Nanosensors and printed electronics integration in future lab on a chip biosensing for cardiovascular disease diagnosis

Nanosensors and printed
electronics integration in future lab
on a chip biosensing for
cardiovascular disease diagnosis
Dr. Daniel J. Thomas

Introduction
The cardiovascular disease (CVD) is now a major threat to global
health, particularly in the Western hemisphere. There is a growing
demand for a range of portable, rapid and low cost biosensing
devices for the detection of CVD.
Biosensors can play an important role in the early diagnosis of
CVD without having to rely on hospital visits where expensive and
time-consuming laboratory tests are recommended. Over the last
decade, many biosensors have been developed to detect a wide
range of cardiac markers to reduce the costs of healthcare.
One of the major challenges is to find a way of predicting the risk
that an individual can suffer from CVD through the use of
detecting different biomarkers (and there concentrations) in the
blood.
Of these, C-reactive protein (CRP) followed by cardiac troponin I
or T, myoglobin, lipoprotein-associated phospholipase A(2),
interlukin-6 (IL-6), interlukin-1 (IL-1), low-density lipoprotein (LDL),
myeloperoxidase (MPO) and tumour necrosis factor alpha (TNF-)
which have been used to predict cardiovascular events.
daniel.thomas@engineer.com

Contents
1. Cardiac biomarkers.
2. Biosensors for detecting cardiovascular disease.
3. Optical biosensors.
4. Acoustic biosensors.
5. Electrochemical biosensors.
6. Silicon nanowire biosensors (first and second
generation).
7. Printed laboratory on a chip technology (third
generation).
9. Conclusions and future perspectives.

The
cardiovascular
system

Cardiovascular Disease• CVD is not a single disease, but it is a group of different
disorders that affect the heart and blood vessels. CVD
includes atherosclerosis condition that develops when a
plaque builds up in the walls of the arteries.

Emerging Biomarkers for Evaluating
Cardiovascular Risk

The Factors
Before the occurrence (Hours and even Days) of a heart
attack, there are a series of biological events which happen.
This results in a series of key biomarkers being released into
the blood stream.
These biomarkers remain in the blood stream for some
time, days in the case of Troponin I.
Over the past decade a number of tests have been
produced to detect these biomarkers. However, they still
can’t be used to predict CVD.
If there was an accurate means to detect the presence of
multiple types of biomarkers simultaneously then there
would be a means to continually monitor the heart and
potentially predict an imminent cardiac event.

Biomarkers
• A summary of primary clinically utilised cardiac biomarkers, highlighting
their respective cut-off values.
• By understanding the biological factors, then a biosensor based devices
can be produced at the correct degree of sensitivity and selectivity

Biosensor devices
• A biosensor is a device designed to detect and quantify target
molecules that is widely used as a powerful analytical tool in medical
diagnostics. It includes proteins detection, nucleic acids or monitoring
antigen–antibody interaction.
• It is fabricated by immobilizing a biological receptor material, for
instance; antibody, DNA, or RNA on the surface of a suitable
transducer that converts the biochemical signal into quantifiable
electronic signals. A range of sensors have been developed for CVD
markers detection.
• This signal can be electrochemical, optical, mass change
(piezoelectric/ acoustic wave) or magnetic in nature.
M. Mascini, S. Tombelli, Biosensors for biomarkers in medical diagnostics, Biomarkers 13 (2008) 637–657.

• Nanowire-based detection strategies provide promising new routes to
rapid bioanalysis and detection of disease at the point of care.
These systems allow for instant diagnosis to be made through the
process of selective sensing of biomarker triggers.
Here, a nanowire-based biosensor was selectively functionalised with
antibodies, which are targeted against a series of biomarkers linked to
CVD.
This has resulted in a system that is able to detect specific biomarkers.
In order to achieve this, an integrated device was fabricated with inbuilt
printed electronic systems, which are electrically connected to a
precision nano-biosensor.
The present work describes techniques for producing a microfluidic
laboratory of a chip with in-situ analysis capability. These results prove
the concept of specific and selective attachment of bioreceptor
antibodies. This subsequently provides a promising new route towards
rapid bioanalysis and subsequent diagnosis at the point of care.
Our Current Research Direction

Required Innovation
• Identification of new and non-inflammatory cardiac biomarkers and their
validation,
• Development of novel biorecognition elements in place of classical antibodies,
• Direct detection of biomarkers in biological fluids (blood) without sample
preparations,
• Miniaturisation of electronic transducers for portability, and
• Patterning arrays and microfluidics suitable for multiple biomarker detection.
Combinations of all the above features are essential to making devices of high
potential for early CVD diagnosis with precision. Improving sensitivity, specificity,
and making biosensors a low-cost and point-of-care capability is another
challenge.

Key biomarkers studied
• 3D structure of the Troponin ribbon representation of the human
cardiac troponin core complex (52 kDa core) in the calcium-
saturated form and troponin interacting with actin.
• Myoglobin consists of a backbone of Myoglobin consists of
eight α-helices (blue) that wrap around a central pocket
containing a heme group, which is capable of binding to
various ligands including oxygen, carbon monoxide and
nitric oxide.
Troponin Myoglobin

Biomarker
Antibody targeted against a
specific biomaker
Nanowire

First Generation: Personal Point of Care
The first generation technology used simple
technology to guide a fluid onto the surface of a
biosensor.

• Here we fabricated a two
SINW biosensor (one
functionalised and the second
control) to allow for a general
comparison to be made.
• Liquid flows over the
biosensor and onto
the chips surface. We
experimented with
different widths of
microchannel 50µm
to 450µm

Functionalisation Processes
• In order to functionalise a biosensor this took the
best part of a day and only one antibody could be
added to the whole chip
• Success rates were 40% using this methods.
• The degree of variability made the process
incompatible for mass manufacturing.
Chemical functionalisation Testing and cleaning Biological functionalisation

Second Generation: Laboratory on a chip technology
• This progresses towards microfluidic systems, printed
electronics and silicon nanowire integration.

• Using a new type of Functionalisation process and
four silicon nanowires, these devices were a little
more sophisticated.

Injection Moulded Microfluidics
• More accurate injection moulded microfluidic systems with
hydrophilic polymers were developed.
• This resulted in the fabrication of a far more accurate means to
control fluid flow and deposition onto the biosensor.
• However, the expense was still far too high to be considered for
mass production.

Printed contacts and functionalised zinc oxide nanowires were
deposited to form a multifunctional system.
Third Generation: Multilayer Printed Laboratory

Mobile device integration
• These new printed devices are currently being integrated
with mobile devices.
• With development this will be completed automated.
• We also have to account for factors such as blood
pressure, BMI, activity and patient history using this
approach.

Conclusions
• It is critically important to diagnose CVD at early stages of its progression,
which will allow for successful treatment and recovery of patients.
Therefore, it is essential to develop simple and sensitive CVD diagnostic
methods that can detect multiple cardiac biomarkers at very low
concentrations in biological fluids.
• Current biosensing platforms can fulfil these demands but require
sophisticated laboratory equipment and training.
• A majority of cardiac biomarkers are also markers of common
inflammation, making it difficult to distinguish the cardiovascular risk.
• An inflammatory process in patients can occur without the existence of
cardiovascular disease, which may incur a high rate of false positives.
• Therefore, a multiple marker detection strategy needs to be adapted using
a combination of established and new cardiac markers, which helps in
making correct clinical decisions.

Future Perspective
• In recent years, nanomaterials have shown wide
applications in biosensing.
• The concept of using nanomaterials as one of the
candidates to further improve the sensitivity in
developing highly sensitive devices for early
diagnosis and point-of-care applications.
• Early diagnosis will increase survival rates that
require precise diagnosis, which is only possible
with multiple biomarker detection for CVD risk.
• However, appropriate investment and funding
support mechanisms are needed to facilitate
moving this technology from research to the
commercial applications.

Dr Daniel Thomas
3Dynamic Systems

Nanosensors and printed electronics integration in future lab on a chip biosensing for cardiovascular disease diagnosis

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