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A mini review on biosensor advancements-emphasis on quantum dots

Devadass Jessy Mercy, Koyeli Girigoswami, Agnishwar Girigoswami

PII: S2211-7156(23)00510-6
DOI: https://doi.org/10.1016/j.rechem.2023.101271
Reference: RECHEM 101271

To appear in: Results in Chemistry

Received Date: 21 November 2023

Accepted Date: 16 December 2023

Please cite this article as: D. Jessy Mercy, K. Girigoswami, A. Girigoswami, A mini review on biosensor
advancements-emphasis on quantum dots, Results in Chemistry (2023), doi: https://doi.org/10.1016/j.rechem.
2023.101271

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A Mini Review on Biosensor Advancements-emphasis on
quantum dots

Devadass Jessy Mercy, Koyeli Girigoswami and Agnishwar Girigoswami*

Medical Bionanotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad
Academy of Research and Education, Chettinad Health City, Kelambakkam, 603103, Tamilnadu, India

*Corresponding Author: E-mail: agnishwarg@gmail.com; Tel.: +91-44-47429046; Fax: +91-44-4741-1011

orcid ids:
Devadass Jessy Mercy- https://orcid.org/0009-0007-0985-8344
Agnishwar Girigoswami- https://orcid.org/0000-0003-0475-2544
Koyeli Girigoswami-https://orcid.org/0000-0003-1554-5241

Abstract

The biosensor analytical device targets the macromolecules and small molecules using a biological
recognition system and later converts it into a measurable signal using a transducer. These biosensors are
broadly used in various domains, enhancing the existing form and making it more specific for several
applications. Presently, it is used for quantifying and detecting the biological-based components in the
fields of forensics, medicine, food quality, pharmaceutical and environmental tracking, etc. These
biosensors are cost-effective and produce safe and assured treatment for patients by examining the
contagious disease biomarkers in the early stage without any side effects. This review has discussed the
five essential components of biosensors and the upgraded form of these biosensors. Depending on the
detection method, biosensors were classified into different types. Amongst various types,
electrochemical and optical biosensors have more sensitivity and are widely used, briefly discussed here.
Nanomaterials play a significant role in modern medical devices due to their excellent selectivity, high
surface-to-volume ratio, strong chemical activity, increased specificity, and sensitivity that pave the way
for more discoveries. Several nanomaterial-based biosensors are already on the market. This review
mainly focuses on the fabrication methods of metal and metal oxide nanoparticles for sensing
applications.

Keywords

Biosensors; electrochemical biosensor; optical biosensor; acoustic biosensor; nanomaterials-based

biosensor.

Introduction

1
A device that alters the facts like the physicochemical properties of a material into an electrical signal is
known as a sensor [1]. Biosensors are vital analytical devices for detecting and quantifying various bio-
based components in the meadow of clinical, forensics, pharmaceutical, food quality, and environmental
tracking. American biochemist Leland Charles Clark discovered the first biosensor for the detection of
oxygen in the blood, and the electrode pre-owned in the sensor was termed the ‘Clark electrode,’ and he
was also acclaimed as the “Father of Biosensors” [2]. These biosensors have the capacity to detect the
biomolecules present in the multiplex sample and convert the signal to an optical or electrical signal, which
can be further read out by digital display [3].

Nanotechnology is the field of science used to design and improvise biosensors and has been found to have
profound applications in the biomedical field. In the last few decades, a bloom has come in the research
field encompassing nanotechnology and its applications in biosensing [4], theranostics [5], drug delivery [6],
nanoformulation of nutraceuticals[6, 7], photodynamic therapy [8], biomedical imaging [9, 10] and nano
fertilizers [11]. Biosensing enables us to detect the trace amount of the analyte, such as DNA, RNA, disease
biomarkers, microbes, enzymes, gases (electronic nose) [12], and so on. The sections below will explain
biosensors' design, classification, and application.

2. Design and principle

The changes in physical quantities, such as heat, force, pressure, movement, humidity, and an electrical
component like current, are detected by a biosensor. A sensor is a device or module that converts such
quantities into signals that can be detected and analyzed. These biosensors are in different shapes and sizes
and can measure the samples (pH levels, pathogens, toxicants, etc.) even at lower concentrations [13].
There are five critical components of a biosensor: an analyte, a substance being detected and measured, a
receptor that communicates with the target, a transducer that transforms the property of the sample into a
signal, an electronic component that tracks these signals, and a display unit/detector to view the analog
(Fig.1). In recent years, the usage of biosensors has been maximized in the field of biomedicine,
biotechnology, environmental monitoring, agriculture, and forensics due to their immense properties like
high specificity, reproducibility, high sensitivity, low cost, excellent stability, and portability [3]. Due to
these properties, the biosensors are progressively high when compared to the presently existing devices.
An antibody, a nucleic acid, or an enzyme was used as a biological element, and an amplifier or transducer
was used as a chemical element in biosensors.

2
 Figure 1. Principle of Biosensors

3. Evolution of Biosensors

The biosensors have been divided into three generations according to the process of integrating the
bioreceptor with the transducer. In the first generation, the substance of the analyte and the product of the
bioreceptor were measured by the biosensor and attached to the transducers, which in turn produced an
electrical signal. This type of biosensor is otherwise called a Mediator-less biosensor. The second
generation is a mediator amperometric biosensor, in which the nanomaterials or other mediators are
attached to the biosensor’s biological component for better analytical effect. In the third generation, no
mediators are included because the biosensor on its own acts as both an element and a mediator [13]
(Fig.2).

3
 Figure 2. Evolution of Biosensors

4. Classifications based on detection methods

The biosensors can be classified depending on their shape, size, and structure. As discussed above, these
are used in multidisciplinary fields. The biosensors are divided depending on the bioreceptor and
transducer. Under the category of bioreceptor, the biosensors are sub-divided into immunosensors,
enzymatic biosensors, aptamers-based biosensors, nucleic acid biosensors, etc. Under the category of
transducer, they are subdivided into electrochemical biosensors, optical biosensors, thermal biosensors,
and acoustic biosensors. However, some biosensors are also subdivided based on detection methods,
including electrical, optical, thermal, acoustic, magnetic, and mechanical biosensors. Biosensors have been
used for various biomedical applications [4, 14-17]. The electrochemical biosensors were further divided
into potentiometric, amperometric, voltammetric, impedimetric, and conductometric biosensors. The
optical biosensors were further divided into fluorescence-based biosensors, chemiluminescence-based,
SPR-based, and optical fiber-based (Fig.3).

Figure 3. Classification of Biosensors

4.1 Electrochemical biosensors

4
This category of biosensor refers to the electrochemical reactions occurring between an analyte and
bioreceptor, which is coated or bonded onto the surface of the transducer. These have the capacity to
produce label-free detection by which the biomolecules are detected without harming the biological
system. This biosensor produces signals in the form of current, voltage, capacitance, and impedance. Based
on the transduction method, the electrochemical biosensors were classified into potentiometric,
amperometric, impedimetric, conductometric biosensors, and voltammetric biosensors [18].

4.1.1 Potentiometric Biosensor

These biosensors determine the concentration of the analyte by measuring the difference between working
and reference electrodes at various concentrations (analyte). Commonly used materials are glass pH
electrodes and ion-selective electrodes. Potentiometric biosensors have many advantages, including low
cost, easy accessibility, and familiarity [19].

4.1.2 Amperometric Biosensor

An amperometric biosensor measures a sensor’s current output with the sensor analyte and uses it as a
measurement parameter [20]. This type of biosensor works based on three electrodes (working). The Clark
oxygen electrode is the most commonly used amperometric biosensor [21]. The biosensor includes a
variety of nanomaterials like metal nanoparticles, oxide nanoparticles, quantum dots, composite
nanoparticles, nanoshells, and nanowires.

4.1.3 Impedimetric Biosensor

The impedimetric biosensor measures the electrode and electrolyte interface impedance when an
excitation signal is applied. Impedance analyzers are used to measure the current response based on the
frequency and low amplitude AC voltage applied to the sensor electrode. Nanomaterials like monometallic,
bimetallic nanoparticles, gold, graphene, and metallic nanocomposites are used in designing impedimetric
biosensors [22].

4.1.4 Conductometric Biosensor

In a conductometric biosensor, an electrical conductivity or resistivity change is measured between a

reference electrode and an analyte concentration [23]. Nanomaterials, polymers, and their composites,
such as chitosan, cellulose, and conducting polymers, are commonly used in biosensor interface design [24].
The use of a highly sensitive conductometric metal oxide platform for IL-6 and CRP detection in real-time
has also been demonstrated [25].

4.1.5 Voltammetric Biosensor

This biosensor involves measuring the current flow between the combinations of three electrolytic cells
present in a solution. The potential applied to the electrode is varied, and the resulting current response is
measured. This current can be used to quantify the concentration of the target analyte, as it is often
proportional to the amount of analyte present. These biosensors offer advantages such as high sensitivity,
rapid response, and the ability to detect multiple analytes simultaneously.

5
4.2 Optical Biosensors

A biosensor is a device that uses a receptor kept close to the transducer and produces quantitative
analytical information displayed in the detector. These biosensors are classified based on transduction and
biological mechanisms. The biosensors are sub-classified based on the transduction method, such as
optical, electrochemical, electronic, and piezoelectrical biosensors. Conceptually, optical biosensors detect
changes in UV/visible/Infrared light absorption caused by chemical reactions or in the amount of light
emitted by luminescent processes. There are several types of optical detection, but in general, optical
detection is based on the measurement of luminescence, fluorescence, and color changes by measuring
absorption, reflectance, or fluorescence emissions that occur within the ultraviolet (UV), visible (VIS), or
near-infrared (NIR) spectrum regions. The optical biosensors are further classified into surface plasmon
resonance and evanescent wave fluorescence, and the electrochemical biosensors are further classified
into amperometric, impedimetric, potentiometric, and conductometric biosensors. Based on biological
mechanisms, the biosensors are sub-classified into immunosensors, enzymatic sensors, DNA aptamers,
peptides, etc. Optical biosensors are the most frequently used biosensors. These biosensors are superior to
traditional analytical techniques because they directly detect various biochemical compounds in real time
without labels. Their multiple properties like low cost, high sensitivity, excellent specificity, high stability,
and small size make them a perfect tool in various fields like medicine, biotechnology, engineering,
pharmaceutical, molecular biology, environmental monitoring, and agriculture and the development of
biosensor in these fields have tremendously increased.

Two detection techniques are involved: i) label-free detection technique and ⅱ ) labeled detection
technique. Interaction of analytes with transducer follows the label-free technique, and interaction of
analytes and label, which generates a signal in the form of fluorescence or luminescence, colorimetric,
detected by the transducer follows the labeled technique. These optical biosensors directly detect the
analytes based on surface-enhanced fluorescence, waveguide, Raman scattering, infrared and plasmonic
sensors [2]. In 1902, a new sensor called Surface Plasmon Resonance (SPR) was discovered to detect the
interactions of biomolecules without a labeling approach, which is exceptional when compared to the
above methods. It occurs when light encounters a metal surface under total internal reflection
circumstances [26]. The connection between metals and prism provides a high accumulation of light on the
surface. These surface plasmon resonance sensors have been classified into various coupling groups like
fiber coupling sensors, prism coupling sensors, waveguide coupling sensors, etc., and these are commonly
used sensors presently. The prism coupling sensor is based on the Kretschmann configuration. The SPR
sensor has immense advantages like prominent sensitivity and specificity, in situ dynamic monitoring, label-
free, no purification of the sample, and strong anti-interference ability, which makes them a magnificent
tool in the field of medicine, water management, environment tracking, and in food quality detection [27].

4.2.1 Luminescence

Over the past decades, fluorescence has had extraordinary growth in instrumentation and application and is
pre-owned in fields like biological sciences, biochemistry, and biophysics. It plays a significant role in
environmental tracking, DNA sequencing, clinical chemistry, and genetic analysis. Besides these, it is also
used to track the movement of cells through fluorescence microscopy [28]. The study of luminescence is
generally moving forward on many fronts, utilizing advanced experimental and theoretical techniques and
interacting more and more with distinct areas of solid state and molecular science [29]. The word
luminescence came into existence through the phenomena in the natural world, ‘a light without a fire’,
which involves seashells, bologna stone, luminous worms, aurora borealis, and others. It was discovered by
German scientist Eilhard Wiedemann in 1888. Luminescence can be described as the transitions of
electrons between various energy levels, accompanied by alterations in energy. Based on the movement of
the excited molecule, luminescence is classified into photoluminescence, chemiluminescence,

6
electrochemiluminescence, bioluminescence, thermoluminescence, triboluminescence, room temperature
phosphorescence, cathodoluminescence, etc. [30].

4.2.1.1 Photoluminescence

The phenomena of an excited molecule when irradiated with visible or ultraviolet light are known as
photoluminescence. Depending on the upconversion of luminescence and nonlinear motion, some
materials absorb light at a longer wavelength and emit it at a shorter wavelength. The light-emitting
materials can be applied for different applications like sensing, engineering, imaging, and harvesting solar
lights. This process can also be observed in numerous organic and inorganic materials [31].
Photoluminescence is the sub-family of luminescence and is further classified into two groups: fluorescence
and phosphorescence. Both the fluorescence and phosphorescence processes are illustrated by a Jablonski
diagram. When a molecule is illuminated with light, it tends to move from a lower state to an excited state,
releasing energy in the form of photons or nothing but fluorescence [32]. For the past decades, the
interesting facts and knowledge about phosphorescence have increased among people. The phenomenon
of phosphorescence is when atoms or molecules absorb energy and then emit electromagnetic radiation
after a period. The importance of the triplet excited state and the phosphorescence process was explained,
and it was justified that the existence of phosphorescence should be applied to every state of matter.
Phosphorescence has outstanding advantages like larger Stoke’s shift and the prolonged lifetime of
luminous and environmentally friendly characteristic materials when compared to singlet fluorescence
signal. By understanding the novelty of the phosphorescence method, the insistent steady room
temperature phosphorescence was developed [33, 34].

The evolution of Room-Temperature Phosphorescence was launched by Roth in 1967, and Paytner’s group
introduced a novel detection technique in 1974 called RTP photometry, which created researchers’ broad
applications and analysis. Phosphorescence has immense applications in photocatalysis, sensing, security
protection, bioimaging, etc. Thus, the majority of phosphorescent substances are pure organic compounds,
rare earth elements containing inorganic molecules, and precious metal complexes. Unfortunately, these
materials frequently have drawbacks restricting their use, such as high cost, poor processing performance,
and significant metal toxicity. Nevertheless, its manufacturing process is relatively complex, and it typically
contains metal components that may pose a biological and environmental concern [34, 35]. Thus, it is highly
preferred to produce innovative types of RTP materials with uncomplicated production, low cost, little
toxicity, and outstanding optical performance. To overcome the drawbacks, semiconductor quantum dots
have been used in a variety of applications as a relatively mature phosphorescent material. Achieving
fluorescence in room temperature and higher conditions for CDs (carbon dots) through the process of room
temperature phosphorescence (RTP) is more challenging due to the presence of triplet excitons, which are
associated with spin-forbidden transitions and are easily disrupted by vibrational relaxation and oxygen
quenching. As a result, studies on the RTP phenomena of CDs are in their formative years [35].

4.2.1.2 Chemiluminescence and Electroluminescence

Chemiluminescence (CL), is a process of irradiation of energy during a chemical reaction, and

Electroluminescence (ECL) is a chemiluminescence process when an electrochemical reaction occurs [36].
Chemiluminescence is used in forensic studies, like pyrosequencing of DNA [37], analyzing the species
present in the solution (organic/inorganic), determining the trace amounts of pollutants or poisons in the
air [38], and notifying/ assaying biomolecules when performing Western Blotting and ELISA, etc. The
occurrence of electrochemiluminescence on Grignard compounds and Luminal compounds was first
reputed in 1927 and 1929. Electrochemiluminescence has a prominent role in biosensing applications.
These are used in Electrochemical or Electrochemiluminescence Immunoassay (ECLIA), a quantified
technique used for determining the concentration of antigens and antibodies present in the system by

7
referring to the ECL signal before and after. Enzyme catalytic electrochemiluminescence biosensing is a
technique that combines an enzyme catalytic reaction with ECL detection and also the enzyme cofactors.
The DNA hybridization electrochemiluminescence biosensing is a technique that uses a sandwich
hybridization method in which the target (ss-DNA) is first hybridized with the probes present on the surface
and then with ECL probes present in the solution [39].

4.2.1.3 Bioluminescence

It is the conversion of chemical energy into light by an enzymatic mechanism in the absence of an excitation
source by living organisms with sensitive and non-intrusive digital displays [40]. Tiny luciferin molecules and
luciferase enzymes create the visible light produced by this technique; even though there are over 30
known bioluminescent systems, only 11 luciferin-luciferase pairings have been fully characterized. Several
innovative systems are actively being researched [41]. The external light source is not essential in
bioluminescence, which makes them a prominent tool in in-vitro chemiluminescence imaging like CL-based
imaging assays, integrated CL imaging devices, and in-vivo chemiluminescence imaging like polymer,
inorganic, and dioxetane based CL imaging [42]. The bioluminescence reaction is currently employed in
various applications, such as detecting protein-protein interactions, gene assays, high-throughput screening
(HTS) for drug development, hygienic monitoring, assessing environmental contamination, and in vivo
imaging of small organisms. Bioluminescence also finds notable uses in biomedicine, including neuronal
regulation and photodynamic treatment (PDT) involving the photo-uncaging of small molecules, among
others [40].

4.2.1.4 Thermoluminescence
Thermoluminescence is the light emitted from a crystalline material from a substance previously exposed
to high-energy radiation, due to which there is an electron displacement within a crystalline lattice [43]. It
generally happens in semiconductors or insulators that absorb ionizing radiations [44]. This phenomenon is
also seen in some mineral particle temperature sensors and crystal phosphors that have already been
excited by light [45]. The trapped electrons within the lattice could be brought back to normal by heating
the substance at a temperature of 450 ℃ and higher. The intensity of the light emitted can be associated
with the duration of the radiation exposed to the substance. Hence, the longer the duration of exposure,
the greater the energy emitted [43]. Thermoluminescence, or optically stimulated luminescence, or
thermally stimulated luminescence, is used in the measurement of radiation dosage through X-rays, gamma
rays, and beta particles from ionizing radiation. The dosage used can be estimated in the specified radiation
field through suitable calibration. The main application of thermoluminescence is in the geological field,
followed by archaeology, personal dosimetry, material characterization, and many more [46].
4.2.1.5 Triboluminescence

Triboluminescence is the term used to describe the light released voluntarily when some materials are
subjected to mechanical stress, which has been observed for the past few decades. It was first discovered
by Sir Francis Bacon in 1620. Triboluminescence is otherwise called mechanoluminescence, and these are
prominently used in many fields. Processes such as fluorescence, chemical reactions, and creatures with
unique biology can produce spontaneous light [47].

4.2.1.6 Room-temperature Luminescence (RTL)

RTL refers to luminescence, where there is a transition in the excitation of radiative energy from the triplet
state to the ground state. The performance of the RTL materials is evaluated based on the quantum yield
and lifetime. Pure organic RTL materials that are metal-free need to be developed since inorganic RTL
materials require rare earth metals that are highly toxic have aqueous environmental instability, and are

8
highly expensive. Several scientists' interest has resulted in the development of pure organic RTL systems
with powerful emission and lengthy afterglow. Several methods include polymer–matrix, crystal
engineering, H-aggregation, and host-guest interactions. This RTL has broad applications in imaging, anti-
counterfeiting, optical devices, and sensing [48]. Polymers are the perfect material for accomplishing RTL
and implementing practical applications because of their flexibility, thermal stability, processability, and
stretchability, with flexible long chains and interlaced structures [49]. RTL polymers interact primarily by
halogen bonds, hydrogen bonds, covalent bonds, stacking, host-guest interactions, and other mechanisms.
Surprisingly, polymers like poly-BrNpA, poly-BrBA, and poly-BrNp had good luminescent behavior with
substantial Stokes shifts, indicating RTL emission, resulting in their extended longevity and excellent
quantum yield [50].

4.2.1.7 Cathodoluminescence

When a material is subjected to a high electron beam, it emits light, known as cathodoluminescence. These
are used in several applications, which include semiconductor analysis, geology, sensing, and material
research [51]. The high-energy electron beam in chemiluminescence emits light typically in the ultraviolet,
visible, or near-infrared spectrum, and its intensity and color can supply information about the composition
and construction of the material being studied. In addition to its use in research, cathodoluminescence is
also used for practical applications, such as in the manufacturing of high-brightness LEDs and in the
inspection of semiconductors and other electronic devices [52].

4.3 Thermal biosensors

The enzyme thermistor is utilized to measure the heat reaction of the enzyme when it comes in contact
with the analyte. This heat reaction is then calibrated against the concentration of the analyte. The amount
of heat produced or absorbed is directly proportional to the molar enthalpy and the total number of
molecules involved in the reaction. Enzyme thermistors, which use a thermistor to measure the
temperature, are particularly suitable for this purpose due to their high sensitivity to thermal changes.
These thermistors are commonly employed in biosensors because they do not require frequent
recalibration and are not affected by the optical and electrochemical properties of the sample. Thermal
biosensors find various applications, including detecting pesticides and pathogenic bacteria [53]. Thermal
biosensors help in measuring the fundamental properties of a biochemical reaction, which is the energy
released or absorbed in the reaction [53, 54]. The principle of thermometric measurement during a
biochemical reaction measures the heat evolved and absorbed. The sum of heat energy released or
absorbed is proportional to the molar enthalpy and the number of molecular products formed in the
biochemical reaction. Numerous applications include enzyme activity, clinical monitoring, process
monitoring, multi-analyte determination, hybrid sensors, environmental non-aqueous media, and other
applications [53].

There are many types of thermal biosensors used, like thermistors and thermopiles. Thermistors are used
when there is a change in the electrical resistance with temperature, which measures the absolute
temperature. Likewise, thermopiles are used to measure two regions' temperature differences [54].
Electrochemical sensors are becoming great compared to other analytical techniques due to their
advantages like portability, long-term stability, simplicity, low cost, and accuracy. It also has a few
drawbacks, such as complexity, poor reputation, and weak sensitivity [54]. Their rapid responses and
accuracy make it possible to detect it directly on-site with intuitive devices. Nowadays, many types of
research have been performed and conducted using electrode modification materials with the help of
antibiotic electrochemical sensors [55].

9
4.4 Acoustic Biosensors

Acoustic wave biosensors are emerging devices in the field of biosensors, widely utilized for detecting mass,
conductivity, viscosity, and density. Among these applications, acoustic biosensors are extensively
employed in the research to detect disease-related biomarkers [56]. These biosensors can simultaneously
detect changes in the surrounding environment's electrical and mechanical characteristics. Acoustic
biosensors find a wide range of applications, including drug screening, medical diagnosis, food analysis,
biochemical assays, and environmental monitoring. They are particularly effective in detecting biomarkers
associated with malignant tumors. There are two types of acoustic biosensors based on their propagation
modes: bulk acoustic wave (BAW) and surface-generated acoustic wave (SGAW). Additionally, they can be
classified based on polarization, the direction of vibrating particle propagation (transverse or longitudinal),
or the displacement of the device surfaces relative to particles [57].

5. Nanomaterial-based Biosensors

5.1 Metal and metal oxide-based Nanoparticles

In the past few years, the role of metallic and metal oxide nanoparticles has increased, and due to their
magnificent properties, scientists have focused on developing nanostructures, nanomaterials, metallic
nanoparticles, and their fabrication methods. These are also used for synthesizing polymers, sensors, and
catalysis that are used in treatment, diagnosis, and labeling media. The metallic and metal oxide
nanoparticle was prepared using two methods. One is the top-down method, and another is the bottom-up
method. The bulk materials are used as an initial substance in the top-down method, and molecules and
atoms are used as the bottom-up initial substance. The fabrication methods categorized under the top-
down process are laser ablation, thermal ablation, sputtering, and mechanical milling, and the bottom-up
was categorized into solid-state methods, hydrothermal, pyrolysis method, liquid state, gas phase, physical
and chemical vapor deposition methods, etc. [58]. The most commonly used metal nanoparticles are gold
nanoparticles, silver nanoparticles, magnetic nanoparticles, copper nanoparticles, titanium nanoparticles,
etc. The various metal nanoparticle-based biosensor fabrication and application are given in Table 1.

Table 1. Different metal nanoparticles and their fabrication method for sensing application

SI. MNPs used Fabrication Work Application References

No. procedure

1 Gold Laser ablation The laser ablation With efficient structural, [59]
nanoparticle technique obtained the optical, and
pure gold nano rod targets morphological
doped with zinc oxide. properties, it is used in
different sensors.

2 Silver Mechanical The POA and POA@Ag
nanoparticle milling nanocomposites were
synthesized through a
mechanomilling process
by which they played a
dual role as oxidants, were
The trace amount of [60]
dopamine was sensed by
the POA@Ag sensor with
great stability,
sensitivity, and
reproducibility compared

10
 used as sensors, and to others.
worked based on various
voltammetry techniques.

3 Titanium Sputtering The titanium nanoparticles They were used for [61]
nanoparticle method were deposited on the sensing highly catalytic
substrate of silica through hydrogen with quick
radio frequency response and great
magnetron sputtering. stable sensing
production.

4 Copper Hydrothermal The Cu-O nanoparticle was It was used as a chemo- [62]
nanoparticle method synthesized and resistive sensor for
characterized by the detecting toluene gas
hydrothermal method. and tested against BTEX
gas, which showed
longer stability and
hence was used as a
sensor to check the
quality of air and track
environmental issues.

5 Silver Pyrolysis The pyrolysis method The ACMPS-loaded [63]

nanoparticle method modified the surface-
activated carbon
microplates (ACMPS) with
potassium permanganate
and loaded with AgNPs.
AgNPs produced high
sensing of E.coli and S.
aureus compared to
normal surface-activated
microplates.

6 Graphene- Chemical The 2D graphene-gold The 2D graphene-gold [64]

gold vapor nanoparticle nanoparticle was
nanoparticle deposition nanocomposites were fabricated as a flexible
developed by the chemical and thin biosensor to
vapor deposition method. detect Amoxycillin.

The commonly used metal oxide nanoparticles are iron oxide, zinc oxide, silver oxide, copper oxide, and
titanium oxide nanoparticles. The recent investigations that used metal nanoparticles for sensing
applications are tabulated in Table 2.

Table 2. Different metal oxide nanoparticles and their fabrication process for sensing

SI. MONPs Fabrication Work done Application References

No method

1 Iron Laser ablation The Fe2O3 was The synthesized Fe2O3 NPs have [65]
oxide effectively synthesized shown a greater degradation
by combining FeCl3 efficiency when compared to

11
 with henna leaf extract Fe2O3. With PLA, the efficiency
using with and without was 95% in 50 mins, and without
pulsed laser ablation PLA, it was 88% in 70 mins.
technique (PLA).

Hydrothermal Fe2O3 NPs were The NPs were tested as a [66]

synthesized using the photocatalytic degradation
extract of coconut pulp catalyst for Rhodamine B
by hydrothermal solution and showed excellent
method. antibacterial and anticancer
action against gram-negative
E.coli, gram-positive S.aureus,
and HepG2 cell lines.

2 Zinc Mechanical The ZnONPs were The anticandidal and [67]

oxide milling synthesized using a antibacterial activities were
high-speed ball milling determined. They found that
technique. milled and unmilled S.aureus
were more resistant to
decreasing nanoparticle size and
increasing inhibition zone.

Pyrolysis The ZnONPs were The antifungal and antibacterial [68]

synthesized using the activity showed better inhibition
root extract of the in higher concentrations and
Saussurea lappa plant against gram +ve strain.
and used as fuel.

3 Silver Laser ablation The silver oxide NPs The synthesized NPs have [69]
oxide were synthesized using excellent stability, and the
the laser ablation combination of Ag/Ta2O5
method. provided high antibacterial
activity when compared to Ag
and Ta2O5.

Chemical The Ag-decorated CNTs The synthesized Ag/CNTs have [70]

vapor were synthesized using less agglomeration and low cost.
deposition the chemical vapor With metals decorated on the
deposition technique. CNTs, they are used as
nanocomposites and
antibacterial sensors.

4 Copper Sputtering The CuO NPs were The mono-dispersed Cu2O NPs [71]
oxide method synthesized from the have high stability with specified
juice of Myrciaria dubia shapes. It is used in the
by the sputtering functionalization of fabrics and
method. has outstanding antibacterial
characteristics in textiles.

12
 Liquid phase The Cu2O NPs were The electrochemical properties [72]
method synthesized using the and crystal structure of Cu2O,
classic synthesis CuO, and CuNa(OH)4 were
method. evaluated. The presence of a
sulfite in commercially available
wine samples was determined.

5.2 Quantum Dots

In the last few years, inorganic particles such as quantum dots, silver and gold nanoparticles, carbon
nanotubes, mesoporous silica nanoparticles, and iron oxides have fascinated researchers. Due to their
immense properties (optical, electrical, and magnetic), these are used as diagnostic agents, molecular
agents, and DNA-functionalized probes. Modifications to their size, composition, shape, and structure can
modify their behavior. When comparing inorganic materials with organic materials, the inorganic materials
were easy to produce and resistant to degradation under physiological conditions. The quantum dots were
recognized in the early 1980s by Brus, Ekimov, and Efros Optical Society of America and received the Nobel
Prize in 2023 in Chemistry. Chemist Moungi Bawendi, chemist Louis Brus, and physicist Alexei Ekimov have
split the 2023 Nobel Prize in chemistry for “the discovery and development of quantum dots, nanoparticles
so tiny that their size determines their properties." Quantum dots are tiny man-made crystals that can
transform a light spectrum into distinct colors. Depending on its size, each dot emits a distinct color. The
factors like structure, shape, size, and composition are used to determine the properties of quantum dots. A
new manufacturing technology that can use numerous batches with consistent parameters of QDs for
various applications like sensing, imaging, electronics, medicine, photonics, and information storage is
needed [73, 74]. Remarkably, they exhibit unique size- and shape-dependent optoelectronic capabilities
that have recently found practical use in bioimaging, light-emitting diode (LED) manufacturing,
photodetectors, computing, and solar cell technology.

Bandgap energy describes the mechanism of a semiconducting nanocrystal. The bandgap energy excites an
electron from the ground state (S0) to a higher state (S2), which forms an electron-hole pair, and as it
returns to its ground state, it emits energy in the form of a fluorescent photon. When obtaining the range of
Bohr radius, the semiconducting nanocrystal acquires distinctive optical and electrical properties. The
semiconducting nanocrystal is indirectly proportional to the bandgap; when the nanocrystal size increases,
the bandgap energy decreases, corresponding to an increase in the emission or excitation wavelengths [75].
Because of their semiconductor qualities, QDs are made from elements in the periodic table groups II-VI
(ZnO, ZnS, CdSe, CdS), III-V (GaN, GaP, InP), and IV-VI (PbSe, PbS). Transition metal dopants such as Mn2,
Cu2, Fe2, Cr2, and Co2 are frequently investigated for their capability to influence the magnetic and optical
characteristics of QDs [74]. Numerous synthesis techniques of QDs are used to determine their properties.
By reviewing the literature, the synthesis process is divided into two types: a top-down approach and a
bottom-up approach. The techniques involving electrochemical, laser ablation, e-beam lithography, and
liquid phase exfoliation fall under the category of a top-down approach, and the hydrothermal,
solvothermal, sol-gel, pyrolysis and microwave-assisted techniques fall under the category of bottom-up
approach [71].

5.2.1 Mechanism of Fluorescence in Quantum Dots

The simple mechanism of fluorescence involved in Quantum Dots is given in Fig. 4. [76].

13
 Figure 4. Fluorescence mechanism in QDs

14
 5.2.2 Classification of Quantum Dots

There are several ways to distinguish quantum dots' properties, some of which are structure and chemical
composition. The chemical composition involves core types, core-shell types, and alloyed quantum dots.
Due to their excellent electrochemical properties, materials like lead, cadmium, zinc, sulfides, and selenides
are used in the field of fluorescence imaging and biosensing by providing outstanding fluorescence
properties [77]. Although these materials have immense properties, the discharge of these metal ions gives
rise to toxicity, which potentially harms every living organism. Hence, a biocompatible, heavy metal-free
QD was established [78]. These include carbon, graphene, germanium, and silica-based quantum dots. In
the field of sensing research, carbon and graphene QDs have the most potential as carbon-based
nanomaterials, among others. This is because they have decreased toxicity, greater solubility in different
solvents, excellent electrical properties, powerful chemical inertness, substantial edge sites for
functionalization, large specific surface areas, and adaptability [79].

i. Carbon Quantum Dot

Carbon dots or carbon quantum dots are an emerging class of fluorescent nanomaterials with high chemical
stability and tremendous optical properties, making them promising materials for visualizing cells in vitro
and in vivo. The optical properties of carbon dots involve photoluminescence, chemiluminescence,
electroluminescence, phosphorescence, near-infrared fluorescence, and surface-enhanced Raman
scattering. Due to these properties, CQDs have potential for applications in bioimaging and sensing. It can
be explored as a fluorescent probe for the detection of pesticides and heavy metal ions, etc. Diamonds,
graphene, graphdiyne, fullerenes, carbon nanotubes, and carbon dots (CDs) make up the majority of the
materials in the carbon family [80]. These materials fascinated the researchers with their outstanding
properties like less toxicity, high photo-stability, chemical stability, and high availability of natural sources,
which make the CQDs a prominent tool for drug delivery, LEDs, food quality monitoring, photocatalysis,
gene delivery, photovoltaic and environmental tracking applications [81]. The fluorescent carbon dot was
discovered in 2004 by Xu and his coworkers when purifying single-wall carbon nanotubes. In 2006, Sun and
his coworkers synthesized surface-functionalized carbon quantum dots that provide enhanced fluorescence
emission [82]. Top-down techniques and bottom-up techniques synthesized the carbon quantum dots. The
top-down techniques involve the plasma method, arc discharge, electron beam lithography, and, most
commonly, laser ablation and electrochemical techniques. The bottom-up techniques involve
hydrothermal, solvothermal, pyrolysis, microwave-assisted, and sol-gel. The method of fabrication of
different types of carbon quantum dots is given in Table 3.

Table 3. Fabrication methods of Carbon Dots are categorized under Top-down and Bottom-up methods for sensing

SI. Fabrication Work done Application References

No method

TOP-DOWN

1 Electrochemical The fluorescent carbon dots They were used for the wireless [83]
were synthesized by an detection of bacteria. The cesium

15
 electrochemical process and
used as luminescent and
electrochemical biosensors.
2 Laser ablation The GQDs functionalized with
amino were used for the
detection of iron ions through
the laser ablation method.
3 Plasma method Bulk carbon dot was synthesized
quickly via the plasma method
using a single step.
4 Electrolysis The Ni-doped carbon quantum
dots were synthesized by
electrolysis from single-atom Ni-
anchored nitrogen-doped
carbon.
BOTTOM-UP
1 Hydrothermal By using the hydrothermal
method, orange emissive water
soluble N, S-doped carbon dots
were prepared from fuchsin dye
and sulfosalicylic acid.
2 Pyrolysis The Cu2+ was doped on the
surface of the carbon dots
during the carbonization process
16
tungsten oxide (CsWO3), NIR
responsive surface coatable
nanohybrid utilizes the catechol
moieties from the FCD surface.
This yielded high fluorescence
emission by interacting with the
bacterial cell wall and leads to
bacterial quenching, which detects
the bacteria.
The amine N groups were easily [84]
integrated into the carbon
network of GQDs and, by surface
modifications, yielded small
particles and narrower distribution
with a sensitive response to Fe3+
ions.
The synthesized CQDs showed the [85]
emission at 415nm for blue
emissive CQDs and 515nm for
green emissive with broad
distribution. These dual emissive
CQDs are used as metal sensors
for tumor detection and diagnosis.
The Ni-doped carbon quantum [86]
dots detected the copper and iron
ions simultaneously because of
the amino group and functional
groups and the EDTA+ quenching
mechanisms.
The synthesized N, S-CDs were [87]
used as an effective signal-off
multimodal sensing device for
detecting tetracycline antibiotics.
The synthesized sensor was used
to determine the chlortetracycline
and quercetin levels in milk and
water with LOD range and was
also used to image oocytes and
yeast cells.
The blue fluorescence in the [88]
synthesized Cu2+ doped CD
emerged by quenching the
 in the pyrolysis method. chromium ions. Also, this was
highly sensitive for S. aureus, thus
acting as a possible antibiotic and
nanoprobe.

3 Solvothermal The sol-gel method synthesized The array of fluorescent sensors [89]
the carbon dots that are sensitively detects the 5-
molecularly imprinted polymers Nitroimidazole antibiotics with
(CDs@MIPs). 100% recognition accuracy in
buffer and water solutions. This
sensor detects the antibiotics and
is also used for analyzing the
environment.

4 Microwave Carbon dots were synthesized
method from citric acid by microwave-
assisted method, which is
mediated for in-vitro and in-vivo
studies against bacteria.
The synthesized carbon dots [90]
showed fluorescence emission
under 450 nm and were carried
out for stability. The S. aureus
bacteria was eliminated when CD-
mediated photodynamic therapy
was carried out in an in vitro
study. Following this, the in-vivo
study was carried out where the
complete healing of wounds was
observed.

Though there are different fabrication methods, they have both advantages and disadvantages in a specific
area. The chemical route synthesis has major disadvantages when compared with the green route.
Likewise, Wang and his coworkers synthesized two-photon nanocarrier-based carbon dots by laser ablation
method for safe and efficient delivery of siRNA and DNA. The size and photoluminescence properties were
easy to control, but the high cost and sophisticated process were the drawbacks [91]. The carbon nanodots
show that ultrasonic treatment synthesized green photoluminescence from food wastes, which had a high
energy cost [92]. Using the Arc discharge method, the purification of carbon nanoparticles was carried out
by agarose gel electrophoresis and glass bead matrices by Xiaoyou et al. Though the fabrication process was
done with a variety of gases, further purification was necessary [93]. Qu and his coworkers prepared N and
S, N doped GQD via hydrothermal synthesis with less toxicity, low cost, and low quantum yield [94].
Compared to the chemical route, the traditional route of synthesis gains more interest from researchers.
For the past years, research in green route synthesis was at its peak due to its magnificent properties like
renewability, less toxicity, easy synthesis procedures, biocompatibility, large-scale synthesis, and low cost.
Developing green carbon dots with various optical, physiochemical, and tunable properties makes it a
better tool than the chemical route.

17
5.2.3 Green route Synthesis of Carbon dots

The chemical products are designed, manufactured, and applied according to green chemistry principles to
minimize or eliminate the use of hazardous materials, including toxic substances, etc. The products are
designed from renewable feedstock, with less energy consumption that can be produced on a large scale.
Carbon dots are one of those materials that are non-toxic and chemically stable. The most commonly used
synthesis method is hydrothermal, which requires high-pressure autoclave vessels and is highly time-
consuming. Rather than the hydrothermal method, the one-pot synthesis method can be used to minimize
consumption time and high pressure [95]. The advantages of the green route of synthesis are given in Fig.5.

Figure 5. Properties of Green route synthesis

Biosensors have versatile applications in the biomedical field. Quantum dots have been explored with
biosensing applications and have also attracted Nobel prizes this year (2023). This review emphasizes the
different advances in biosensors and their applications. There are various categories of quantum dots, and
with their magnificent properties of fluorescence emission based on their size have been explored to detect
many diseases and nano cargos for drug delivery. Their inherent fluorescent properties allow them to be
visualized under the fluorescent microscope or in vivo in a live animal imaging system. We can do live
tracking of the quantum dot carrying the drug and understand the fate of the drug in a living system. Even
the bare carbon dots have been used for multimodal imaging [9], which is a leap forward that is
advantageous to the chemical-based contrast agents.

6. Conclusions

The basics allow us to discover, organize, and improve the sustained life of humankind. In this review, we
have discussed the fundamentals and origin of biosensors. There are several classifications of biosensors,
and here we have briefly reviewed the classifications based on the detection methods. The biosensors like

18
electrochemical, optical, acoustic, and thermal have also been summarized, and the luminescence
principles were discussed more elaborately. A class of electrochemical biosensors and optical biosensors
was elucidated in brief. Following the classification of biosensors, the role of nanomaterial-based
biosensors and their types was also discussed. Since these nanomaterials are widely used for various
applications, we have intended explicitly to focus on metal and metal oxide-based nanoparticles and their
production process. A glimpse of the synthesis method is also mentioned. This review provides the
foundations of biosensors and their classes for sensing platforms that increase the knowledge and progress
of discovering new biosensors.

Acknowledgements: We are grateful to Chettinad Academy of Research and Education for providing the
infrastructure. D.J.M. acknowledge Chettinad Academy of Research and Education for providing the PhD
fellowship.

Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

Author's contribution

Conceptualization, writing review and editing, supervision: D.J.M., K.G., A.G.; data curation writing original
draft: K.G., A.G., D.J.M. All authors have read and agreed to the published version of the manuscript.

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Author's contribution

Conceptualization, writing review and editing, supervision: D.J.M., K.G., A.G.; data curation writing original
draft: K.G., A.G., D.J.M. All authors have read and agreed to the published version of the manuscript.

29