymes, and nucleic acids have recently entered the field of disease diagnosis. Nano biosensors have also been employed to develop diseasediagnostic biosensors, because of their ultrasmall size and unique features. With the use of a multidisciplinary combination of chemistry, medical science, and nanotechnology, biosensors can quickly assess health state, illness start, and progression, and can help plan therapy for various diseases. The gadgets are lowcost, extremely sensitive, quick, and user-friendly, and they may be massproduced for human usage. Biosensors may help with rapid diagnosis, good health care, and reducing the time it takes for findings to be distributed, which is extremely stressful for patients. This article examines biosensors for the diagnosis and therapeutics of cardiovascular disease. Biosensor's Distinct Characteristics in Healthcare Services Biosensors have found their most useful uses in various industries, the most prominent of which are medical, healthcare, and clinical services. Disease detection, retinal prosthesis, contrast imaging during MRIs, cardiac diagnostics, medical mycology, health monitoring, and other broad categories of biosensor applications are effectively serviced (Fig. 1). With great social services, these wide capacities raise healthcare to a new level [5, 6]. COVID-19 is a highly contagious pandemic caused by a newly discovered coronavirus that has spread

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over the world. Various infectious diseases, including SARS, nipah, hendra, and avian influenza, have drawn interest. Biosensors technology possesses massive capabilities and offer enormous probabilities and capability for examining viral and/or disease outburst. Another important feature of the biosensor is its capacity to diagnose cardiac problems. Cardiovascular illnesses are the leading cause of mortality globally. The use of biomarkers in biosensors is critical in the diagnostic revolution of cardiovascular illnesses. For the exact detection of cardiac disorders, the design and development of highly sensitive and selective biosensors employing practical surface chemistries and non-materials are critical. Diabetes prevalence and diabetic patients' use of bio-sensors are significant factors in corporate earnings globally. The demand for rapid and preventative diabetes diagnosis is growing. Advancements in biosensors monitored blood glucose levels on a large scale in the presence of varied temperature gradation. The accuracy and sensitivity of biosensors to detect samples within a minute are developing in the area of diabetics and also have huge market demand, with a great capacity for treatment, monitoring, diagnosis, fitness, and well-being. Portable electronic devices are an integral element of the total healthcare system. They will work together to increase preventative activities and a better understanding of their well-being, using a combination of therapy tools available in hospitals and emergency rooms. It has been seen that acute kidney injury and chronic kidney disease were correctly identified in living mice by photoacoustic imaging using synthetic black phosphorous quantum dots (BPQDs) with an ultra-small size (1.74 0.23 nm after surface modification), with improved detection sensitivity than the clinical serum indices examination method [7]. Moreover, drug hepatotoxicity has been successfully assessed using a polydopamine polyethyleneimine/quantum dot sensor at the cellular level [8]. The market is being driven by technological advancements and the rising usage of biosensors in a variety of applications. Wearable biosensors have improved the quality of life [9, 10]. In addition, the deployment of wearable devices reduces the financial burden of health-care costs. As a result, growing senior populations and rising wearable technology preferences among young people may open up new market segments. Biosensors are an effective approach to diagnosing diseases, detecting microorganisms, and detecting dangerous substances in humans and the environment. A studydeveloped fluorescent sensor shows tremendous potential for the speedy and precise identification of diseases brought on by bacterial infection. It may be utilised to differentiate between pathogenic bacteria that are found in the urinary system [11]. Research suggests that kidney damage progression can be monitored by determining the dimensions and polarity of urine protein. In order to expand the sensor array's potential medical uses, the researchers further boosted the sensor array's high resolution by including more sensor components [12].

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Fig. (1). Applications of Biosensor in health care services [9].

Biomarkers for Cardiovascular Diseases Biomarkers help identify individuals who are at the most risk of CVDs, and it is associated with cardiac inflammation or tissue damage [13]. Some of the biomarkers are well proven in disease diagnosis, like myoglobin, troponin I and T and creatine-kinase MB (CK-MB), while some of them are still under studies, like B-type natriuretic peptide (BNP) and creative protein (CRP) [14] (Table 1). The sensitivity and specificity of the biomarkers were found to have differed with various disease conditions, therefore, the approach of multibiomarkers is more helpful in the detection of CVDs. The occurrence of CVD in the body can be detected by the elevated level of a biological analyte in the blood, known as a cardiac marker [15]. Advancements in the field of genomics and proteomics turn up new biomarkers playing a vital part in the diagnosis of CVDs in the near future. Table 1. Biomarkers for the diagnosis of CVDs [16]. Cardiovascular Biomarker

Examples

Myocyte Stress

C-type natriuretic peptide(CNP), Brain natriuretic peptide (BRP), Atrial natriuretic peptide (ANP)

Myocyte Injury

Myoglobin, Creatine kinase MB(CK-MB), Cardiac troponin I (cTnI) and Cardiac troponin T(cTnT)

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(Table ) cont.....

Cardiovascular Biomarker

Examples

Neurohormones

Arginine vasopressin, Angiotensin, Renin

Oxidative Stress

Myeloperoxidase, Oxidised Low-density lipoproteins

Inflammation

C-reactive protein(CRP), Tumour necrosis factor alpha (TNF-α)

Extracellular Matrix Remodellers

Tissue inhibitors of matrix metalloproteinases (TIMP), Metalloproteinases (MMP)

Potential New Markers

Growth differentiation factors-15, Copeptin

Biosensor Biosensor is an analytical device that helps detect and convert biological processes into electrical signals. Cardiovascular biosensors are known to be an important and vital diagnosing approach for the survival of patients and a timesaving, effective diagnosis of the disease. Biosensor is designed to identify the target molecule in medical analytical treatment [17]. Its main principle lies in the interaction between biological components and target molecules into measurable signals, which is taken by incapacitation of biological constituents, like DNA or RNA, antibodies and enzymes on the surface of a transducer to transform it into electronic signals [18]. High antigen-antibody affinities are assumed to be the most convenient approach to detecting biomarkers in samples of humans [19]. Biosensor comprises two major elements (Fig. 2) 1. a bio-element and 2. a sensorelement. A particular “bio” element can recognized a specific analyte, and then the “sensor” element, can transfuse the conversion of the biological molecule into measurable signals like calorimetric, optical and electrical. Highly analyte specific is the bio-element and unable to detect other analytes. A combination of different bio-elements and sensor-elements develops different types of biosensors on the basis of their varied applications (Fig. 3). There are four ways of “bio” and “sensor” element combinations, including Membrane Entrapment, Covalent Bonding, Physical Adsorption and Matrix Entrapment. Immunosensors are biosensors with immuno-reagents as bio-elements or receptors, including immobilized antigens or antibodies in close contact with transducers like optical fibres and electrodes. Measurement of the analyte is possible due to specific transfuse of the binding between receptor to its target, for instance, antigen-antibody binding results in a measurable electrical or optical signal. The continuous detection of various analytes is possible due to immunosensors. However, there are limitations like difficulties in the regeneration of the immune-surface and interference or cross-reactivity issues. On the basis of transducing mechanism, biosensors are categorised into radiant or optical, elect-

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ric, magnetic, frequency, thermal and mechanical transducers (Fig. 4). Electrochemical transducer biosensors are mostly potentiometric and amperometric mentioned in most of the studies.

Fig. (2). Diagrammatic representation of a biosensor [20].

Fig. (3). Components of Biosensor [20].

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Fig. (4). Classification of Biosensor [20].

The most widely used transducer-based biosensors for the diagnosis and therapeutics purpose of CVDs are mentioned below: Optical Biosensor It is one of the best methods used for diagnosing biochemical analytes. Optical biosensor consists of a light source, modulator and photodetector to process the optical signal. Light is the transduced signal in an optical biosensor as a result of either optical diffraction or electro-chemiluminescence. The transduced structure is the most important part, and various transducers are able to use for generating an optical signal, including fluorescence, colorimetric and surface plasmon resonance (SPR). Colorimetric or fluorescence-based biosensing diagnosis, the bio-element are labelled with fluorescent dyes or tags [21]. The determination of the target bio-element depends on the changes in the intensity of colour signal and fluorescence. However, biosensors based on these methods can show efficient results with limitations like low sensitivity, smallness and expenditure efficacy. The detection in SPR is based on the interaction between bio-element that are immobilized on the surface of the metal and its bio-specific target [22]. SPR immunosensors are the fast detector of human troponin. Currently, luminescencebased biosensors have been used to quickly detect cardiac biomarkers [23]. The

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measurable limit for troponin quantification is the concentration with a total inaccuracy (coefficient of variation, CV) of 10%. A small amount of cardiacspecific troponin is vital for the detection of increasing risk and suggesting myocardial damage. The development of SPR sensors depends on the principle of immunosensors biomarkers for CVDs like myoglobin, CRP, cTnI and cTnT. The detection of CVDs can also be performed by other optical-based biosensor systems, such as fluorescence resonance energy transfer (FRET) [24] and SPRbased optic sensors [25]. Piezoelectric/Acoustic Biosensor Quartz Crystal Microbalance (QCM) is a delicate equipment sensing mass and the potentiality of mass measurement on a nanogram scale. It is a piezoelectric device engineered of a thin quartz plate with electrodes attached to each side of the plate. QCM sensor possesses a detector of acoustic impedance by loading of mass. QCM operates on the principle of immobilization of antigen-antibody on the surface of a piezoelectric material [26]. The significant immunochemical detection reaction changed the frequency of the natural vibration of the support. Various marketable piezoelectric detectors are now available with varied applications. QCM shows the possibility of developing quick detection techniques for CVDs. Carboxylic polyvinyl chloride was used to detect the cTnT biomarker by placing it on the surface of the QCM sensor and finding 5ng/ml as the detection limit [27]. Electrochemical Biosensor The principle behind the electrochemical transducer biosensor is that the oxidation-reduction in a chemical reaction changes the electric potential of the chemical reaction, which is quantified as an electrical signal. The most extensively used biosensor system is the electrochemical transducer-based biosensor. It is categorized into amperometric, potentiometric and conductometric. Immuno-electrochemical assays have been used to detect CVD biomarkers like myoglobin, cardiac troponins and CRP. Label-free direct immuno-electrochemical detection can be achieved by impedance spectroscopy, chronoamperometry, cyclic voltammetry and quantifying the potential pulse current known as pulsed amperometry detection. Such methods are able to identify a variation in the resistance or capacitance of the electrode persuaded by protein binding. However, labelled amperometric immunosensor are mostly developed and widely used [28]. Competitive or sandwich immunoassays are two types of assays generally utilized depending on the size of the analyte.

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Variety of Diagnostic Biosensors for Cardiovascular Diseases Cardiovascular disease comprising of various medical conditions of the heart and blood vessels (Table 2); further details can be found in various research studies [29]. Table 2. Cardiovascular Diseases and Causes. Cardiovascular diseases

Causes

References

Coronary heart disease

Deposition of fatty substances in coronary arteries results in the blockage of heart’s blood supply

[30]

Atherosclerosis

Fatty deposits called atheroma clogged the arteries' walls

[31]

Cerebrovascular disease (CeVD)

Long-term hypertension changes the structure of blood vessels affecting the supply of blood vessels into the brain.

[30]

Rheumatic heart disease

Streptococcal bacterial infection damages the valves in the heart and muscles through rheumatic fever

[30]

Congenital heart disease

Malformations of the heart and defects by birth

[30]

Deep vein thrombosis and pulmonary embolism

Delocalised blood clotting from the leg veins dislocates to the heart and lungs

[30]

Heart failure and stroke

Blockage in coronary arteries

[30]

Peripheral arterial disease

Affecting the blood vessels supplying the arms and legs

[30]

A short processing period is crucial for effective cardiovascular disease treatments. Longer time gets consumed from the period of blood collection from a sufferer and till a report is generated. The ideal period of generating a report after collecting blood from a patient should be within 30 minutes or less, which is possible only when the examination takes place in a centralised laboratory. Under such circumstances, biosensor devices which can be handled by hand are most suitable because of on-the-spot testing, assisting in immediate diagnosing and no hastening for hospitals, point-of-care devices have taken a step in that direction [30]. Benchtop analysers are a good example of this type of instrument. These analysers may evaluate a single sample for a range of cardiac indicators and can use various methods, such as spectrophotometry, evaluation of enzyme activity, immunological assay, haematological study and biosensors [32]. An outline of commercially available devices such as Vidas CK-MB (bioMérieux, France), RAMPs cardiac marker system (ResponseBiomedical,Canada/Roche,Germany), Stratus (DadeBehring, Germany), Triages cartridge (AlereInc.,USA), Cardiac reader (Roche,Germany), AlphaDX (First Medical, USA and i-STARs (Abbott,UK) have been reviewed [33] (Fig. 5). These biosensors combine fluorescent microfluidics, a machine analyser, and a disc with a desktop reader,

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with readout times ranging from 10 to 18 minutes. The cost of such systems is still exorbitant and uncompetitive for home users, which is a big disadvantage. The systems also necessitate a bigger sample of blood than the glucose biosensor device, limiting their utility as over-the-counter diagnostics. Triages cartridge and RAMPs working procedure are briefly discussed below: Triage Cartridge Heart failure, cardiac myopathies, and end-stage renal disease can all induce aberrant troponin levels, which can be detected with high-sensitivity troponin tests. High-sensitivity troponin tests may be effective in directing the therapy of heart failure, according to recent studies. Increased troponin levels were linked to worsening cardiac function in one study of people at risk for cardiomyopathy as a result of high-dose chemotherapy [34]. Higher troponin T levels were linked to an increased risk of cardiovascular disease, particularly heart failure, in another investigation [35]. As a result, hs-troponin tests are thought to be effective in detecting which individuals will benefit from early intervention and in directing ongoing illness care. A growing number of studies are looking into the use of high-sensitivity troponin testing in heart failure patients for prognosis rather than diagnosis. For individuals with heart failure, circulating troponins, for example, is thought to have substantial predictive significance. Compared to a hs-cTnI test, a hs-cTnT test gives accurate prognostic information and boosts prognostic usefulness, according to recent research. In fact, the hs-cTnT test properly predicted a two-fold increase in mortality, as well as an increase in heart failure hospitalizations [36]. RAMP Cardiac Marker System RAMP (Rapid Analyte Measurement Platform, Response Biomedical Crop, Burnaby, Canada) is based on a technique that permits immunologically active chemicals to be quantified. The system comprises analyte restricted immunochromatographic strip of the nitrocellulose membrane of non-reusable cartridges and a convenient reader of fluorescence which quantifies the fluorescence excited during the period of detection and includes the region internal control of the strip in the system. Differences occur due to several factors like sample temperature, viscosity, humidity and related factors, which are adjusted by the internal control system. The basis of cTnI detection and quantification is done by applying a sandwich immunoassay, comprising monoclonal antibodies, one attached to fluorescently labelled latex material and the other at the region of strip detection. cTnI concentration is proportional to fluorescence intensity at the detecting zone.

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The internal control comprised latex materials labelled with varied fluorescent dye and antibodies of different classes present in the region of internal control and applied to manage variation in the strip with the lateral flow. The field of cardiovascular disease diagnostics and the creation of appropriate biosensors is still blooming, as seen by newly published literature. There is a variety of biosensor-based CVDs devices developed that use varied sensing platforms to detect single or many biomarkers in serum, buffer, or blood samples. Investigations on various CVD diagnostic biosensors were carried out in various studies. An effective diagnosis of such disorders requires an early and rapid diagnosis. Many biomarkers, including myoglobin, cardiac troponins (I and T), BNP,CRP, interferons and interleukins, have been identified for usage in the development of non-technology and medicine. Optical, auditory, electrochemical, and magnetic-based biosensors were employed in the development of these cardiac signature biomarkers. Only a handful of these biomarkers have become essential diagnostic tools in the medical field, despite their predictive usefulness independent of prior established risk factors. Patients with the suspected acute coronary syndrome have been diagnosed and risk stratified using the troponin biomarker. Artificial intelligence (AI) progression opened up a new area in bioscience, allowing for the development of innovative tools and planned advancement for medical usage, including cardiac disorders.

Fig. (5). Different biosensors for cardiovascular diagnosis [37].

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CONCLUDING REMARK Biosensor technology with biomarkers is becoming increasingly important in diagnosing and progressing cardiovascular disease. The development of highly precise biosensor platforms based on well-established interface coatings and nanomaterials is critical for the detection of various disease markers and the precise diagnosis of heart disease. Analysis of several markers with a single test using modest amounts of blood significantly improves the device's applicability in disease-stage quantification while lowering diagnostic costs. This is due to the fact that most clinical outcomes from cardiac markers are better relevant when they are part of a panel of numerous markers that provide multiple sets of data from a single sample. This allows clinicians to make more precise diagnoses while also reducing turnaround times and increasing sample yield. Microfluidics, proteomics, and polymer sciences, in combination with biomarker discovery and biosensor development, can deliver miniaturised, easy-to-use, reliable, and costeffective point-of-care sagacity equipment’s. Additionally, the association of immunosensor in microfluidic tools has the ability to control the movement of the substrate, and controlling the power of the sample will bring about the study towards high business trade. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 9

Biosensors for Food Analysis, Food Additives, Contaminants and Packaging Amitabh Aharwar1, Khageshwar Prasad2, Annpurna Sahu2 and Dharmendra Kumar Parihar2,* Government College Harrai, Chhindwara, Madhya Pradesh, India (480224) Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India (495009)

1 2

Abstract: It is essential to manage the food requirement for the growing population. Food safety is important for health, but maintaining nutrients and food quality is also necessary for better health. Food storage and packing should be done carefully in order to avoid food contamination and ensure long-term food storage. There are various types of food hazards (biological, chemical, and others) that may contaminate food and cause food poisoning, foodborne diseases, allergies, and other health issues. For food quality examination, traditional procedures, such as chromatographic methods, are used, but these are time-consuming, labour-intensive and require an expert in instrumentation. It is critical to inspect the quality of food on a regular basis and as quickly as feasible. The greatest approach for overcoming these issues is the use of biosensor. As food additives and pollutants, the biosensor is extremely quick, sensitive, and selective. Biosensors are equipped with a transducer and a biological identification element, allowing them to evaluate food quality. Pesticides, poisons, microbial growth, protein, metals, fatty acids, antibiotics, vitamins, and other compounds can all be detected in food using biosensors. Biosensors have a wide range of applications in the food industries but there is also the demand for novel, inexpensive, simple, small-sized, portable, and multifunctional biosensors for food analysis. Biosensor can also detect food additives and pollutants throughout the packaging process.

Keywords: Food analysis, Food contaminants, Food packaging, Types of Biosensor. INTRODUCTION Food is a major source of energy that also shows antioxidant, antimicrobial, antiCorresponding author Dharmendra Kumar Parihar: Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, C.G. 495009, India; Tel: +91 9977170733; Fax: +91-07752-260146; E-mail: [email protected] *

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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viral, anti-inflammatory, anti-mutagenic and other health-making activities. Food contamination and foodborne disease are the major problems during food storage and processing. There are different food contaminants, such as physical, chemical and biological contaminants. Microorganisms and toxins are the major food contaminants and health hazards. Food contaminants cause different types of diseases, such as infectious and lifethreatening diseases. A much part of the budget in the growing country is spent to control food contamination and foodborne disease. Different molecular techniques such as Fluorescence microscopy, PCR and Hybridization, and ribosomal DNA sequencing are used in microbial detection. However, good hygienic practices and food regulation (FDA) are being used to reduce food contamination and foodborne disease [1]. But, a new reliable, stable and real-time method is needed for better assessment of food quality. Food quality maintenance and food safety measures are important features in food storage and preservation for a long time. Food quality monitoring is also an essential part of food safety. Analytical methods are used for the food quality measurements, but it is time-consuming, laborious, and requires an experienced person. Therefore, there is a need for special techniques which should be fast, reliable, time-saving and sensitive for food quality measurement. A biosensor is a device that is being used in food industries due to its rapid and specific food quality measurement. In the food sector, it is used in many different ways. It is predicated on the idea that a physical amount can be measured and transformed into a signal that an observer can sense. It is a small bio-electronic device which is consisting of a sensing element with a signal transducer [2]. It consists of a receptor biomolecule that measures the amount of analyte while a transducer detects the amount of analyte. The receptor biomolecules may be the enzymes, proteins, organelles, antibodies, nucleic acid (DNA), tissues, receptors and microorganisms. Different types of biosensors are available, which are based on different working principles. Based on the different transducers, different biosensors are available such as Optical biosensors (based on fluorescent or luminescent/ chemiluminescent reactions), Potentiometric biosensors (change in voltage), Amperometric biosensors (current generated between electrodes), Piezoelectric biosensors (changes in the oscillating frequency of a piezoelectric crystal) and Thermal or Calorimetric biosensors (change in thermal energy). Whereas based on the biological receptor element there are enzyme-based, the whole cell-based (Microbial) and affinity-based biosensors (antibody, nucleic acid and receptor) [2, 3]. Food packaging is an important procedure to protect food from chemical, biological and physical changes. The main contaminants are heat, moisture and

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microorganisms. Food packaging material is also an important factor to avoid the contamination of food during packing. Plastic packaging is being used at present, but there is a need to make a biodegradable packing material that can protect food quality. Food processing causes change in the food structure, taste, texture and function [4]. In food packaging, a food sentinel system (having antibodies) has been designed to detect pathogens in food packages [3]. But, smart food packaging is being used at present that senses and conveys information about the state of a product. It also provides information about food quality during transport and distribution [11, 41]. BIOSENSOR The biosensor is an analytical device which consists of a transducer and a receptor that transforms input signals into a continuous output signal. In a biosensor, receptors convert physical or chemical data into an energy form which is converted into a useful analytical signal, like an electrical signal by a transducer. The biosensor was created in the 1960s by Clark and Lyons [5]. It involves a biological sensing component that is either integrated inside or close to a physicochemical transducer as a quantitative or semiquantitative analytical experimental technique [6]. Chemical information is transformed into a signal that may be used for analysis by a chemical sensor. These sensors typically couple a physicochemical transducer with a chemical (molecular) recognition mechanism (receptor). Similar to chemical sensors, biosensors use a biological process to interface with an optoelectronic system via the recognition system [6, 7]. It is a tool that recognizes chemical compounds by means of specific biological processes mediated by individual enzymes, immune systems, tissues, organelles or whole cells, typically employing electrical, thermal or optical signals [8]. In order to create a reagent-free sensing system that is selective for the target analyte, the biosensor consists of a biological sensing component and a signal transducer. Highly specialized macromolecules or complex systems with the proper selectivity and sensitivity make up the biological component of a biosensor. Biosensor Principle The main element of a biosensor, which exploits a physical change brought on by the reaction, is the transducer (Fig. 1). It senses the difference in light output or light absorbance between the reactants and products (Optical biosensors) and based on the mass of the reactants or products, are examples of heat output (or absorption) by the reaction (Calorimetric biosensors), changes in electrical or electronic output (Electrochemical biosensors), and redox reaction (Amperometric biosensors) (Piezo-electric biosensors). Despite the relatively modest difference

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between the signals, it is amplified into a readable output. The preceding procedure eliminates unnecessary noise from the signal. The analog signal generated by the amplifier is often transformed into a digital signal and sent to a microprocessor. The data is processed, translated to concentration units, and then output to a display device or data storage device [9] which is often transformed into a digital signal and sent to a CPU. A bioreceptor is a specific kind of receptor that can swiftly identify and find specific chemicals or chemical reactions. On a selective permeability membrane, the bio-component might be trapped or immobilized. The transducer, which is also adjacent to the electronic component, is assembled near the membrane. As illustrated below, there are four main methods for immobilizing or connecting biomolecules to transducers (Fig. 2).

Fig. (1). Biosensor components are represented in a schematic manner.

Adsorption Active charcoal, silica gel, clay, and other substances are utilized to adsorb the biomolecule by physical factors such as hydrogen bonding or hydrophobic interactions [10]. Entrapment A water-soluble polymer like polyacrylamide type gel and naturally occurring gels like cellulose triacetate, agar, gelatin, carrageenan, alginate, etc. are used to entrap or encapsulate biomolecules through electrostatic interaction between ionic groups [10].

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Fig. (2). Biosensor immobilization approaches [11]: (A) covalent binding; (B) adsorption; (C) entrapment; (D) encapsulation; and, (E) cross-linking.

Covalent Bonding Agarose, cellulose, resins, and other substances form a stable covalent bond with biomolecules under a wide range of pH, ionic strength, and other diverse conditions. Cross-Linking A biomaterial is affixed chemically to stable support or a cross-linking substance like glutaraldehyde or diazonium. Basic Attributes of Biosensors Limit of Detection It speaks about the analyte concentration that results in the least discernible differential signal. Specificity A biosensor should only react to changes in the concentration of the target analyte, and the presence of other chemical species should not affect this reaction. Dynamic response How quickly a biosensor reacts to a change in the concentration of the target analyte depends on its physical characteristics and relative size. Lifetime The least durable part of the system in terms of life is frequently the biomaterials used in biosensors.

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Sensitivity Sensitivity is the ability of a biosensor to modify its steady-state magnitude of output in response to variations in analyte concentration. Linearity It should be high in order to detect high substrate concentrations [3]. Biosensor classification According to their biological and transduction components, they have been grouped into different types of biosensors (Fig. 3) [12].

Fig. (3). Types of Biosensors.

Optically Based Biosensors Enzymes attached to the fiber optic bundle's tip can produce fluorescent or luminescent/chemiluminescent processes that result in light, which is subsequently sent to a detector via an optical fiber. They function well with

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fluorescent cofactor-consuming or -producing enzymes, such as NAD(P)H [13]. Surface Plasma Resonance (SPR), a phenomenon that occurs when light is reflected off thin metal films placed on the reflecting surface of a glass prism, is the main technology behind these biosensors. SPR may be used to measure the interaction of biomolecules on the surface (Fig. 4). A fluorescent biosensor array was created by Yu et al. to instantly and precisely identify the course of kidney injury via “doubled” signals moreover Zhang et al. used fluorescent biosensor for the detection of urinary tract bacterial infections.

Fig. (4). Diagrammatic representation of optical biosensor, Source [2].

Potentiometric Biosensor The aggregation of the right ions results in a voltage shift with relatively little current flow. They might be suitable when producing or consuming H+, NH4+, or CO2 using an ion-selective electrode. The potential difference between an indicator electrode and a reference electrode serves as the foundation for potentiometric measurements [13] (French and Cardosi, 2007) (Fig. 5). The transducer may be an ion-selective electrode, an electrochemical sensor based on thin films or selective membranes as recognition components [14]. Although different ion (F-, I-, CN-, Na+, K+, Ca2+, NH4+) or gas (CO2, NH3) selective electrodes are available, pH electrodes are the most common potentiometric apparatuses. Zhang et al. created a brand-new, quick-response approach for assessing cell viability using cell surface charge. A polydopaminepolyethyleneimine/quantum dot (PDA-PEI/QD) sensor based on fluorescence resonance energy transfer was introduced. It was built by electrostatically interacting positively charged PDA-PEI and negatively charged QD to produce a fluorescent signal change that was induced by the presence of various charged materials on the cell surface. Varied hepatotoxic medications produced different fluorescence signals as a result, which revealed the differences.

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Fig. (5). Diagrammatic representation of potentiometric biosensor, [2].

Thermal Biosensors Biosensors that measure thermal energy produced or absorbed in biochemical reactions are called thermal or calorimetric biosensors [15]. It works by employing a thermistor to detect very small amounts of heat created by an enzyme-catalyzed reaction. The bio receptor is immobilized in the thermistor. As long as the heat produced by the reaction can be measured with enough sensitivity, thermal detection of enzyme reactions is theoretically possible for any enzyme type. Piezoelectric Biosensors Piezoelectric biosensors function on the basis of a linear relationship between fluctuations in a piezoelectric crystal's oscillating frequency when the mass on its surface fluctuates as a result of an interaction between an analyte and a bioreceptor. The basis for detection is the alteration in the surface coating's mechanical properties as its mass increases, which is measured by modifications in its vibration frequency when an electrical current is applied [13].

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Amperometric Biosensors Amperometric biosensor systems are commonly used and easily available on the market today. Biochemical signals are converted into electrical signals in these types of electrochemical biosensor [16]. When a redox-active molecule is reduced or oxidized at the electrode surface, a current is produced and measured using amperometry. This transmission works best when a reaction generates or consumes a redox-active substance, such as O2, H2O2, NAD(P)H, etc [13]. Oxygen, oligonucleotides, phenols, sugars, alcohols, and others are all detectable using amperometric biosensors. The detection of OP pesticides using single and multiple enzymes has been the subject of reports [17]. Acetyl cholinesterase (AChE) or butyryl cholinesterase (BuChE) is the biological component of single enzyme-based biosensors, and thiocholine formation is assessed amperometrically, or acid production is monitored potentiometrically [18]. In multi-enzyme biosensor systems, cholinesterase and choline oxidase are utilized to measure oxygen consumption or hydrogen peroxide formation [17, 19]. Enzyme Biosensors The capacity of an enzyme to generate a signal that can be recognized and converted into an electrical response determines this. Depending on the analyte and physical transducer, either a single-enzyme or multi-enzyme system is utilized in various kinds of enzyme biosensors [20]. The simplest sort of enzymatic biosensors can cause reversible reduction or oxidation on the electrode when the electrochemically active potential is applied. Substrate and inhibitor sensors are additional categories for enzyme sensors [1]. A biosensor built on acetylcholinesterase (AChE)-reduced graphene oxide (RGO) hybrid films has been reported. Large amounts of enzyme were immobilized using RGO, which also created an ideal milieu for the continuation of AChE activity. At room temperature, the organophosphorus neurotoxin was discovered in the gas phase by the use of a biosensor [21]. Immunosensor Devices that detect antibodies produced by specific biological species (usually bacteria) in a reaction are known as immunosensors, also referred to as bioaffinity sensors. There are two types of detection: labeled type (which uses a labeling agents like enzymes, nanoparticles, and a fluorescent or electrochemiluminescent probe to quantify the number of antibodies or analytes) and label-free type (which detects analyte and antibodies on a transducer surface without any label) [3].

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Microbial Sensors The concentration of a substrate is measured by microbial cells connected to a physical transducer. The metabolic activity in the cells is measured by an electrochemical change proportional to the substrate concentration [3]. Biosensor Based on Nucleic Acids In recent years, foodborne illnesses have been identified using DNA and RNA. These sensors use hybridization to recognize a particular set of nucleic acid bases. To assess the hybridization between the DNA probe and its corresponding DNA stands, the oligonucleotide sequence/single standard DNA (probe) is mounted on a separate electrode in a DNA sensor. Monoclonal antibody immunoassay and DNA probe applications do, in fact, regularly cross over, putting the two approaches in direct competition. Testing for viral infections is one of the most important uses of DNA probes [22]. It is believed that all strains of infectious diseases have a similar DNA sequence region, making it possible for a single probe to detect them all. When a virus triggers a cell's antigenic response, which results in the creation of antibodies, the virus is able to be identified in an immunoassay [23]. Another form of biosensor developed by the Naval Research Laboratory uses a magnetic field rather than optics or fluorescence [24]. Sensors and microbeads can be used to determine the presence and concentration of bioagents [25]. On the magnetic sensor, single-stranded DNA probes specific for a given bio-agent or sample DNA are deposited (group of sensors). A single magnetic microbead is bound when a single strand of DNA from the probe and a strand of DNA from the sample come together to form a double-stranded (doublehelix) structure. A magnetic bead can be detected and measured because its presence reduces the resistance of a sensor surface. BIOSENSORS FOR FOOD QUALITY AND ADDITIVES CONTROL Existing food preparation equipment frequently has microprocessors that are actuated by electrochemical or biological sensors. Recent advancements in electronic vision and computer technology have expanded the research horizons for better control, product sorting, and operation precision. The development of technological devices in this industry focuses on monitoring and assessing the quality and flavour of items on the inside and outside [26]. For quality assessment, grading, and sorting of food goods, several types of electronic sensors that can enable quick and non-destructive determination of product internal qualities have been investigated and reported in the literature. The sugar content

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of unharmed peaches can be quickly assessed using a near-infrared detection method. This method has been applied to the examination of avocado oil content and kiwifruit starch and sugar content, among other commodities. For postharvest product sorting and grading, machine vision is being tested on a variety of commodities. Current research include a high-speed prune fault sorter, a colour and flaw detector for fresh market stone fruits, raisin grading machines, and flower grading machines. This technique employs electronic cameras to monitor items in a variety of packing-line handling scenarios. Product grading and sorting are possible with the control system, and quality characteristics are calculated from scanned images. Sensors in the NIR/VIS spectrum (Near Infrared/Visible Spectroscopy) have been used in a variety of applications. Crochon proposed the development of a glove-shaped device with multiple microscopic sensors that offer data on fruit quality features such as sugar content, ripeness, mechanical attributes (firmness, stiffness), and interior colour [27]. The sugar content and interior colour were determined using a miniaturised spectrometer (NIR/VIS) coupled to optical fibres. A sound sensor was used to evaluate the mechanical characteristics, and a potentiometer was positioned at the hand aperture to measure the size. These sensors were linked to a microprocessor, which analysed data about the fruit across all quality categories in accordance with previously established variety and quality requirements. The glove can be used before harvest to track crop growth and forecast harvest dates, during harvest to choose fruits with certain characteristics, or after harvest to control and assess crop quality. The mechanical quality features of green beans, broccoli, and carrots were evaluated in the NIR/VIS spectrum utilizing chlorophyll fluorescence and reflectance [28]. Raman and mid-infrared (MIR) spectroscopy are based on the activation of fundamental vibration modes, they are effective techniques (as biosensor) for the precise detection of molecule (or biomolecules) [29]. The Molecular Imprinted Polymers (MIP) technology is a ground-breaking method for creating biosensor substrates [30]. Predefined specificity recognition sites are imprinted into cross-linked synthetic polymers to create the polymers. As a result, the polymer may rebind the imprinted molecule selectively [31]. These sensing compounds are known as artificial antibodies [32]. This method has been successfully utilized to develop and refine a plug-in detection cartridge for use with the molecularly imprinted polymer test for detecting different -lactam antibiotics in milk [33]. The sensor is made up of a microfabricated column with an optical detecting window. MIP-based technology can be used in sensors to instantly detect toxins in food products [34 - 36]. An SPR-based sensor delivers similar results in dairy product quality applications [37]. It was discovered that at-line immunological sensors might use amperometric detection of the resultant antibody-antigen complexes [38]. The safety of hazardous chlorophenolic fungicides and their chloroanisole breakdown

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products in potable water, wine, and fruit juices was examined by an electrochemical immuno-sensor, using monoclonal antibody preparations. Horseradish peroxidase is an acceptable term for investigating the analyteantibody immunological complex. Guilbault employed immunosensors to detect hormone molecules that promote growth [39]. The sensor should be utilized to analyze and determine the amounts of testosterone, 19-nortestosterone, methyltestosterone, trenbolone and stanozolol, in biological fluids before slaughter (blood). In comparison to current laboratory testing, which takes 24–36 hours, the analysis took only 30 minutes. Sweeteners are one of the most widely used food additives today, and they are linked to a variety of disorders, including dental cavities, cardiovascular disease, obesity, and type 2 diabetes. Artificial sweeteners are thought to be addictive, inducing us to eat more high-energy foods unintentionally, resulting in weight gain. Multichannel biosensors, which measure the electrophysiological activities of the taste epithelium, have been examined as a more effectual means of combining lipid films with electrochemical techniques as biosensors for rapid and sensitive screening of sweeteners [5]. BIOSENSOR FOR FOOD CONTAMINATION DETECTION Consumers have become much more concerned about food poisoning in recent decades [40]. Food contamination can happen at any time of year for various reasons (physical, chemical, and biological), but pathogenic bacteria cause the bulk of fatal food contamination [41]. Contamination of food is a global health threat. Physical pollution from heavy metals like mercury, arsenic, cadmium, and lead [42], chemical contamination from pesticides, toxins, or pharmaceutical compounds [43], and microbiological food pollutants are different types of contaminants. Pesticides and veterinary drug residues are commonly used in modern agriculture, resulting in food contamination. Escherichia coli, Salmonella Typhimurium, Listeria monocytogenes, Yersinia enterocolitica, Clostridium perfringens, etc., were responsible for foodborne illness and found in contaminated packaged foods such as tuna, salmon, dairy products, chicken, hardboiled eggs, ground beef, and pork [44, 45]. Although preliminary indications such as color, odour, and texture criteria are routinely used to assess the quality of foods before packaging, outliers make it difficult to establish the quality of foods after packaging [46]. Modern food packaging technology is crucial in this context because it makes it easier for customers and packaged foods to connect. As a result, there is a growing demand for rapid detection of hazardous food pollutants around the world. The most commonly used lab-based analytical techniques for detecting food pollutants are mass spectrometry, chromatography-based methods,

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plasma mass spectrometry, and atomic absorption/emission spectroscopy [47, 48]. But, these methods have some drawbacks, such as being laborious, expensive, and time-consuming. A new type of dual-responsive electrochemical/fluorescent biosensor has been designed to detect pesticides [49]. A fluorescence-based biosensor based on DNA molecules was recently developed to detect Hg+2 ions whereas a colorimetric aptasensor was used to detect aflatoxin B1 compounds [50]. These biosensors could be used in conjunction with smart food packaging to detect physical and chemical pollutants in food. Microbiological pollutants found in food are exceedingly harmful and must be carefully monitored to maintain food safety. Several biosensors for detecting microbial contamination in foods have been proposed (Table 1). The optical biosensor, for example, is a color-based sensor that displays color changes using sound transduction. The optical biosensor is a color-based sensor that detects color changes when in contact with bacteria Salmonella typhimurium, Staphylococcal enterotoxin A and B, Salmonella group B, D, and E, E. coli, and E. coli 0157:H7 using auditory transduction [41]. This optical biosensor could be used in food packaging to detect diseases. These electrochemical-based biosensors can be used in food packaging to check the condition of perishable packaged goods. Microbial metabolism generates food-spoiling gas, which has been detected using conducting polymer-based sensors [51]. Conductive polymers with resistance fluctuations that correspond to the volume of gas released are created when conducting nanoparticles are added to a polymer matrix. These conducting-based biosensors can be utilized to construct smart food packaging sensors when combined with polymer packaging. A cell-based biosensor has recently been employed in research to regulate the freshness of meat. Since septic bacteria use the amino acids produced by meat enzymes as a source of nutrition, the number of bacterial cells rises as the level of amino acids rises. The sensor response matches the rise in via ble counts and amino acid concentrations in the meat during the first stage of aging. The water was loaded into a flow injection analysis (FIA) system linked to a microbiological detector that used yeast (Trichosporon cutaneum) as a sensitive component [52]. A portable NMR-based (pNMR) biosensor is developed for E.coli contamination detection. NMR is widely used in biomedical analysis and food monitoring, and it gives crucial structural information for a variety of dietary components [53]. Zeinhom et al. created a fluorescent imaging system based on the current camera module of a smartphone as a portable biosensor for the on-site monitoring of E. coli O157:H7 in food [54]. For the real-time identification of E. coli in food samples, PC software-based portable cyclic voltammetry (PCV) systems were also taken into consideration. Electrochemical testing methods like cyclic

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voltammetry (CV) under linear voltage scanning excitation are widely used in many fields [55]. Hu et al. developed a portable quantum dot biosensor for the on-site detection of S. Typhimurium moreover, it offered greater sensitivity and accuracy for straightforward and quick identification of S. Typhimurium in different food samples within 10 minutes [56]. Wang et al. created a portable AuNP-based ICT strip that can simultaneously identify the five common SEs, SEA, SEB, SEC, SED, and SEE, on-site [57]. Based on the surface plasmon resonance (SPR) sensor, one of the successful portable biosensors for fungal aflatoxin detection was created. Surface plasmon resonances (SPR) on metallic films smaller than 50 nm and the possibility that the metal's surface will be functionalized to achieve selectivity are key components of the SPR biosensing technique [58, 59]. Table 1. List of Biosensors for Toxins detection [60]. Type of Biosensor

Matrix

Toxins

Electrochemical (amperometry)

Corn, cereal, Maize, babyfood

Zearalenone

Lake water

Microcystin-LR

Corn, grapes, barley, milk

Aflatoxins

Electrochemical (square wave voltammetry)

Mussels, Razor clams

Brevetoxin B

Mussels

Okadaic acid

Electrochemical immunosensor

Water

Alternariol, alternariol monomethyl ether

Corn, Maize, baby food cereal

Zearalenone

BIOSENSORS FOR FOOD PACKAGING Today, most food sold comes packed. Benefits of food packaging include barrier protection, physical protection, and the ability to better preserve food, which increases the shelf life of the product. Food and beverage packaging paved the way for the meal sector to respond to the demand for convenient food options in a variety of forms over time. Materials for packaging have historically been chosen for their convenience and to prevent unintended contact with food. Packaging innovations from the 20th century, like those that contain antimicrobials and oxygen scavengers, have set new standards for extending shelf life and shielding food from external factors. Different additives (such as antioxidants, stabilizers, sliding agents, or plasticizers, among others) are continuously supplied to the polymers during the production of food packaging in order to improve the material qualities [61].

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Active packaging is the name given to these novel packaging designs, which give protection [41]. The makers are quite concerned about the presence of extraneous objects in processed foods. For a long time, identifying foreign entities in powdered and flowing products has been aided by mechanical separation techniques based on the size and weight of various components. Regarding their shape and color, optical inspection techniques were able to increase the variety of foreign items that might be found in free-flowing materials. Metallic traces inside the product were discovered thanks to metal detectors. Modern foreign body detection devices are becoming available thanks to recent advances in sensor technology [62]. Zhao et al. explained the design and operation of an ultrasonic transducer system with an auto-alignment mechanism, which has been applied to the detection of foreign objects in beverage containers [63]. Farooq et al. described nano-spheres of silica immobilized with a fluorescent dye, and this biosensor may be ideal for meat and dairy food packaging because it can detect contaminated bacteria, such as E. coli 0157:H7, by demonstrating the color shift that occurs when meat and fish are rotten [64]. Active food packaging helps to preserve food by extending and maintaining the shelf life of items. One of the major disadvantages of active food packaging is the inability to display the quality features of packaged foods. Furthermore, by utilizing packaging nanotechnology to track packed items, modern civilization is aiming to expand the role of active packaging [65]. Smart food packaging is another component of active packaging that has grown as a result of nanotechnology and other breakthroughs. Smart food packaging is another component of active packaging that has evolved as a result of breakthroughs in nanotechnology and e-commerce [66]. It can identify and report on the condition of packaged foods in real-time, as well as offer customers online and offline information about the product's status [41]. The majority of smart food packaging materials incorporate biosensor and indicator concepts [46]. Although a few biosensors and indicators for food packaging, including time-temperature integrators (TTI), microbial spoilage biosensors, time-freshness indicators, pathogens, and contamination biosensors have been developed and show promise, there is still a long way to go before biosensors are successfully applied in smart food packaging. The main role of the sensors-packaging system is to detect the package surroundings and product status and exchange data with external databases in order to convey data for decision-making. The integrated system of a complicated structure with distinct sensor and data carrier parts is known as intelligent packaging. The setting of sensitive elements into package materials and/or labels, as well as integration of sensor data into the intelligent packaging information flow, i.e., data layer, are all part of the technical execution of such a packaging

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system. This integration enables online and “off-the-shelf” control of internal and/or external packages. Chemically modifying and sensitizing packaging labels, integrating micro-devices, or putting micro- and nano-sensitive materials into the mark or package itself can all be used to make biosensors. This method could be employed in the future to direct the controlled delivery of bioactive components as well as the targeted delivery of protective chemicals into meals [67]. As a result, intelligent packaging can be defined as a system that keeps track of the state of packaged food in order to convey data about its quality during transportation and storage. Chemical or biological sensors are used in smart packaging to track the quality and safety of food from manufacturers to consumers. With the use of this technology, a wide range of sensor designs are suited for tracking freshness, pathogens, leakage, carbon dioxide, oxygen, pH, time or temperature of food may be created. Smart package designs make it easier to check food quality, while active packaging contains strong mechanisms to limit oxidation, microbial development, and moisture. Time-temperature indicators, ripeness indicators, chemical sensors, biosensors, microbial spoilage sensors, physical shock indicators, leakage sensors, allergen sensors, microbial growth sensors, pathogens and contaminants sensors are used in smart food packaging [41]. Fluorescent and microfluidics sensors, electrochemical/imprinted biosensors, gas detection sensors, immunological sensors, and thermal biosensors are commonly used in food applications [68]. The electrochemical-based biosensor is one of the promising approaches for monitoring food quality based on its function. Biocatalytic sensor devices and affinity-based biosensors are two types of electrochemical biosensors [69]. A single-walled carbon nanotube (SWCNT) based biosensor is used to determine food microorganisms [70]. The gas sensor can be used to detect gas leaks in packaging and to determine the quality of food. Spoiling gas such as nitrogen compounds, oxygen, and carbon dioxide released during food degradation can be detected [11, 71, 72]. A sensing electrode that simultaneously serves as a working electrode, a counter electrode, and a reference electrode make up the system. The gas diffuses across the hydrophobic barrier and contacts the working electrode to commence. The target gas is detected by a gas sensor device on the working electrode, which gives an electrochemical signal. It's also used to identify carbamate pesticides in fruits and vegetables, whereas it could test meat rancidity. Figs. (6a and 6b) are showing a gas sensor design for detecting CO2 elements inside food containers [11, 65]. A fluorescent or phosphorescent dye is immobilized in a solid polymer matrix to create a fluorescent-based biosensor. Dye polymer coatings are integrated onto a thin sheet to generate the biosensor device. The sensitive coatings of the luminous sensor influence the presence of molecular oxygen released in the packaging headspace via the simple diffusion method and quench light in a dynamic approach. The oxygen concentration is then determined using a calibration curve based on the

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degree of change in luminescence properties [73, 74]. The most prevalent biosensors being considered for smart food packaging are listed below (Table 2).

Fig. (6). (a). Basic principle of gas sensor, (b) Gas sensor for CO2 gas detection after food decomposition. Table 2. List of the most common biosensors for smart food packaging [11]. Biosensor Type

Biosensor Format

Analytes

Reference

Electrochemical based biosensor

SWCNT-based biosensor

Y. enterocolitica

[70]

CNT-based electronic transistor

Salmonella Infantis

[75]

Amperometric biosensor

L-malic acid

[76]

Microcantilever sensor

H2S

[77]

Carbon codoped acetone sensor

Acetone

[78]

Pd coated SnO2 nanofiber

H2

[79]

Magnetic-based fluorescent biosensor

E. coli O157:H7

[80]

Poly(dimethylsiloxane) coated microfluidic sensor

H2O2

[81]

Microfluidic biosensor

Salmonella typhimurium

[82, 83]

Gas biosensor

Microfluidic and fluorescent biosensor

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The Fluorescence-based biosensor can also produce a range of colors when it comes into contact with food pathogens. Another biosensor format based on a microfluidic device for effective real-time pathogen detection with high sensitivity has been created. Silicon-based microfluidic devices are popular as laboratory-on-a-chip sensing devices [84]. Despite the fact that these sensor devices are widely used in a variety of industries, including medical, biological, and chemical analysis [11, 85]. CONCLUSION The biosensor is a potent and cutting-edge analytical tool that uses a biological sensing component. Depending on their biological or transducing components, different types of biosensors are available, each with unique advantages and disadvantages. The stability, affordability, and reproducibility of biosensors are the key characteristics. Many of them even enable immediate on-site analyte detection. Applications for biosensors include determining the amount of identifying antibiotics, heavy metals, allergens, toxins and other contaminants and monitoring food allergens. In the food sector, food quality control is crucial. Today, effective quality assurance is becoming more and more crucial. Food inspectors want safe production procedures, adequate product labeling, and adherence to FDA standards, whereas consumers demand food products of appropriate quality, at a reasonable price, with long shelf lives, and high levels of product safety. The usage of biosensors is anticipated to increase gradually in the food sector as reliable analytical tools for speedy on-site and online detection for food quality and safety applications and to fill the gap left by traditional analytical techniques. Since biosensors are time and cost-effective in the food and agricultural diagnosis industries. Advancements in biotechnology, bioelectronics, electronics, and material sciences are helpful in biosensor manufacturing with great features to solve food-related problems. Food safety is a serious issue for the entire world, especially in developing nations, where contaminated foods are a major cause of many diseases and yearly fatalities. Accordingly, it is urgent to develop quick, inexpensive, and online methods for food contamination analysis, particularly for biological contaminants, to ensure the safety and caliber of food products. Small, user-friendly, affordable, and mobile diagnostic biomedical equipment called portable biosensors allow for real-time food contamination screening. Researchers are able to create and construct portable biosensors with the aid of a variety of cutting-edge technologies, including nanotechnology, microfluidics, cellphones, biological design techniques, and wireless communication systems. One of the most cutting-edge technologies in recent years, the biosensor is regarded as a useful tool for creating intelligent food packaging. It is a quick, accurate, and trustworthy procedure. The scientific

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community is seeing increased interest in smart food packaging. Future efforts should focus on some characteristics, such as size, cost, reproducibility, and accuracy. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 10

Biosensors For Monitoring Heavy Contamination In The Wastewater

Metals

Gaurav Kumar Pandit1, Ritesh Kumar Tiwari1, Ashutosh Kumar1, Veer Singh2, Nidhi Singh3 and Vishal Mishra2,* Department of Botany, Patna University, Patna-800005, India School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi-221005, India 3 Centre of Bioinformatics, University of Allahabad, Prayagraj, India – 211002 1 2

Abstract: Several anthropogenic activities, chemical manufacturing, mining, nuclear waste, painting, metal processing, agricultural activities, cosmetic products and industrial activities are associated with heavy metal contamination in the wastewater. Heavy metals, such as arsenic, cadmium, chromium, lead mercury and nickel, are nonbiodegradable and highly toxic. They can directly or indirectly enter the food chain and cause several health issues, such as cancer, liver and kidney, asthma and mental retardation. Analytical methods such as inductively coupled plasma mass spectrometry (ICP-MS), atomic absorption spectroscopy (AAS), ultraviolet-visible spectroscopy and chromatography are widely used for heavy metal monitoring in heavy metal contaminations. These methods provide a sufficient level of sensitivity and selectivity, but these methods are costly, time-consuming and require sample preparation. Currently, biosensors are considered an alternative to conventional heavy metal monitoring methods due to high sensitivity, selectivity, inexpensiveness and simplicity. Herein, the authors report several biosensors and their application in monitoring heavy metal contaminations.

Keywords: Biosensor, Heavy metals, Microorganisms, Wastewater. INTRODUCTION With the inception of industrialization, mankind has grown much over the past centuries [1]. However, the dark side of it comes with it, which manifests itself in our ecosystem in various forms. One such impact is visible in our water bodies, such as water pollution [2, 3]. Wastewater can be defined as used water from any combination of domestic, ind* Corresponding author Vishal Mishra: School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi-221005, India; E-mail: [email protected]

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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ustrial, commercial or agricultural activities, surface runoff/stormwater, and any sewer inflow or sewer infiltration [4, 5]. Effluents from a large number of industries viz., electroplating, leather, tannery, textile, pigment & dyes, paint, wood processing, petroleum refining, photographic film production, and water from Agricultural lands (containing fertilizers, weedicides, herbicides, etc.) add a significant amount of heavy metals in the wastewater [6, 7]. Reports of water pollution, aquatic habitat degradation, and decline in aquatic biodiversity are increasing rapidly while on the other hand, freshwater reserves are depleting, and about 71% of the world’s population (about 4.3 billion people) is facing some form of water adversity or scarcity during some months of the year [8]. It is a very well-established fact that high levels of heavy metals are highly toxic for all life forms, especially aquatic life forms and humans. The wastewater is usually substantially loaded with heavy metal pollutants, due to agricultural sullage, industrial effluents, nuclear wastes, metal processing, etc [9]. It is well known that biochemical reactions need certain heavy metals such as Co, Cu, Fe, Mn, Mo, Ni, Se, and Zn. However, there are some non-essential Heavy metals present in the wastewater, such as Lead (Pb), Chromium (Cr), Cadmium (Cd), Mercury (Hg), and Arsenic (As), which are non-biodegradable and are highly toxic and carcinogenic even in low dosage. They can bind to the surface of microorganisms and reach humans via the food chain (Jaishankar et al. 2014). Biosensors A biosensor is an analytical device used to detect a chemical substance that combines a biological component with a physicochemical detector. A biosensor consists of two components: A Bioreceptor and a transducer. The Bioreceptor is a biomolecule that recognizes the target analyte, and the transducer converts the recognition event into a measurable signal [10]. The components of the functional biosensor are shown in Fig. (1). There are several characteristics of biosensors are given: 1. 2. 3. 4.

Sensitivity: Response of the sensor to per unit change in analyte concentration. Selectivity: Ability of the sensor to respond to the only target analyte. Reproducibility: Accuracy with which the sensor’s output can be obtained. Stability: Characterizes the changes in its baseline or sensitivity over a fixed period time. 5. Range (Linearity): is the concentration range over which the sensitivity of the sensor is good.

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Fig. (1). Biosensor and its components.

Types of Biosensors and Their Applications There are several types of biosensors, such as Enzyme based, whole-cell-based, piezoelectric, optoelectronic, electrochemical transducer, and thermal sensors. Biosensors are very specific and designed for the specific application. The various type of biosensors and their application is shown in Fig. (2).

Fig. (2). Schematic illustration of various types of biosensors [11].

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Bacterial Biosensor Nowadays, bacteria use biosensors for the detection of heavy metal contaminations. Recombinant E. coli strains have been used for the detection of water contaminations, including heavy metal contaminations. When the E. coli strain comes in contact with the heavy metals, it starts to increase the expression of a fluorescent protein [12, 13]. Enzyme Based Biosensors Instead of whole bacterial cells, enzymes can be used for the detection of heavy metal ions. These proteins are also used for the reduction of heavy metal ions [14]. Porous silicon has been used as an enzyme-based biosensor due to its specific enzyme immobilization capacity and optical properties for monitoring chromium ions in wastewater [15]. Optical Fibre Biosensor Enzymes also can be immobilized on optical fibres, for example, acid phosphatase immobilized on optical fibres was employed to detect trace levels of Hg2+via the enzyme inhibition principle [16]. Another efficient example is a rapid β- galactosidase (β-GAL)-based colourimetric bioactive paper sensor, which could measure Ag+, Cr4+, and Ni2+ in PPM concentration levels. The upside of this method is that it does not require any external instrumentation, rather it offers a colourimetric assay, which is visible by the naked eye [17]. DNA Enzyme Based Biosensor High-precision nano-biosensors prove very efficient and precise for the detection of heavy metal levels in wastewater. It uses the Fluorescence resonance energy transfer principle (FRET). This Biosensor consists of quantum dots (QD) conjugated with a thick silica layer that is covalently coupled to DNAzymes and two quenchers. Using the same principles, it can then be multiplexed to detect different metals, as the QD will give separate signals for the different metal ions [18]. The DNAzyme-based biosensor is shown in Fig. (3). In the absence of a metal ion, the DNAzyme remains inactive, and the quencher via FRET prevents the fluorophore from exhibiting fluorescence. However, when the metal ion binds to the DNAzyme, it gets activated and cleaves the DNA, causing the quencher to be released and the fluorophore to exhibit fluorescence. This fluorescence signal can then be used to interpret the quantitative/qualitative estimation of the presence of metal ions in the sample [18].

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Fig. (3). DNAzyme based biosensor and its application in heavy metal detection.

Electrochemical Biosensors Aptamers are oligomers, typically based on synthetic DNA or RNA sequences that bind a specific target molecule. In recent years, electrochemical aptasenors have proved to be promising candidates for heavy metal biosensor applications as they have high affinity and sensitivity even towards low levels of metal ions such as arsenic [19, 20]. Combining Nanotechnology with Biosensors Technological advancements are also made by combining electrochemical biosensors and nanomaterial, which can drastically improve the device’s performance [21, 22]. An electrochemical aptasensor made for Cu2+ detection was enhanced by the addition of gold nanoparticles (GNPs) to make it more sensitive [23]. Rahman et al., 2012 demonstrated modified Multi-Walled carbon nanotubes with the addition of peptides which showed enhanced peak-current density, rate of reaction and higher sensitivity. The limit of detection of these biosensors is well below the mentioned levels of EPA guidelines for Hg2+ and Cd2+ in drinking water [24]. A nano-biosensor to detect multiple ions (e.g., Cd2+, Pb2+, Cu2+ and Hg2+) within the acceptable LOD values. It has also been developed based on L-cysteine functionalized reduced graphene oxide (rGO) on glassy carbon electrodes, which can serve as an excellent tool for the detection of major heavy metals in wastewater [25].

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Piezoelectric Biosensor Piezoelectric biosensors are a group of analytical devices, which work on the principle of affinity interaction. It has a piezoelectric crystal that act as a sensor part on the principle of oscillations change due to a mass bound on the piezoelectric crystal surface. This type of biosensor has also been used for the detection of Zn2+ and Cd2+ ions in wastewater with the use of covalently attached metallothionein onto a quartz crystal [26 - 28]. CONCLUSION Treatment of wastewater is one of the biggest challenges. Human and other organisms in the ecosystem is always at risk caused of the contaminants and pollutants in the water. So, monitoring techniques should be standard analytical techniques, however, the present technique is laborious, expensive, sensitive and accurate but unsuitable for on-site monitoring of complex water samples. Electrochemical biosensors are very sensitive and cost-effective compared to standard analytical methods and have great potential. Various research is going on using polymer and nanomaterials to modify it and innovative biorecognition elements. The human population and other organisms in the ecosystem face water pollution, and there is continuous fear about the risks caused by pollutants or contamination. There is a need to stop or reduce the heavy metal contamination from their sources, which means that industries will have to make an extra effort to purify as much wastewater as possible. The use of adsorbents and other methods should be implied to deal with the extreme contamination of heavy metals. Similarly, a focus should be on the use of less fertilizer, and pesticides should be imparted. Secondarily, the screening and regulation of wastewater for contamination becomes a major challenge. Hence, development of new and robust technologies like the ones we discussed should be advanced and promoted, as the risk of these contaminants entering the biological food chain is far too dangerous to be overlooked. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors are thankful to the IIT (BHU), Patna University, and the University of Allahabad for financial and technical support of the present research work.

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L. Zhang, B. Wang, G. Yin, J. Wang, M. He, Y. Yang, T. Wang, T. Tang, X.A. Yu, and J. Tian, "Rapid Fluorescence Sensor Guided Detection of Urinary Tract Bacterial Infections", Int. J. Nanomedicine, vol. 17, pp. 3723-3733, 2022. [http://dx.doi.org/10.2147/IJN.S377575] [PMID: 36061124]

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SUBJECT INDEX A

B

Acid 8, 12, 48, 64, 89, 90, 100, 101, 102, 128, 129, 131, 133, 147, 152, 153, 155, 179, 191 aristolochic 8 carboxylic 48 deoxyribonucleic 147 hyaluronic 64 nucleic 12, 89, 90, 100, 101, 102, 128, 129, 131, 133, 152, 153, 179 okadaic 155, 191 pyruvic 155 Activity 2, 7, 9, 15, 112, 117, 122, 177, 156, 187, 189, 203, 204 agricultural 203, 204 anthropogenic 203 bioelectrical 117 catalytic 2 electrophysiological 189 industrial 203 metabolic 112, 117, 187 Affinity 18, 179, 193 based biosensors 179, 193 chromatography 18 Allosteric enzymes 101 Amperometric biosensors 102, 179, 180, 186, 194 Amplification 81, 88, 90, 92, 99, 152 enzyme-assisted 152 Apoptosis 98, 99, 104 Applications 57, 59, 61, 64, 124, 152 bioanalytical 124 bioimaging 61 of DNA sensors 152 of graphene-based nanomaterials 57, 59, 61 of nanomaterials based on graphene 64 Aspergillus ochraceus 153 Atomic absorption spectroscopy (AAS) 203 Atrial natriuretic peptide (ANP) 166

Bioanalyte receptor system 114 Bioanalytical processes 135 Bioimaging 17, 31, 32, 45, 57, 61, 66, 124 techniques 124 technologies 61 Biolayer interferometry system 86 Biological 133, 195 design techniques 195 interaction processes 133 Biosensors 103, 105, 148, 149, 150, 151, 152, 153, 169, 179, 180, 185, 186, 190, 193, 195 aptamer-based 149, 152 calorimetric 105, 179, 180, 185 chronopotentiometric transduction 103 electrical 149 electrochemical-based 103, 190, 193 electrochemical DNA 150, 151, 152, 153 enzyme 148, 186 fluorescence-based 190, 195 luminescence-based 169 Bovine 7, 64, 87 serum albumin (BSA) 7, 64 viral diarrhea virus (BVDV) 87

C Calorimetric assay 89 Cancer 1, 2, 5, 6, 7, 30, 31, 33, 34, 38, 54, 91, 98, 99, 101, 102, 106, 117, 121, 122, 131, 132, 150 cervical 98 colon 98 disorders 117 oral 91 ovarian 99 prostate 91, 101 proteins 102 ionic liquid electrode (CILE) 150

Vivek K. Chaturvedi, Dawesh P. Yadav and Mohan P. Singh (Eds.) All rights reserved-© 2023 Bentham Science Publishers

Subject Index

nanotubes (CNTs) 1, 2, 5, 6, 7, 30, 31, 33, 34, 54, 106, 121, 122, 131, 132 quantum dots 38 Carcinoma protein analysis 103 Cardiac 166, 172 inflammation 166 myopathies 172 Cardiomyocytes 117 Cardiomyopathy 172 Cardiovascular 166, 167, 173 biomarker 166, 167 biosensors 167 disease diagnostics 173 Chemical vapour deposition (CVDs) 6, 7, 8, 9, 50, 52, 53, 163, 164, 166, 169, 170, 173 Chromatography, high-performance liquid 153 Chronoamperometry 170 Clostridium perfringens 189 Colorimetric analyte detection 125 Computerized tomography (CT) 13, 119, 124, 164 Contamination, chemical 189 Cytomegalovirus 87

D Deep vein thrombosis 171 Defects, replication 99 Dendrimer’s structure 10 Devices 1, 7, 62, 87, 88, 91, 102, 103, 114, 115, 116, 132, 133, 134, 147, 173 angiogenic gene delivery 62 biosensor-based CVDs 173 fluidic nanobiosensor 132 fluorescent biosensing 7 Diseases 12, 16, 115, 165, 171, 172, 178, 179 cerebrovascular 171 chronic kidney 115, 165 foodborne 178, 179 immunological 12 life-threatening 179 neurological 16 renal 172 Disorders 11, 93, 115, 119, 128, 164, 165, 173, 189 cardiac 164, 165, 173 metabolic 128 neurodegenerative 119 protein-related 93

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Dysfunction, autoimmune 98

E Electrical conductivity 30, 47, 56, 63, 122 Electrochemical 17, 32, 35, 38, 60, 102, 103, 106, 131, 135, 149, 150, 170, 180, 184, 186, 191, 193, 207, 208 aptamer sensors 149 aptasensor 207 biosensors 102, 103, 106, 131, 135, 170, 180, 186, 193, 207, 208 immunosensor 191 recognition of DNA hybridization 150 sensors 17, 32, 35, 38, 60, 149, 184 Electrode 16, 61 catalytic performance 61 immunoassay 16 ELISA technology 103 Enzyme 17, 88, 125, 135, 152, 155, 206 assisted amplification (EAA) 152 based biosensors 206 linked immuno-assay (ELISA) 17, 88, 125, 135 linked immunosorbent assay 17 penicillinase 155 Eosinophil cationic protein 15

F Fischer-Tropsch synthesis (FTS) 57 Flower grading machines 188 Fluorescence 13, 14, 170, 179, 184, 204, 206 microscopy 179 resonance energy transfer (FRET) 13, 14, 170, 184, 206 Fluorescent 152, 184, 194 based biosensors 152 biosensors 152, 184, 194 Food contamination 178, 179, 180, 189

G Gas 31, 32, 135, 153, 184, 190, 193, 194 biosensor 194 chromatography 153 detection sensors 193 Glucose 1, 15, 16, 34, 35, 100, 101, 102, 103, 114, 127, 134, 135, 137, 155, 174, 174

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Chaturvedi et al.

biosensor device 172 nanobiosensor 135 sensitivity 35 sensor 102, 103, 137, 155 Glucose oxidase 34, 101, 119, 135, 155 immobilized 135

Lowest unoccupied molecular orbital (LUMO) 59 Luminescence properties 194 Luminous semiconducting nanocrystals 123 Lung metastasis 64 Lymphocytes 64

H

M

Heart disease 115, 163, 174 Heat reduction 55 Hemoglobin 31 Hepatocellular carcinomas 99 Horseradish peroxidase 92, 151, 189 Human 88 immunodeficiency virus (HIV) 88 papillomavirus 88 Hydrothermal technique 52

Magnetic nanoparticle (MNPs) 2, 14, 15, 124, 125 Magnetic resonance 11, 32, 45, 61, 63, 105, 119, 164 imaging (MRI) 11, 32, 45, 61, 105, 119, 164 Mass 133, 153, 189 spectrometry 153, 189 spectroscopy 133 Mechanical separation techniques 192 Medicines 2, 9, 46, 62, 63, 97, 104, 112, 113, 116, 122, 123, 136, 152, 173 anticancer 104 regenerative 112, 116, 122, 123, 136 Microbial 187, 193 sensors 187 spoilage sensors 193 Microfluidic(s) 171, 193, 194 biosensor 194 fluorescent 171 sensors 193 Mitochondrial malfunction 117 Mycotoxins 152, 153 Myeloperoxidase 167 Myocardial damage 170

I Illnesses 12, 164, 165, 187, 189 autoimmune 12 cardiovascular 164, 165 foodborne 187, 189 Imaging, magnetic resonance 11, 45, 61, 105, 119, 164 Immobilization technique 2 Immuno-electrochemical assays 170 Infections 16, 92, 130, 132, 156, 165, 184 bacterial 156, 165, 184 parasitic 92 Intensity 13, 81, 83, 106, 124, 169 electromagnetic 81 Interface 2, 153 biomaterials 2 sensing 153

L Laser 62, 51 cancer microsurgery 62 synthesis method 51 Light-addressable potentiometric sensor (LAPS) 102 Listeria monocytogenes 189 Localized surface plasmon resonance (LSPR) 16, 78, 80, 124, 125, 134

N Nanobiosenensor technology 137 Nanomaterials, polymeric 4 Nucleic acid 90, 106 -based sensors 106 biosensing 90 Nucleic corrosion 150

O Optical fiber 133, 134, 206 sensor 133, 134 biosensor 206

Subject Index

Optical 16, 132, 192 immunoassays 16 inspection techniques 192 transduction methods 132 Oxidative stress 8, 66, 167 Oxygen 57, 58, 155 consuming enzyme 155 evolution response (OER) 58 reduction reaction (ORR) 57, 58

P Pathways 18, 59, 90 electrocatalytic 59 Pencil graphite electrodes (PGE) 150 Phagocytosis 132 Photocatalysis 58, 59, 66, 135 Photocatalytic hydrolysis 59 Photoluminescence imaging 32 Photonic crystal 104 biosensors 104 sensor 104 Piezoelectric biosensors 105, 147, 179, 185, 208 Plasmon resonances 84 Pollutants 35, 147, 189, 190, 204 chemical 190 environmental 35, 147 heavy metal 204 microbiological food 189 Polymerase chain reaction (PCR) 148, 179 Polymers 12, 132 natural 12 thermoplastic 132 Positron emission tomography 45 Properties 19, 45, 47, 49, 59, 62, 113, 116, 119, 120, 122, 125, 126, 127, 150 electrocatalytic 126 natural fluorescence 45 photocatalytic 59 photoelectric 150 Proteins 1, 2, 9, 34, 35, 60, 78, 99, 100, 101, 122, 123, 128, 154, 155, 165, 206 fluorescent 206 urine 165 Proteomics 133, 174 Pulmonary embolism 171

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R Raman spectroscopy (RS) 125 Reaction 57, 115, 130 enzyme-based 130 immunogenic 115 oxygen reduction 57 Reduction 35, 57 electrochemical 35 hydrothermal 57 Respiratory syncytial virus (RSV) 88 Retinoblastoma protein 99 Reverse transcription polymerase chain reaction (RTPCR) 90 Rheumatic fever 171 Rheumatoid arthritis 92 RNA 89, 90, 92, 97, 99, 102, 129, 132, 147, 148, 164, 167, 187 aptamer microarray format 92 microarray 92 oligonucleotides 102 transcribed 90

S Sandwich immunoassays 170, 172 Seed-mediated technique 16 SELEX technology 102 Semiconductor quantum dots (SQDs) 56, 57 Sensitive bioassays 123 Sensors 15, 30, 31, 32, 33, 34, 35, 36, 38, 60, 79, 104, 131, 147, 155, 186, 187, 188, 193, 204 allergen 193 amperometric 155 aptamer-based 147 enzyme 131, 186 fluorescence-based 147 magnetic 15, 187 Severe acute respiratory syndrome (SARS) 88, 165 Single-photon emission computed tomography (SPECT) 64 Sonication 52, 55 SPR 79, 80, 86, 88, 91, 92, 170, 191 biosensing technique 191 biosensors 79, 80, 86, 88, 91, 92 biosensor technology 92 sensors 170

216 Recent Advances in Biosensor Technology, Vol. 1

SPR-based 93, 188 sensing technology 93 sensor 188 Surface 8, 74, 84, 106, 134 enhanced raman scattering (SERS) 8, 84, 106, 134 plasmonic resonance 78, 84 Surface plasmon 17, 78, 79, 81, 83, 84, 85, 86, 88, 92, 125, 129, 169, 184, 191 microscopy 79 resonance (SPR) 17, 78, 79, 81, 83, 84, 85, 86, 88, 92, 125, 129, 169, 184, 191 Suspected acute coronary syndrome 173 Systems 16, 20, 117, 186, 195 luminol chemiluminescence 16 microfluidic 117 multi-enzyme biosensor 186 traditional costly sensing 20 wireless communication 195

T Techniques 52, 54, 55, 63, 78, 79, 80, 81, 84, 87, 88, 89, 91, 92, 149, 150, 151, 153 bioassay 149 chromatographic 153 therapeutic 63 Technology 33, 98, 103 developing biosensor 98 electrochemical transducer 103 renewable energy 33 Therapy 12, 18, 45, 63, 64, 66, 100, 104, 112, 116, 172 anticancer 12 photodynamic 45, 63 photothermal 63, 64, 66 Therapy photothermal therapy 45 Thermal 53, 54, 55, 126, 135, 179, 185, 205 decomposition 53, 54, 126 deposition 53 detection 185 energy 179 reduction 55 sensors 205 transduction 135 Thrombin binding aptamer (TBA) 14 Tissue 62, 106, 112, 113, 116, 117, 122, 123, 126, 127, 135, 136, 137, 179, 180 cardiac 62 heart 117

Chaturvedi et al.

injured 116 malignant 106 Traditional carbon-based sensors 35 Transcription factors 101 Transducer-based biosensors 129, 130, 169 Transfer 13, 170, 184 bioluminescence resonance energy 13 fluorescence resonance energy 13, 170, 184 Troponin biomarker 173 Tumor 64, 91, 98, 99 margin mapping 91 necrosis factor-alpha 91 suppressor gene (TSGs) 98, 99 targeting protein 64

U Ultrasensitive technique 128

V Vascular endothelial growth factor (VEGF) 15, 92 Viral surface protein 90 Virus 15, 87, 88, 89, 133, 187 dengue 133 herpes simplex 15, 89 mumps 88 respiratory syncytial 88 respiratory syndrome 87

W Waals forces 122

Y Yersinia enterocolitica 189