Chau-Minh Phan is a research scientist at the Centre for Ocular Research & Education, and co-founder of Tricolops Technology and OcuBlink Inc. His research interests primarily focus on developing biomaterials for ocular drug delivery and in vitro eye models.
Introduction
The
last decade has ushered in an age of smart devices and wearables that have
rapidly changed the way we live. Not surprisingly, this movement also has
inspired the contact lens market, with over 140 million wearers worldwide,1 to ponder what else can we
do with contact lenses aside from vision correction. Researchers across the
world are developing ‘smart contact lenses’ for ocular drug delivery,2
myopia control,3 visual displays,4 and biosensing of tear film
components.5
While all of these developments are equally exciting, this overview will only address
contact lenses for biosensing.
If
the eyes are the windows to the soul, then the tear film is the window to the
body. Tears contain not only water and salts, but also very complex proteins,
enzymes, polysaccharides and lipids.6 Even small changes in the composition of these tear components
can trigger or indicate a state of disease.7, 8 In
other words, tears contain a wealth of information about our health; the
challenge is how to detect and make sense of it all.
The
traditional approach for analysis of bodily fluid involves collecting samples
from the subject, and then analyzing them at a lab. This approach however,
while highly accurate, only provides a snap-shot in time. For many diseases
such as glaucoma and diabetes, the factors that need to be monitored can
fluctuate immensely throughout the day, and a one-point measurement will likely
miss these transient changes. The advantage of a contact lens biosensor is that
it sits right in the tear film, thereby being able to provide real-time and
continuous monitoring. In addition, contact lenses are also non-invasive and
relatively more comfortable than current invasive methods for monitoring
diseases. Therefore, a contact lens biosensor could significantly improve the management
of diseases that require continuous monitoring.
Sensimed – first smart contact lens for assessment of IOP
More than 67 million people worldwide are affected by glaucoma, the
second leading cause of blindness in the world.9 The monitoring and management of intraocular pressure (IOP) is
key to the successful treatment of glaucoma. Goldmann applanation tonometry
(GAT) has been considered the gold standard for measuring IOP, which measures
the applanation of the cornea. The limitation of this approach is that GAT can
only provide a one-time measure of the IOP, which is taken typically during the
day. As a result, it can easily miss transient changes in IOP, especially
during the night time where the IOP is highest.10
Considering that a contact lens rests on the cornea, it made
perfect sense to include a sensor that could potentially measure changes in
IOP. In 2009, Sensimed AG (Lausanne, Switzerland) was the first company to
successfully commercialize a contact lens sensor for IOP measurement (the Triggerfish®
lens).11-13 The sensor contains four circular strain gauges embedded in the
lens that can sense minor changes in the circumference at the limbus.11-13 Consequently, IOP is measured indirectly by volume changes in the
eye, in contrast to measuring the pressure via corneal applanation.11-13 While there was initial skepticism as to how accurate this
approach would be, Triggerfish® has gone through tremendous amounts
of peer review to date to prove its accuracy and reliability.11-20
The biosensor is integrated with a wireless microprocessor and
antenna for power and data transmission. The entire platform is mounted on a
single-use silicone contact lens and can be worn for an entire day.11-13 The 24-h data generated by Triggerfish® provides the clinician
with a wealth of information they can use to effectively provide appropriate management
for the patient’s glaucoma care. More interestingly, this device has also
created opportunities to study IOP fluctuations in other everyday scenarios,
such as during exercise,16 playing wind instruments,18 and post-surgery.17 These collective data and future data on IOP using the
Triggerfish® will help shed more light on the underlying causes of
glaucoma.
Evolution of the glucose-sensing smart contact lens
Diabetes affects more than 382 million people globally.21 Control and monitoring of blood glucose is the cornerstone of successful diabetic management, which significantly improves quality of life for those affected.22, 23 The traditional approach uses a finger prick method to sample blood glucose, which is painful, prone to infections, and inconvenient.24 Interestingly, glucose is also present in tear fluid, and in significantly higher concentration in diabetic individuals compared to normal individuals.25 This finding has sparked numerous attempts to develop contact lens for glucose monitoring.4, 24, 26-39
Initial attempts at creating a glucose-monitoring contact lens utilized optical changes in the contact lens to measure glucose concentration. One approach utilized boronic acids, which bind to glucose to provide a unique colorimetric or fluorescence change.26, 27 Another similar method utilized concanavalin A, a protein which binds to glucose and increases in fluorescence in response to glucose concentration.28, 29 In these approaches, the patient would need to use a hand-held device to manually measure the changes in colour or fluorescence of their lens. Since optical responses to glucose changes are difficult to quantify, these lenses would be to indicate whether an excess amount of glucose is present in the tears or not.30
Perhaps
the most promising development in this area was spearheaded by one of Google’s subsidiary,
X (formerly Google X). Their approach took advantage of an enzyme-electrode-based
mechanism for glucose detection. In brief, an enzyme known as glucose oxidase
breaks down glucose in a series of chemical reactions into hydrogen, oxygen,
and free electrons. The free electrons produce an electric current, which correlate
to the glucose concentration. While this mechanism was reported as early as
1962,40 the real challenge came in how to couple this process with
electronics that could fit onto a contact lens.
It was more than a half century later that Liao et al. described a
platform that could couple a glucose sensor with an antenna and wireless
powering system, and also was small enough to fit onto a contact lens.31, 32 This development ignited numerous smart contact lens projects for
glucose detection, the most prominent one being led by a collaboration between Google and Novartis in 2014.33
If successful, the contact lens biosensor would
continuously monitor glucose in the tears and transmit this information in
real-time to a smart phone. A smart app would then record this data and
determine the appropriate response, such as telling the patient to inject their
insulin, or notifying their physician.
One
of the main disadvantages of using an enzymatic based system is long term
stability. Enzymes are also easily affected by common sterilization methods used
in the contact lens industry.34 These limitations can be addressed by using non-enzymatic
electrochemical sensors consisting of metals, such as platinum,34 copper oxide,35 or gold.36 However, these sensors are naturally not as sensitive or specific
as an enzyme. As a result, there has been a great deal of research in
nanotechnology to produce accurate non-enzymatic glucose sensors for smart
contact lenses.4, 24, 34-39
Despite
significant efforts by numerous researchers, experts, and global “giants” like
Google and Novartis, the commercialization for a glucose sensing contact lens
has still not yet materialized. In fact, the excitement behind Google and
Novartis seemed to have stopped by 2018, when they announced that the development
of the glucose contact lens was put on hold.41
It seems that although there has been tremendous progress in both biosensors
and the accompanying microelectronics, the underlying problem may be that
measuring glucose in tears is simply not as reliable as measuring glucose in
blood. For instance, there is a lag time between glucose in blood and tears
that cannot be overcome with technology.33,
42-44Furthermore, the measurements in tears
can easily be affected by environmental factors such as temperature and
humidity, or interference by other biomolecules in the tears.41
So while glucose detection with a contact lens is certainly possible, the question
is whether the information is reliable enough to lead to actionable outcomes. Only
time will tell.
Non-continuous sensing opportunities
While
many of the current developments for smart lenses are focusing on continuous
monitoring, there are also opportunities to use traditional contact lenses as a
one-time diagnostic tool. A contact lens worn throughout the day absorbs
significant amounts of tear components that could be analyzed for certain
biomarkers indicative of diseases.45, 46
Of significant interests are biomarkers related to dry eyes47, 48
and cancer.49-51 Therefore, it may be of future interest to design contact lenses
with materials or nanoparticles that could bind specific biomarkers, which can
then be analyzed post-wear for a particular disease.
Challenges to smart contact lenses
There
are several technical challenges that need to be solved for the successful
commercialization of a smart contact lens. For instance, the biosensor must be
sensitive enough to detect small changes of the analyte of interest in the tear
fluid. Furthermore, it needs to be integrated with an antenna and a power
source in a form factor that can fit a contact lens. The entire system must
also be thin and flexible enough to be comfortable to wear. Another important factor
is whether the biomarker in the tear can be used as a reliable indicator. For
example, for glucose there is a lag time of 20 minutes between tear glucose and
blood glucose.33,
42-44 This lag time is long enough
to give the wrong information to the patient. A final consideration is the actual
costs of these devices. While expensive smart lenses may be adopted by the
wealthy, the innovators, and early adopters, they may not be widely accepted by
the general public – which makes them a gimmick rather than a useful
application.
Final thoughts
The tremendous amount of work already expended on creating a smart contact lens biosensor has created so much excitement that it has expanded to other areas, such as drug delivery and augmented reality. After all, the same platform developed to sense biomarkers in the tears could be used for a wide array of other applications in the eye. For instance, even though the Google glucose contact lens has been put on hold, the same research groups are now working on smart accommodating contact lenses and intraocular lenses.41 The success with Sensimed Triggerfish® for measuring IOP has shown that a smart contact lens is not just science fiction, but a reality that can drastically change the ways diseases are treated. So despite all the hiccups thus far, the future for smart sensing contact lenses is looking as clear as ever.
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