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Aspects of nano-enabling biosensing systems for intelligent healthcare; towards

COVID-19 management

Mubarak A. Mujawar, Hardik Gohel, Sheetal Kaushik Bhardwaj, Sesha Srinivasan,

Nicolerta Hickman, Ajeet Kaushik

PII: S2468-5194(20)30066-5
DOI: https://doi.org/10.1016/j.mtchem.2020.100306
Reference: MTCHEM 100306

To appear in: Materials Today Chemistry

Received Date: 11 May 2020

Revised Date: 28 May 2020
Accepted Date: 30 May 2020

Please cite this article as: M.A. Mujawar, H. Gohel, S.K. Bhardwaj, S. Srinivasan, N. Hickman, A.
Kaushik, Aspects of nano-enabling biosensing systems for intelligent healthcare; towards COVID-19
management, Materials Today Chemistry, https://doi.org/10.1016/j.mtchem.2020.100306.

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 Aspects of nano-enabling biosensing systems for intelligent healthcare;
towards COVID-19 management
Mubarak A. Mujawara#, Hardik Gohelb#, Sheetal Kaushik Bhardwajc, Sesha Srinivasand,
Nicolerta Hickmand, Ajeet Kaushikd*
a
Department of Electrical and Computer Engineering, College of Engineering and Computing,
Florida International University, Miami, FL 33174 USA
b
Department of Computer Science, School of Art and Sciences, University of Houston, Victoria,
TX, USA
c
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098
XH, Amsterdam (The Netherlands)
d
NnaoBioTech Laboratory, Department of Natural Sciences, Division of Sciences, Art, & Mathematics,
Florida Polytechnic University, Lakeland, FL 33805, USA

# Authors contributed equally

Corresponding Author Email: [email protected]

Abstract: Biosensors are emerging as efficient (sensitive and selective) and affordable analytical
diagnostic tools for early-stage disease detection, as required for personalized health wellness
management. Low-level detection of a targeted disease biomarker (pM level) has emerged
extremely useful to evaluate the progression of disease under therapy. Such collected
bioinformatics and its multi-aspects-oriented analytics is in demand to explore the
effectiveness of prescribed treatment, optimize therapy, and correlate biomarker level with
disease pathogenesis. Owing to nanotechnology-enabled advancements in sensing unit
fabrication, device integration, interfacing, packaging, and sensing performance at point-of-care
(POC) made diagnostics according to the requirements of disease management and patient
disease profile i.e., in a personalized manner. Efforts are continuously being made to promote
state of art biosensing technology as a next-generation non-invasive disease diagnostics
methodology. Keeping this in view, this progressive opinion article describes personalized
health care management related analytical tools which provide access to better health for
everyone, overall to manage healthy tomorrow timely. Considering accomplishments and
predictions, such affordable intelligent diagnostics tools are urgently required to manage
COVID-19 pandemic, a life-threatening respiratory infectious disease, where a rapid, selective
and sensitive detection of human beta severe acute respiratory system coronavirus (SARS-
COoV-2) protein is the key factor.

Keywords: Biosensors, nano-sensors, BioMEMS, smart diagnostics, point-of-care systems,

disease management, personalized health care, COVID-19 diagnostics.

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1. Emergence of nanotechnology-enabled biosensor-based diagnostics

Since the discovery of biosensors, efforts are continuously being made for translating a
demonstrated and optimized sensing prototype to an analytical diagnostics tool [1-3] for clinical
applications. Considering technological advancements and constant demand raised by experts,
the biosensor market is predicted to be reaching up to 28 Billion USD with a compound annual
growth rate (CAGR) of 8.4% by the year 2022 [4], as illustrated in Figure 1A. For developing a
biosensor of tunable salient features, all the aspects of nanoscience and nanotechnology have
been introduced in the fabrication of next-generation systems that involve functionalized
nanostructures, thin films, biocompatible functionalized materials, miniaturized transducers,
introduction of microfluidic manifolds, device packaging, etc. (Figure 1 B, C, & D) [1,2].

A surface-enhanced Raman scattering (SERS) phenomena based selective and sensitive

geno-sensing of specific neuro biomarker/cDNA (TuJ1) using graphene−Au hybrid nanoarray
was investigated, as illustrated in Fig. 1B. In this research, Raman active dye-labelled probe DNA
oligonucleotide were conjugated onto the graphene-Au nanoarray which participate in the
enhancement of chemical and electromagnetic mechanism (EM) for SERS based biosensing. The
plasmonic Au nanostructures participate in the amplification of Raman signal via
electromagnetic mechanism whereas graphene simultaneously enhances the signal via
chemical mechanism which brings into line the energy level of graphene oxide with the
targeted analyte. Such developed efficient hybrid SERS nanoarray system could be useful to
explore the cellular phenomena (stem cell differentiation, disease evolution etc.) [5]. A concept
of Internet of Bio-Nano Things (IoBNT) was proposed by Akyildiz et al. for investigating
nanoscale devices (Fig. 1C) to perform intra body sensing, environmental control for toxic
substances and the pollution. The IoBNT is capable to transfer health informatics from inside
the body to the external health provider via internet which has potential to evaluate drug
delivery and efficacy. Further, electronic artificial tattoos are being designed for bio-cyber
interface. In this direction, the biocyber interface is a set of process to translate biochemical
information of IoBNT to the internet cyber domain via electromagnetic communications and
vice versa as portrayed (Fig. 1C). Artificial cells are another successful nanotechnology tool
applied for gene therapy, drug delivery, and artificial blood cell production. Therefore, IoBNT is
a new technology which could be potentially explored for various health related issues [6]. A 3D
analytical biosensing platform based on thread was fabricated by Mostafalu et al. (Fig. 1D).
These threads acted 3D microfluidic channels for sensors and electronics needed for health
monitoring. This group developed combination of physical and chemical sensors integrated
within the microfluidic network. The microfluidic platform was developed via hydrophilic
threads decorated onto the hydrophobic fabric (as illustrated in Fig. 1 C). The treads serve as
microfluidic channel for the controlled delivery of body fluids to the sensing platform.
Nanomaterial based conductive threads were used as electrodes for measurements of pH,
temperature, glucose and strain. The output of the sensing platform was connected to
electronic readout for wireless communication and signal processing to a smart phone or
computers. These thread-based devices could be used as implantable devices in the body for
health monitoring [7].

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 Most importantly, cost-effective, miniaturized, easy to operate sensing devices are
getting considerable attention in academia, laboratories, and industries to promote smart
(highly sensitive and selective) biosensors as smart (keeping desired and physiological range in
view) diagnostic systems [3-7].

Figure 1. A) Biosensor market analysis in the USA. This prediction is based on the various
applications and types of biosensors [4]. B) smart ultrathin graphene layer fabricated on Au
substrate integrated with Raman spectrophotometer for genetic (RNA, extracted from stem
cell) materials detection [5]. C) Exploring artificial cells for the nano-bio interface-based
networking. This approach of nanosensor development is an optimized combination and
interfacing of artificial cells, nano-transmitter, bio-cyber interface, and electronic tattoo [6]. D)
presentation of a transdermal health monitoring toolkit fabricated using thread-based chemical
and physical sensors, microfluidic channels, and interconnects for the realization of a thread-
based diagnostic device [7].

As of now, developed sensing products, either wearable or non-wearable biosensors,

based on electrochemical, optical, thermal and piezoelectric transduction technology, have
shown remarkable performance, especially in the testing of blood glucose, cholesterol,
triglycerides, pregnancy testing, infectious diseases, drug discovery, blood gas analysis, etc. [8-
11]. Despite significant progress, efforts are being continuously made to improve the state of
art sensing technology using more efficient and updated technologies to achieve sensing at a

3
low level, especially picomolar (pM) level. However, the need for detecting a targeted
biomarker at femtomolar (fM) is also emerging for infectious diseases management which
raised the scope to develop smart biosensor i.e., more sensitive and selective. It has been
reported that smart bio-sensing materials (selected to immobilized bio-active compounds
involve enzyme, DNA, RNA, and antibody), based biosensing prototype chip integrated with a
miniaturized potentiostat (M-P) fabricated using micro/nanoelectronics) is getting attention for
performing diagnostics at POC applications (Figure 2). Further, the interfacing M-P with a
smartphone to operate M-P and to manage data for data storage and timely informatics
analysis is commonly used practice to develop a biosensor of high performance and reliability
[19,20].

Figure 2. The potential application of POC testing. An optimized smart POC diagnostics tool can
detect the desired biomarker. Such of informatics can be analyzed for personalized health
wellness.

2. Towards Point-of-care diagnostics for personalized health wellness

Modern material science has facilitated the preparation and fabrication of nano-enabled
smart sensing substrates (Figure 1B) such as biopolymers, conducting polymers, metal oxides,
gold, carbon nanotubes, graphene, quantum dots, composites, and hybrids [21, 22]. The need
to achieve high loading of biomolecules to achieve wide detection range and signal
amplification to achieve sensing at a low level of biomarker raised the demand of exploring
novel electro-active surface-functionalized nanostructures (Figure 1C). Such nano-systems have

4
also been successfully fabricated onto interdigitated microelectrodes (IDµE) for the
development of a biosensor which can detect targeted biomarkers at a very low level (pM and
fM). Such a low-level detection limit of a biosensor is very important to detect a disease-specific
biomarker at an early stage i.e. onset of disease and to monitor a disease's progression under a
prescribed therapy. Such of biosensors are recommended for the management of the diseases
of infectious diseases causes by virus e.g., Zika and Ebola outbreak. In those diseases, the virus
replicates in low concertation which is not detectable using polymerase chain reaction (PCR)
and enzyme-linked immunosorbent assay (ELISA) but nano-enabled IDµE based biosensors are
efficient to perform this task. This approach is also highly recommended to manage several
other diseases (such as cancers and stress) along with environmental, agriculture, and food
security-related aspects. More towards advancements sides, the IDµE-based bio-sensing chips
are being integrated with M-P to promote bio-sensing applications from laboratory to field [4].
This micro/nano electronics-based approach is useful to design and develop portable
biosensors of reduced form factors which is the foundation of diagnostics at POC application
(Figure 2) to perform personalized diagnostics [3,8, 23-25].

Biosensors facilitate rapid sensing of a targeted biomarker, thereby it is possible to carry

out the biomarker detection (or diseases diagnostics) multiple times in a day or a real-time
manner. These features project such biosensors to generate enough of bioinformatics to
understand the symptom variation and optimize timely therapeutics. Another sensing approach
that is being explored to manage disease diagnostics in a real-time manner is MEMS/BioMEMS
based bio-sensing. BioMEMS bio-sensing devices based on the pressure sensor, accelerometer,
microfluidics, microphones, and ultrasonic sensors are in demand for health management due
to automated handling and precise measurement (Figure 1D). Due to the involvement of major
players like Google, Apple, Amazon, etc., and the proven multiple benefits, the market business
of BioMEMS based sensing devices will be around 6.9 Billion USD in 2023 with CAGR of 14.9%
from 2017 to 2023, as proposed by Yole Development Inc [4]. However, a well-recommended
focus towards exploring novel sensing methodologies such as capacitive/piezoelectric
ultrasound detection, a cellphone mobile-based health care wherein smartphone enables easy
operation and data recording, and internet of medical things (IoMT) [26, 27] for efficient data
analysis and data sharing have been suggested by experts as E (electronics) - health to I
(intelligent) – health [28]. The E-health includes smartphone-assisted sensing and personalized
electronics for rapid bio-informatics collection along with real-time patient care monitoring,
diagnostics at certain internal, and self-aware based diagnostics performance. In this era, the
smartphone is very common electronic people keep this most of the time everywhere. This
common practice can be useful to design a well-planned diagnostics or bio-informatics
collection, where the differences of ecology, race, gender, age, etc., are important points of
consideration to manage a targeted disease. Such of the intelligent use of electronic devices-
based diagnostics in medical practice refers as I-health [29].

5
Figure 3. A) Schematic illustration of SAM/IDE-based electrochemical cortisol immuno-sensor
interfaced with a M-P and microfluidic system for cortisol detection at for POC application [20],
B) fabrication of IDE-based electrochemical Zika immunosensor and its integration with a
smartphone to perform POC diagnostics[19], C) chip-based electrochemical system to monitor
cell electro-physiology of human astrocyte cell on HIV infection in setting with drug abuse
(cocaine), with/without FDA recommended drug [23].

On applying fundamental of nano-biosensor technology, our research has also proposed

development of smart miniaturized biosensing platform to detect a targeted biomarker such as
Ebola, beta-amyloid, cortisol, and Zika-virus protein at low level (10 pM) needed to establish
methodologies of rapid diagnostics at early-stage and disease progression monitoring
with/without therapy [1-3, 12-21]. These salient features enable diseases diagnostics and per
requirement and generate bioinformatics to decide therapy timely and establishing a
correlation between diseases progression and pathogenesis. Our established sensing
prototypes are suitable for POC application [1-3, 12, 17]. For example, we have fabricated an
electrochemical biosensor using IDEs modified using an appropriate self-assembled monolayer
(SAM) to detect cortisol [15-16], a psychological stress biomarker at 10 pM within 40 minutes
(Fig. 3A). The SAM based biosensor was tested using saliva collected from farmworker and
plasma of HIV infected patients, and sensing outcomes were validated using ELISA [16]. This
miniaturized IDE based cortisol immune-sensor was integrated with a microfluidic manifold for

6
automated sampling of 10 µL and customized M-P (LMP 9100, Texas instrumentation) for
fabricating a potable cortisol biosensor. As planned this fabricated sensing device was very
useful to perform cortisol sensing at POC [20]. As Zika-virus infection declared as international
health emergency due its association with microcephaly, a significant attention was made to
develop miniaturized electrochemical biosensors to detect zika-virus protein at very low level to
achieve early stage diagnostics [3,19]. To achieve this task, Kaushik et al developed an
electrochemical zika virus immunosensor (Fig. 3B) using a SAM functionalized IDEs to detect
envelop virus protein at 10 pM selectively (in comparison of dengue and malaria). Such Zika
sensor was interfaced with a M-P which can be operated using a smartphone to perform POC
diagnostics and easy data management. The integration of IDE based efficient sensor with
smartphone make user friendly (easy to use) and performance according to the need of clinical
such as rapid sharing and analytics [19]. In order to explore smart electro-active sensing
platforms, our groups explored the alternated of ELISA, needed to evaluate diseases
progression and efficacy of a therapy. In this research, a chip based electrochemical system was
developed to monitor electrophysiology of targeted cells infected with HIV in setting of drug
abuse (cocaine) and therapies (Fig. 3C) [23]. It was observed that on infection and treatment
selected cell types goes under a distinctive electro-physiology changed which can be monitored
using a sensitive electrochemical chip-based technology. Outcomes of this research confirmed
that such chip-based sensing system are suitable for rapid to diagnose HIV-infection, monitor
efficacy of a therapy, and rapid optimization of a suitable therapy. These affordable and
sensitive sensing systems are easy to fabricate and optimize and emerging as an alternate of
ELISA and PCR for managing HIV diseases in personalized manner [23].

Wearable electronic micro-sensors are considered as the first generation of smart

sensing (the year 2000) [30]. Later, numerous papers and flexible substrate-based sensor
prototypes were developed to fabricate efficient wearable biosensors. The interfacial electrical
and optical properties of material-targeted biological compounds have been leveraged to
develop wireless sensing systems [22, 31]. Due to this feature, it is possible to monitor health
variation in a real-time manner. Such sensing systems are second-generation (Year from 2010
to 2014) of biosensors which facilitate miniaturization of integrated circuits and low power
consumption [32]. The current era, as the third generation of the biosensor, is of non-invasive
biosensors (2017 to 2020) i.e., nanosensor [33]. This generation is emerging with significant
advancements in self-powered electronics, bioelectronics, stretchable electronics, and flexible
and body compatible materials.

3. Artificial intelligent supported POC diagnostics for intelligent healthcare

Innovations in biomedical devices are continuously making health care delivery easy,
timely, affordable, manageable, and user friendly. As an outcome, the investigation and
introduction of new non-invasive approaches of reduced form factor features have made health
monitoring more personalized. However, the right analysis of generated bio-informatics has
raised the demand for smart deep learning towards artifical intelligence (AI), an approach to
mimic human condition by a computer, which can analyze the data efficiently by considering
demands and potential challenges in mind. This huge data analysis and data management is

7
needed to understand targeted diseases/symptoms monitoring, correlation of targeted
biomarker level with disease variation, efficacy monitoring, and disease management. To
categorize data concerning health parameter preferences, a new tool that can digitalize
diagnostics systemically for a patient profile is urgently in demand. This can be completely
manageable if the IoT methodology associates with the AI-based approach. The IoT approach is
capable of digitalizing every possible information intelligently by using the cyber-physical smart
passive framework. This feature can filter bio-informatics analysis using AI to optimize the
parameter according to the patient profile. Such an AI-assisted IoT based bio-informatics is very
crucial to manage targeted diseases in a personalized manner.

At present, system development is emerging as a key factor for developing an efficient

diagnostics device of reduced form factor and capable to perform at POC applications (Figure
2). This has raised the demand for exploring internet of medical things (IoMT), a hardware-
based approach involving a smartphone [34]. Although both IoT and IoMT have a lot of
similarities but the connecting devices for biomedical application in the health care industry is
growing under IoMT. Recently, the IoMT is emerging rapidly in biomedical research because of
rapid data sharing and analysis. It has been predicted that AI-IoMT assisted diagnostic will be a
focus to develop the next generation of bio-sensing systems [27-29, 35]. Such systems are
predicted more reliable due to easy calibration because of portability, as a well-packaged
miniaturized sensing technology. Future biosensors will enable patient care at home in a real-
time manner and will provide diagnostics information to clinicians/health experts to know
about disease progression and medication. To achieve such claims and tasks, a systematic step-
by-step approach is recommended by experts as illustrated in Figure 4.

Figure 4. Illustration of a systematic approach to developing an efficient and affordable

biosensor for clinical and POC applications.

Despite recent developments in biosensing systems, several challenges such as

affordability, sensitivity, portability, stability, compatibility with bio-active molecules, etc., are
yet to be overcome to achieve disease diagnostics at home, POC or both. Developing novel

8
electro-active biomaterials (especially biopolymer such as chitosan, scaffolds, etc.) exhibiting
absolute immune compatibility and desired interfacing with the human body will be one of the
major concerns in sensor development. The investigation of M-P operated by a smartphone will
also be a key component to achieve diagnostics at POC required for disease management at the
epidemic site in a real-time manner. Bio-sensing based on MEMS seems to be a game-changing
approach to investigate nano-toxicity aspects of nanomaterials, cell physiology on the exposure
of external factors for example inhalation of pollutants particles, viruses, transmitted diseases,
etc. Such sensors which are based on advanced chip technology will be very useful to optimize a
dose of various nanoparticle selected for biomedical applications, evaluate drug efficacy, and
therapy efficacy assessment [36-39]. The outcomes of such of sensing strategy will provide
desired informatics to optimize a product to everyday use and drug/vaccine therapy to provide
better treatment, as illustrated in Figure 5.

4. Viewpoint and suggested approaches for intelligent healthcare

In today's world, where time is precious, people, the working class especially, spend
most of the day shuttling between various tasks and tend to ignore their health and fitness.
Even a simple appointment with a doctor in a clinic can require several tests set for diagnosis,
prescription, and finally treatment, which can take a lot of time [40]. Therefore, many patients
only go to a clinic when they are suffering from a serious illness. Hence, many people are
seeking an alternative, such as a device that can be worn on the body, which would not only
continuously monitor the user's health in real-time but also provide timely insights on various
health parameters to the user as well as his or her physician. Rural health care [41] is one of the
biggest challenges in the world, especially in developing countries where over 55% of people
live in rural areas [42]. Thus, the Internet of Things is considered very useful. Data Transfer and
Automation (IoT) is the fastest growing technology [43, 44] using the Internet of Things. This
includes sensors, cyber systems - IoT, and cloud computing [45]. Web systems collaborate at
every stage of the web to reach the right people in real-time. In rural areas, the patient must
take the medication on time. The IoT can be very useful for those who suffer from the disease
[46]. Keeping this in view, IoT users are also focusing on some authentication improvements.
The IoT is a device that connects multiple devices locally, including electronics, software,
sensors, actuators, and networks [47]. Various applications of the IoT include smart healthcare,
smart cities, automation in industries, agriculture, and transportation decision making [48].
They convert the radiofrequency energy emitted by the reader device into a few feet
transmitted signals. Given the huge shortage of trained manpower and the high cost of setting
up government facilities, it is often impossible to provide proper health care services in rural
and remote areas [49].

However, IoT is considered viable [50]. Living as healthy people can lead to economic
growth and they are more productive thus, the country grows. Many health monitoring systems
have been developed over the years to improve the quality of life by providing better health
[51]. The Internet has become an important part of our daily lives. The whole concept of IoT
enables users to communicate and access information about sensors, gateways, and wireless
networks [52]. The Internet of Things has a role to play in improving quality of life [53]. It is an

9
ever-growing network of smart objects connected using the internet. It can be used to diagnose
the disease at home and take appropriate medication [54]. The overview of the healthcare
monitoring system is depicted in the below block diagram.

Figure 5. Illustration of next-generation biosensor-based diagnostics approach for personalized

health wellness.

As illustrated in Figure 6, IoT wearable devices and AI-based healthcare monitoring

systems elaborated. Patients' vital parameters such as Heartbeat and the temperature is
continuously monitored via medical sensors and periodically stored in cloud service. The system
collects real-time data from the patients and delivers an updated patients’ status to the medical
professionals and the caretakers using a wireless sensing network (WSN). This autonomous
system replaced the traditional method to collect the parameters regularly by the nurse. It
avoids human errors in collecting the patients' data manually. Data transfer protocol helps to
transfer the messages. The observed vital signs of the patients are analyzed and checked
against the standard range to detect the abnormal condition of the patients.

10
Figure 6: Deception of IoT wearable devices and AI-based healthcare monitoring system

The IoT wearable devices and AI-based healthcare monitoring system incorporates IoT Edge
and AI technologies to provide predictive capabilities. The IoT Edge technology provides a way
to package and deploy AI models on the cloud or at the edge itself which reduce tremendous
computational power. The healthcare data collection and storage can be done by the smart
biosensors discussed in the earlier sections of the paper. After data collection completes, AI
infrastructure needs to design and develop AI models which includes machine learning and
deep learning algorithm development and enhancement. Once AI models will be ready for the
deployment, there are two possible ways to deploy it. First, deploy AI model at IoT device or
wearable device and another is to deploy it on IoT edge gate way. The deployment scenario as
shown in Figure 7, a machine learning, deep learning or AI model will be used for deployment at
the edge of IoT. It can be done using IoT function container to the data of process retrieved
from IoT wearable devices in real time processing. The appropriate action will be taken only
after AI model predict anomalies on the streaming data and generate proper actions.

Figure 7: AI model deployment on IoT edge gateway

There is also a possibility of AI model deployment at IoT device or wearable device. In that
cases, all real-time data processing will be done at the microcontroller level and anomalies will
be identified at the wearable device to take appropriate actions based on real-time prediction.
There are multiple benefits of proposed AI model deployment on IoT edge and wearable
devices. It monitors patient health indicators in real time. It provides secure transmission of
data collected by the wearable devices to the cloud. It’s also analyzed patient data to prompt
urgent actions and provide long-term healthcare guidance with timely emergency notifications.
At last, it also provides potential for analysis of aggregated patient data to identify health risk
patterns across a population.

5. Intelligent Diagnostics for COVID-19 management.

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A life-threatening respiratory infectious disease known as COVID-19, associated with novel RNA
envelope human beta severe acute respiratory syndrome (SARS-CoV-2) virus, strike China in
late December 30, 2019. This new infectious disease has affected over 5 million people around
globe (30 % them belong to the United States of America) and continuing to grow because of
easy human to human transmission, no effective of therapeutics, and lacking effective
diagnostics systems. Health agencies monitored COVID-19 epidemic sincerely and latter
declared it as a pandemic and alert every country to plane joint efforts to combat against this
international health emergency. Every country pain serious attention to develop regulatory
guidelines, therapies, and diagnostics systems to manage COVID-19 pandemic. But the variation
in categories and strains of SARS-CoV-2 virus projected developing high efficacy therapy as an
unpredictive and long-term goal [55-57].

This obstacle turned the attention of experts to think about management COVID-19 infectious
diseases which bring the need of investigating efficient sensor to detect SARS-CoV-2 selectively
and timely as an urgent focus. As demonstrated, SARS-CoV-2 spreads through person-to-person
which raised to demand of using precautions like mask [58] and investigating diagnostics at POC
without need of labor extensive sophisticated laboratories. To achieve desired diagnostics, we
suggested that an optimized compartmentalization approach, as discussed above, could be the
best way fabricate a nano-enable miniaturized biosensor for SARS-CoV-2 virus protein detection
at site of epidemic [57].

Such of desired SARS-CoV-2 sensing supported by AI and IoT is emerging a key factor to manage
COVID-19 pandemic management. The need of developing such smart sensing system to
COVID-19 pandemic because of asymptomatic carries and hospital discharges patient again got
SARS-CoV-2 virus infection. These challenges demand the real-time SARS-CoV-2 detection and
tracing to population [59,60]. If such intelligent system implemented, then smart management
of COVID-19 pandemic can be achieved successfully (Fig. 8) due to advantages as follows.

• A miniaturized IDE-based SASR-CoV-2 biosensor can be fabricated via selecting specific

Anti-SASR-CoV-2 virus protein antibody for selective and sensitive detection within 30-
40 minutes of operation time.
• Such biosensor can be transformed to develop POC analytical devices to perform SASR-
CoV-2 at POC needed to manage COVID-19 in personalized manner.
• Such SASR-CoV-2 detection will generate bioinformatic to understand the diseases
progression, efficacy of therapy, optimization of a good therapy, and correlating
between SASR-CoV-2 level and pathogenesis.
• MEMS based can designed to evaluate the efficacy of a new drug prior to test using
animal model.
• Introduction of IoT in SASR-CoV-2 biosensing may be useful to develop wireless system
for POC diagnostics.
• AI supported POC diagnostics of COVID-19 will be emerged as breakthrough in big data
analytics needed explore.

12
• An optimized combination of nano-enabled SASR-CoV-2 biosensing, IoT and AI will be a
perfect platform to manage COVID-19 pandemic intelligently without errors at
personalized level.
• Tunable features and programmable operation will be useful to manage COVOD-19
diagnostics after considering variabilities associated with population, race, gender, and
medical history.
• AI-supported algorithm will be useful to optimize a therapy among available drugs,
vaccines, and combinations,
• AI-supported analytic can direct expert to plan for targeted testing or where the
attention is most required i.e., high risk areas.
• AI-assisted big data analytics will be useful to predict the need and understanding of
social/physical distancing.
• AI and IoT supported COVID-19 management strategy is acceptable to evaluate the risk
factors, tracing of population, and suggesting option, which are the primary
requirement of every county to remove lock down and open business, mainly
universities.
• AI and IoT assisted approach will be useful to assess the needs of an individual is there is
a factor of neurobehavior alteration and safe work practice.
• AI and IoT supported POC diagnostics can manage COVID-19 pandemic in personalized
manner.
• Technology supported intelligent healthcare will be driving force to trace and eradicate
COVID-19 pandemic.

13
Figure 8. A) Biological structures of SARS-CoV-2 virus protein [57], B) possibility of human to
human transmission and it possibility to avoid spreading using a mask [58], C) Nano-enabled
sensing supported by AI and IoT for smart diagnostics of COVID-19, an approach toward
personalized COVID-19 management.

6. Viewpoint
As summary, this opinion article explores the state of art bio-sensing technological
approaches that have been investigated and are being under investigation for disease
diagnostics and management. Keeping capabilities of sensitive and selective diagnostics at POC,
the future bio-sensor market projection suggested developments, and related challenges with a
viewpoint are also described. This report is oriented as a call to experts for developing
advanced analytical bio-sensing devices for disease diagnostics needed for personalized health
care and wellness at home and POC. As future research, it is strongly recommended to
introduce the concept of miniaturization in biosensors to explore required for POC application.
Further, the operation of POC biosensors using a smartphone for useful bio-informatics analysis
supported by AI and IoMT (for data storage, sharing, and security) for rapid and essential
diagnostics emerged very usefully for timely therapy optimization and personalized diseases
diagnostics. This report is a request for investigating AI and IoT supported SARS-CoV-2
detection selectively at low level desired for early-stage COVID-19 diagnostics at POC to
manage pandemic successfully, in personalized manner.

Acknowledgment: Authors acknowledges respective institutions and department for providing

facilities and support. AK acknowledges a research grant (GR-2000024) funded by Florida
Polytechnic University, Lakeland, FL, USA.

Conflict of Interest: The authors declare no conflict of interest.

References:

1. A. Kaushik, M. Mujawar, Point of Care Sensing Devices: Better Care for Everyone. Sensors 18,
(2018) 4303.
2. A. Kaushik, S. Tiwari, R.D. Jayant, A. Marty, M. Nair,Towards detection and diagnosis of Ebola
virus disease at point-of-care. Biosensors and Bioelectronics 75 (2016), 254-272.
3. A. Kaushik, S. Tiwari, R.D. Jayant, A. Vashist, R. Nikkhah-Moshaie, N. El-Hage, N. Nair,
Electrochemical biosensors for early stage Zika diagnostics. Trends in biotechnology 35 (2017),
308-317 (2017).
4. J. Mouly, S. Clerc, A, Siari, BioMEMS & Non-Invasive sensors: microsystems for Life Sciences &
Healthcare 2018 Report, division at Yole Développement (Yole). https://www.i-
micronews.com/products/biomems-non-invasive-sensors-microsystems-for-life-sciences-
healthcare-2018/
5. L. Yang, J.H. Lee, C. Rathnam, Y. Hou, J.W. Choi, K/B. Lee, Dual-Enhanced Raman Scattering-
Based Characterization of Stem Cell Differentiation Using Graphene-Plasmonic Hybrid
Nanoarray. Nano letters, 19(2019), 8138-8148.

14
6. I.F. Akyildiz, M. Pierobon, S. Balasubramaniam, Y. Koucheryavy, The internet of bio-nano things.
IEEE Communications Magazine, 53(2015), 32-40.
7. P. Mostafalu, M. Akbari, K.A. Alberti, Q. Xu, A. Khademhosseini, S.R. Sonkusale, A toolkit of
thread-based microfluidics, sensors, and electronics for 3D tissue embedding for medical
diagnostics. Microsystems & Nanoengineering, 2 (2016),16039.
8. A.K Kaushik, C.K. Dixit, Nanobiotechnology for Sensing Applications: From Lab to Field. (Apple
Academic Press, 2016).
9. S.K. Bhardwaj, P. Yadav, S. Ghosh, T. Basu, A.K. Mahapatro, Biosensing Test-Bed Using
Electrochemically Deposited Reduced Graphene Oxide. ACS Appl. Mater. Interfaces 8 (2016),
24350–24360. .
10. S.K. Bhardwaj, T. Basu, Study on Binding Phenomenon of Lipase Enzyme with Tributyrin on the
Surface of Graphene Oxide Array Using Surface Plasmon Resonance. Thin Solid Films 645 (2018),
10–18.
11. S.K. Bhardwaj, R. Chauhan, P. Yadav, S. Ghosh, T. Basu, A.K. Mahapatro, Bi-Enzyme
Functionalized Electro-Chemically Reduced Transparent Graphene Oxide Platform for
Triglyceride Detection. Biomater. Sci. 7 (2019), 1598–1606.
12. A. Kaushik, A. Vasudev, S.K. Arya, S.K., Pasha, S. Bhansali, Recent advances in cortisol sensing
technologies for point-of-care application. Biosensors and Bioelectronics, 53 (2014), 499-512.
13. A. Kaushik, A. Vasudev, S.K. Arya, Pasha, S. Bhansali, Mediator and label free estimation of stress
biomarker using electrophoretically deposited Ag@ AgO–polyaniline hybrid nanocomposite.
Biosensors and Bioelectronics, 50 (2013) 35-41.
14. P.K. Vabbina, A. Kaushik, N. Pokhrel, S. Bhansali, N. Pala, Electrochemical cortisol
immunosensors based on sonochemically synthesized zinc oxide 1D nanorods and 2D
nanoflakes. Biosensors and Bioelectronics, 63 (2015) 124-130.
15. A. Vasudev, A. Kaushik, Y. Tomizawa, N. Norena, S. Bhansali, An LTCC-based microfluidic system
for label-free, electrochemical detection of cortisol. Sensors and Actuators B: Chemical, 182
(2013), 139-146.
16. A. Kaushik, A. Yndart, R.D. Jayant, V. Sagar, V. Atluri, S. Bhansali, M. Nair, Electrochemical
sensing method for point-of-care cortisol detection in human immunodeficiency virus-infected
patients. International Journal of Nanomedicine, 10 (2005), 677.
17. A. Kaushik, R.D. Jayant, S. Tiwari, A. Vashist, M. Nair, Nano-biosensors to detect beta-amyloid for
Alzheimer's disease management. Biosensors and bioelectronics, 80 (2016), 273-287.
18. A. Kaushik, P. Shah, P.K. Vabbina, R.D. Jayant, S. Tiwari, A. Vashist, A. Yndart, M. Nair, A label-
free electrochemical immunosensor for beta-amyloid detection. Analytical Methods, 8 (2016),
6115-6120.
19. A. Kaushik, A. Yndart, S. Kumar, R.D. Jayant, A. Vashist, A.N. Brown, C.J. Li, M. Nair, A sensitive
electrochemical immunosensor for label-free detection of Zika-virus protein. Scientific Reports 8
(2018), 9700.
20. A.F.D. Cruz, N. Norena, A. Kaushik, S. Bhansali, A low-cost miniaturized potentiostat for point-of-
care diagnosis. Biosensors and Bioelectronics 62 (2014), 249-254.
21. V. Bhardwaj, A. Kaushik, Biomedical Applications of Nanotechnology and Nanomaterials.
Micromachines 8 (2017) 298.
22. P.R. Solanki, A, Kaushik, V.V. Agrawal, B.D. Malhotra, Nanostructured metal oxide-based
biosensors. NPG Asia Materials 3, (2011) 17.
23. A. Kaushik, P.K. Vabbina, V. Atluri, P. Shah, A. Vashist, R.D. Jayant, A. Yandart, A. and M. Nair,
Electrochemical monitoring-on-chip (E-MoC) of HIV-infection in presence of cocaine and
therapeutics. Biosensors and Bioelectronics 86, 426-431 (2016).

15
24. P.Shah, A. Kaushik, X. Zhu, C. Zhang, C. C.-Z. Li, Chip based single cell analysis for nanotoxicity
assessment. Analyst 139 (2014), 2088-2098.
25. C. Dixit, A. Kaushik, Microfluidics for biologists. Berlin, Germany:: Springer; 2016.
26. D.V. Dimitrov, Medical internet of things and big data in healthcare. Healthcare informatics
research 22 (2016) 156-163.
27. J. Gubbi, R. Buyya, S. Marusic, M. Palaniswami, Internet of Things (IoT): A vision, architectural
elements, and future directions. Future generation computer systems 29 (2013), 1645-1660.
28. S. Berrouiguet, M.M. Perez-Rodriguez, M. Larsen, E. Baca-García, P. Courtet, M. Oquendo, From
eHealth to iHealth: Transition to participatory and personalized medicine in mental health.
Journal of medical Internet research 20 (2018).
29. S. Yang, P. Zhou, K. Duan, M.S. Hossain, M.F. Alhamid, emHealth: towards emotion health
through depression prediction and intelligent health recommender system." Mobile Networks
and Applications 23 (2018) 216-226.
30. S. Sony, S. Laventure, A.A. Sadhu, A literature review of next-generation smart sensing
technology in structural health monitoring. Structural Control and Health Monitoring, 26 (2019),
e2321.
31. S. Sang, Y. Wang, Q. Feng, Y. Wei, J. Ji, W. Zhang, Progress of new label-free techniques for
biosensors: a review. Critical reviews in biotechnology, 36 (2016), 465-481.
32. J. Polastre, J. Hill, D. Culler, November. Versatile low power media access for wireless sensor
networks. In Proceedings of the 2nd international conference on Embedded networked sensor
systems 2004, 95-107.
33. L. Stoica, R. Ludwig, D. Haltrich, L. Gorton, Third-generation biosensor for lactose based on
newly discovered cellobiose dehydrogenase. Analytical chemistry, 78 (2006), 393-398.
34. J. Song, V. Pandian, M.G. Mauk, H.H. Bau, S. Cherry, L.C. Tisi, C. Liu, Smartphone-based mobile
detection platform for molecular diagnostics and spatiotemporal disease mapping. Analytical
chemistry, 90 (2018), 4823-4831.
35. P. Yager, G.J. Domingo, J. Gerdes, Point-of-care diagnostics for global health. Annual review of
biomedical engineering 10 (2008).
36. S. Kumar, M. Nehra, J. Mehta, N. Dilbaghi, G. Marrazza, A. Kaushik, 2019. Point-of-care
strategies for detection of waterborne pathogens. Sensors, 19 (2019), 4476.
37. A. Kaushik, Biomedical nanotechnology related grand challenges and perspectives. Frontiers in
Nanotechnology 1, (2019).
38. M.A. Ali, L. Dong, J. Dhau, A. Khosla, A. Kaushik, Perspective—Electrochemical Sensors for Soil
Quality Assessment. Journal of The Electrochemical Society, 167 (2020), 037550.
39. R.B. Shinde, M. Veerapandian, P. Manickam, A. Kaushik, State-of-art bio-assay systems and
electrochemical approaches for nanotoxicity assessment. Frontiers in Bioengineering and
Biotechnology, 8 (2020), 325.
40. A.C. Tolga, Real options valuation of an IoT based healthcare device with interval Type-2 fuzzy
numbers. Socio-Economic Planning Sciences. 69 (2019) 100693.
41. H. Gohel, Looking Back at the Evolution of the Internet”, CSI Communications-Knowledge Digest
for IT Community, 38 (2014) 23-26.
42. Y. Xia, H. Zhang, L. Xu, Z. Gao, H. Zhang, H. Liu, S. Li, S. An automatic cardiac arrhythmia
classification system with wearable electrocardiogram, IEEE Access, 6 (2016), 16529-16538.
43. S.W. Park, J. Park, K. Bong, D. Shin, J. Lee, S. Choi, H.J. Yoo, An energy-efficient and scalable deep
learning/inference processor with tetra-parallel MIMD architecture for big data
applications.IEEE transactions on biomedical circuits and systems, 9 (2015), 838-848.
44. H.A. Gohel, Cyber Security and Social Media, CSI Communications – Knowledge Digest for IT
Community, 39 (2015)

16
45. D. Levy, H.A. Gohel, H. Upadhyay, A. Pons and L.E. Lagos, Design of Virtualization Framework to
Detect Cyber Threats in Linux Environment, IEEE 4th International Conference on Cyber Security
and Cloud Computing (CSCloud), New York, NY, (2017), 316-320
46. G. Yang, J. Deng, G. Pang, H. Zhang, J. Li, B. Deng, Z. Pang, J. Xu, M. Jiang, P. Liljeberg, H. Xie, An
IoT-enabled stroke rehabilitation system based on smart wearable armband and machine
learning. IEEE journal of translational engineering in health and medicine, 6 (2008), 1-10.
47. P. De Chazal, M. O'Dwyer, R.B. Reilly, Automatic classification of heartbeats using ECG
morphology and heartbeat interval features. IEEE transactions on biomedical engineering, 51
(2004), 1196-1206.
48. S. Fallmann, L. Chen, Computational Sleep Behavior Analysis: A Survey. IEEE Access, 7 (2019),
142421-142440.
49. A. Krause, A. Smailagic, D.P. Siewiorek, Context-aware mobile computing: Learning context-
dependent personal preferences from a wearable sensor array. IEEE Transactions on Mobile
Computing, 5 (2005), 113-127.
50. F. Ali, S.R. Islam, D. Kwak, P. Khan, N. Ullah, S.J. Yoo, K.S. Kwak, Type-2 fuzzy ontology–aided
recommendation systems for IoT–based healthcare. Computer Communications, 119 (2018),
138-155.
51. D. Ravì, C. Wong, F. Deligianni, M. Berthelot, J. Andreu-Perez, B. Lo, G.Z. Yang, Deep learning for
health informatics. IEEE journal of biomedical and health informatics, 21(2016), 4-21.
52. H. A. Gohel, H. Upadhyay, L. Lagos, K. Cooper, A. Sanzetenea, Predictive Maintenance
Architecture Development for Nuclear Infrastructure using Machine Learning. Nuclear
Engineering and Technology, 2020. https://doi.org/10.1016/j.net.2019.12.029
53. V. Bianchi, M. Bassoli, G. Lombardo, P. Fornacciari, M. Mordonini, I. De Munari, IoT Wearable
Sensor and Deep Learning: An Integrated Approach for Personalized Human Activity Recognition
in a Smart Home Environment. IEEE Internet of Things Journal, 6 (2019), 8553-8562.
54. D. Ravi, C. Wong, B. Lo, G.Z. Yang, Deep learning for human activity recognition: A resource
efficient implementation on low-power devices. In 2016 IEEE 13th international conference on
wearable and implantable body sensor networks (BSN) 2016, 71-76. IEEE.
55. M.A. Shereen, S. Khan, A. Kazmi, N. Bashirand, R. Siddique, COVID-19 infection: origin,
transmission, and characteristics of human coronaviruses. Journal of Advanced
Research, 24 (2020) 91-98,
56. H.A. Rothan, S.N. Byrareddy, The epidemiology and pathogenesis of coronavirus disease
(COVID-19) outbreak. Journal of autoimmunity, 109 (2020) 102433.
57. E. Morales-Narváez, C. Dincer, The impact of biosensing in a pandemic outbreak: COVID-
19. Biosensors and Bioelectronics, 2020, 112274.
58. Kimberly A. Prather1, Chia C. Wang2,3, Robert T. Schooley, Reducing transmission of
SARS-CoV-2, Science, 2020, DOI: 10.1126/science.abc6197
59. B. McCall, COVID-19 and artificial intelligence: protecting health-care workers and
curbing the spread. The Lancet Digital Health, 2(2020) e166-e167.
60. D.S.W. Ting, L. Carin, V. Dzau, T.Y. Wong, Digital technology and COVID-19. Nature
medicine, 26(2020) 459-461.

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Highlights

• Investigating efficient and effective novel diagnostic biosensor is in demand

• These miniaturized nano-enabled sensors are suitable for POC diagnostics
• Smartphone assisted POC diagnostics is making personalized diagnostics possible
• AI is managing bioinformatics and big data analytics to optimize personalized wellness
• AI supported IoT-based diagnostics is emerging for targeted disease management
• AI and IoT assisted POC diagnostics are needed for COVID-19 pandemic management
Declaration of Competing Interest

There are no conflicts of interest declared by the authors.