REVIEW

published: 08 December 2021

doi: 10.3389/fbioe.2021.774210

The Application of Wearable Glucose

Sensors in Point-of-Care Testing
Sheng Zhang 1†, Junyan Zeng 1†, Chunge Wang 2†, Luying Feng 1, Zening Song 1, Wenjie Zhao 1,
Qianqian Wang 1,3* and Chen Liu 1*
1
State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Ningbo Research Institute,
Zhejiang University, Hangzhou, China, 2School of Mechanical and Energy Engineering, Ningbo Tech University, Ningbo, China,
3
College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China

Diabetes and its complications have become a worldwide concern that influences human
health negatively and even leads to death. The real-time and convenient glucose detection
in biofluids is urgently needed. Traditional glucose testing is detecting glucose in blood and
Edited by: is invasive, which cannot be continuous and results in discomfort for the users.
Zhugen Yang,
Consequently, wearable glucose sensors toward continuous point-of-care glucose
Cranfield University, United Kingdom
testing in biofluids have attracted great attention, and the trend of glucose testing is
Reviewed by:
Juliane R. Sempionatto, from invasive to non-invasive. In this review, the wearable point-of-care glucose sensors
University of California, San Diego, for the detection of different biofluids including blood, sweat, saliva, tears, and interstitial
United States
Lianbin Zhang,
fluid are discussed, and the future trend of development is prospected.
Huazhong University of Science and
Keywords: glucose sensor, wearable, point-of-care testing, non-invasive, biofluids
Technology, China
Jie Wu,
Nanjing University, China
INTRODUCTION
*Correspondence:
Chen Liu Diabetes has become one of the most common chronic diseases caused by modern lifestyles (Bonora
[email protected]
et al., 2021). The reduction in the number of the pancreatic β-cells leads to the shortage of insulin or
Qianqian Wang
[email protected]
the resistance from the target cells and results in type-1 diabetes or type-2 diabetes, respectively (Xiao
†
et al., 2019a). Globally, 5–10% of the patients with diabetes have type-1 diabetes, while type-2
These authors have contributed
diabetes comprises 90–95% global diabetes (American Diabetes Association, 2014). Together with
equally to this work
the complications, diabetes leads to a large number of premature mortalities in humans every year
and is be the 7th leading cause of death according to the prediction of the World Health Organization
Specialty section:
This article was submitted to
(WHO) (Van Dieren et al., 2010; Adeel et al., 2020). As a result, continuous monitoring of the glucose
Biosensors and Biomolecular level in biofluids is much needed (Kim et al., 2019; Villena Gonzales et al., 2019; Phan et al., 2021).
Electronics, The most traditional detected biofluid is blood. However, the collection of blood is invasive and thus
a section of the journal causes discomfort and inconvenience for the users. Furthermore, invasive collection hinders
Frontiers in Bioengineering and continuous monitoring of blood glucose (Lee et al., 2018). Consequently, more research studies
Biotechnology are toward sweat (Bariya et al., 2018), saliva (Mani et al., 2021), tears (Guo et al., 2021), and
Received: 11 September 2021 interstitial fluid (Kim et al., 2018) as alternatives to develop non-invasive, continuous, wearable, and
Accepted: 18 November 2021 point-of-care monitoring of glucose (Yoon et al., 2020).
Published: 08 December 2021
Unlike the traditional diagnostic tests which need to analyze the sample in a laboratory and obtain
Citation: the results after hours and even several days, point-of-care testing (POCT) has been applied in
Zhang S, Zeng J, Wang C, Feng L, resource-limited areas and hospital emergency rooms (Narinx et al., 2020; Raiten et al., 2020;
Song Z, Zhao W, Wang Q and Liu C
Holmström et al., 2021). Although the pain brought by blood collection can be alleviated, it is not
(2021) The Application of Wearable
Glucose Sensors in Point-of-
suitable for continuous blood glucose monitoring, especially during exercise (Muñoz Fabra et al.,
Care Testing. 2021). Besides the fast analysis time and less pain for patients, compared with the routine diagnostic
Front. Bioeng. Biotechnol. 9:774210. test, point-of-care testing is normally easy to use, portable, and inexpensive and has less risk for
doi: 10.3389/fbioe.2021.774210 infections (Darwish et al., 2018; Nichols, 2020; Shrivastava et al., 2020). Therefore, point-of-care

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Zhang et al. Wearable Point-of-Care Glucose Sensor

FIGURE 1 | (i) Schematic diagram showing the fabrication process of Ni-Co-S@CF electrodes (Hekmat et al., 2021). (ii) Prospective toward the long-term glucose
monitoring application of point-of-care wearable glucose sensors, iGLU 2.0 (Joshi et al., 2020).

testing displays great potential not only in continuous, long-term et al., 2014). Blood glucose testing is mostly used in our daily life
monitoring of various kinds of diseases including diabetes (Zhang and has also been applied for point-of-care testing. However, the
et al., 2020) but also in food safety analysis and environmental sensitivity of commercial blood glucose instruments is not high
monitoring (Xu et al., 2020; Zaczek-Moczydlowska et al., 2021). enough so the patients should test their blood glucose level several
In this review, wearable glucose sensors in point-of-care times to make the result precise. The commercial blood glucose
testing are divided into six classifications according to the instruments are unwearable and not portable, thus causing
sensing target: blood, sweat, saliva, tears, interstitial fluid, and inconvenience for users. Some studies have been conducted to
urine. Additionally, the prospect of wearable glucose sensors address these concerns.
toward POCT is outlook. For example, in Hekmat et al., a point-of-care platform toward
the sensing of blood glucose was constructed (Hekmat et al.,
2021). Using a micro-assisted method, ternary nickel cobalt
BIOFLUIDS DETECTED sulfide was decorated on the commercial cotton fabrics to
form the Ni-Co-S@CFs electrodes (Figure 1(i)). The method
Blood was facile and just needs one step. The unique structure of the
The glucose level in blood is the most traditional indicator and the electrode enabled the sensor with satisfactory repeatability, long-
gold standard for diabetes (Lee et al., 2018). Although blood term stability, outstanding selectivity, low detection limit, and a
testing is invasive, blood glucose testing possesses satisfactory wide sensing range, and it can be used in alkaline media. Besides,
sensitivity both for testing in the laboratory and the finger prick this sensor could also detect the glucose level in saliva. Although
test at home, is reliable and low cost, and is a well-established all these advantages and many other evolutions have been made
technique (Wang and Lee, 2015). Therefore, blood glucose is for the blood glucose sensor, the traditional blood sample
regarded as the gold standard for diabetes diagnosis, and the collection method is invasive and thus causes discomfort for
wearable sensors toward the detection of blood glucose play a the patients and increases the risk of being infected (Lee et al.,
significant part in the health care of diabetes patients (Makaram 2018). The invasive collection method also prevents the

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Zhang et al. Wearable Point-of-Care Glucose Sensor

point-of-care detection from being continuous (Rodin et al., self-powered, low-cost, and facile wearable sensor for the
2019). These are also shortcomings in the commercial blood point-of-care detection of glucose levels in sweat was reported
glucose instruments. As a result, Joshi et al. designed a new to be developed by Zhang et al. (2018a). Au/multiwalled carbon
wearable point-of-care device for the non-invasive and nanotube (MWCNT) glucose dehydrogenase was applied to
continuous measurement of blood glucose (Joshi et al., 2020). monitor the glucose in sweat [Figure 2(i)]. The use of Au/
The wearable sensor was based on near-infrared (NIR) Prussian blue indicating electrodes enabled the users to regard
spectroscopy and incorporated with an Internet of Medical the color change as the indicator of glucose level. As a result, there
Things (IoMT) to sense, transmit, and restore the data from was no need for other instruments, thereby reducing the weight
patients on the cloud. In this way, the data could be available for and cost of the sensor. The electrodes were deposited on the filter
patients and medical personnel, and continuous monitoring of paper to improve the sensing performance of the sensor. The
glucose could be achieved [Figure 1(ii)]. The following sensing component was assembled with an energy component by
experiments demonstrated that the point-of-care device was a transparent adhesive tape so that the sensor could be self-
cost-efficient and precise and could detect blood glucose in a powered and display remarkable sensing performance, holding
wide range from 80 to 420 mg/dl. The device was called iGLU 2.0 promise in the application of point-of-care testing. Similarly,
and indicated a broad prospect in smart health care in the future. Zheng et al. fabricated a point-of-care device based on filter paper
Apart from blood, sweat (Bariya et al., 2018), saliva (Mani and carbon nanotubes (CNTs) for the detection of the glucose
et al., 2021), tears (Guo et al., 2021), interstitial fluid (Kim et al., level in sweat (Zheng et al., 2021). A new wearable cloth-based
2018),and urine (Zhang et al., 2021a) can also be indicators for electrochemical sensor (WCECS) containing superior sweat
diabetes as their chemistry is closely related to blood and thus all collection and transport channel was applied to analyze the
being the target for the point-of-care testing. Moreover, glucose level in sweat. Sweat was transported into a cloth-
compared with blood, the collection of these body fluids does based chip which was constructed by the facile and low-cost
not need to destroy the stratum corneum so that is easier to screen printing technology [Figure 2(ii)]. Therefore, the sensor
achieve non-invasive and continuous detection of glucose. As a not only exhibited prominent stability, reproducibility, and
result, more researchers tend to fabricate non-invasive point-of- selectivity but also was low cost and can monitor for 9 h
care wearable glucose sensors toward the detection in these body continuously. The paper-based point-of-care device (PAD)
fluids, especially sweat. with the cotton thread as the microchannel for sweat harvest
is a satisfactory choice to sense the glucose level in sweat. In Xiao
Sweat et al., a microfluidic thread/paper-based analytical device
The research studies toward the point-of-care wearable sweat (μTPAD) made of filter paper and a cotton thread was
glucose sensor are the most common among the other body fluids fabricated (Xiao et al., 2019b). By optimizing the amounts of
(Morse et al., 2016; Lee et al., 2017; Thulasi et al., 2017; Bhide reagents and enzymes on the functionalized filter paper, the
et al., 2018a; Bhide et al., 2018b; Xuan et al., 2018; Zhang et al., highest colorimetric sensing performance toward sweat glucose
2018a; He et al., 2019; Xiao et al., 2019b; Veeralingam et al., 2020; was found, while the wicking properties of the cotton thread were
Bauer et al., 2021; Zheng et al., 2021) because compared with also optimized with the assistance of the oxygen plasma.
saliva, tears, and interstitial fluid, sweat is easier to access and will Additionally, by integrating with an arm guard and the
not cause discomfort for patients and the detection of sweat application of a smartphone, a low-cost, non-invasive, and
exhibits less risk for infection (Arakawa et al., 2016; Yu et al., easy-to-use point-of-care glucose sensing system with excellent
2019; Zheng et al., 2021). Despite all these advantages, there exist compatibility and wearability was established.
some disadvantages/challenges to the application of point-of-care Besides the filter paper, distinct kinds of films can also be the
wearable sweat glucose sensors. Without iontophoretic basic materials of the wearable point-of-care device toward the
stimulation, sampling will be irregular for individuals during sensing of sweat glucose (Bhide et al., 2018a; Veeralingam et al.,
the day (Heikenfeld, 2016) and the sample production rate will be 2020; Müsse et al., 2021). For instance, Veeralingam et al. first
extremely low (Sonner et al., 2015). The method to dissolve these reported a wearable multifunctional sensor platform enabled with
problems is to increase the sensitivity of the sweat glucose sensor artificial intelligence/machine learning (AI/ML) (Veeralingam
so that the volume of sweat samples needed for glucose detection et al., 2020). This sensor could continuously monitor pH and
can be decreased. In order to increase the sensitivity, researchers glucose levels in sweat and the hydration level of the skin with
try to use filter papers and distinct classification of films, patches, high speed and accuracy. A facile hydrothermal method was
and nanosheets as substrates of the sweat glucose sensors. applied to synthesize RuS2 nanoparticles (NPs), and the RuS2 NPs
Furthermore, the thickness of these basic materials is were deposited on the PDMS film substrates by layer-by-layer
extremely low, especially for the nanosheets, a kind of two- spin coating technology. The application of K-nearest neighbors
dimensional material, so that the size of the sweat glucose (KNN) which is based on artificial intelligence in the open-source
sensors decreases, and thus easier to achieve wearability. microcontroller board (QueSSence) greatly ensured the precision
Paper-based substrates are one of the optimal basis materials and fast data acquisition of glucose, and it was demonstrated that
for the wearable glucose sensor, and there exist a large number of the wearable sensor platform possessed prominent reusability
wearable point-of-care glucose sensors based on the filter paper and stability at room temperature [Figure 3(i)]. Moreover, Bhide
fabricated by researchers (Cho et al., 2017; Zhang et al., 2018a; et al. integrated zinc oxide films into a flexible nanoporous
Zhang et al., 2019; Zheng et al., 2021). For instance, a electrode to form an electrode system (Bhide et al., 2018a).

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Zhang et al. Wearable Point-of-Care Glucose Sensor

FIGURE 2 | (i) Schematic illustration demonstrating the fabrication of the self-powered sensor for point-of-care sweat monitoring (A), a photograph of the
fabricated sensor (B), and photographs of the point-of-care sensor on the forehead of the volunteer when exercising 0 min (C), after 29-min exercise (D), and after 32-
min exercise (E) (Zhang et al., 2018a). (ii) Working of the WCECS in real time on the body. (A) Photograph of the WCECS attached on the back of a human subject. (B)
EC response of sweat glucose in the post-meal and fasting state. (C) Contrast of the sweat glucose concentrations sensed by the WCECS glucometer and glucose
test kit. (D) Comparison of the glucose concentrations detected in 1 day by the glucometer, glucose test kit, and WCECS. (E) Evaluation of durability of the WCECS
(Zheng et al., 2021).

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FIGURE 3 | (i) (A) Different skin conditions for artificial skin and the sensor tied on the human skin. (B) Equivalent circuit representation of the designed RuS2/
PDMS-based hydration sensor. (C) Impedance value detected at the increase in humidity conditions on artificial skin at an alternating current frequency of 10 kHz. (D)
Capacitance and resistance as the function of the increase in relative humidity conditions when the sensor was tied on the human skin. (E) Capacitance and resistance
values of the human skin and artificial skin at distinct hydration environments (Veeralingam et al., 2020). (ii) (A) Immunoassay with the ability of the combined
monitoring of glucose and alcohol. (B) Sweat sensor array displaying fluid confinement in the active detection region, size comparison with one cent, and the flexibility of
sensor (Bhide et al., 2018a).

The sensing mechanism of the sensor was to measure the sensor could monitor glucose levels with a low volume of
impedance change resulting from the glucose bonding on the sweat and show great accuracy, wide sensing range, and low
surface of the electrode, which was detected by electrochemical detection limit in point-of-care testing.
impedance spectroscopy [Figure 3(ii)]. Glucose oxidase enzyme A patch-based point-of-care device for the monitoring of
and alcohol oxidase enzyme were applied to functionalize the glucose levels in sweat was reported to be proposed by Lee
surface of the zinc oxide film electrodes to improve the sensing et al. (2017). The unique multilayer patche structure
range of the wearable sweat glucose sensor from hypo- to minimized the sensor and remarkably increased the sensing
hyperglycemia (50–100 mg/dl), and when compared with the efficiency. Besides, the porous structure provided a large
data of a commercial breathalyzer, the calibration of the number of electrochemical sites and thus higher enzyme
sensor was excellent. As a result, this lancet-free glucose immobilization (Figure 4). According to the glucose level

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Zhang et al. Wearable Point-of-Care Glucose Sensor

FIGURE 4 | (A) Photograph of the wearable patch-based glucose sensor with a waterproof band and a sweat collection layer. (B) Photograph of wearable patch-
based glucose sensor under deformation. (C) Optical image of disposable patch-based glucose sensor on the human skin with sweat (Lee et al., 2017).

FIGURE 5 | Optical images and schematic diagrams displaying the wearable point-of-care biosensor toward the detection of glucose in perspiration. Photographs
(A,B) of the constructed wearable sensor. Schematic illustration of the whole wearable point-of-care sensor (C) and exploded view (D) (Xuan et al., 2018).

detected by the glucose sensors, the device could also release the surface-to-volume ratio and thus numerous electrocatalyst sites
precise, controlled, and multistage drug for the patients. (Zhang et al., 2017; Liu et al., 2021a; Zhang et al., 2021b).
Hyaluronic acid hydrogel microneedles were coated with Consequently, innovative research studies toward the
phase change materials and two distinct temperature- application of 2D nanomaterials are increasing, especially in
responsive phase change nanoparticles to achieve feedback the field of sensing application, including the wearable point-
transdermal therapy. This wearable point-of-care device not of-care glucose sensor for the detection of sweat (Zhang et al.,
only provides a novel structure for the monitoring of sweat 2018b; Xuan et al., 2018; Guo et al., 2019; Yang et al., 2019). In
glucose with high efficiency but also paves a way for the Xuan et al., reduced graphene oxide (rGO) nanosheets were
closed-loop solution of diabetes management. coated with platinum and gold nanoparticles to form rGO
Nanosheets, two-dimensional (2D) materials, display nanocomposites as the working electrode (Xuan et al., 2018).
prominent catalyst properties due to their high After being microfabricated, the nanostructures were

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FIGURE 6 | (i) Schematic illustration indicating the μPAD assembled into a mouth guard by a 3D-printed holder to form the wearable paper-based devices for point-
of-care testing of glucose concentration in saliva. (A), (B), and (C) illustrate the arrangement of the μPAD in the 3D-printed holder, the final device before and after
integration into the mouth guard, respectively (de Castro et al., 2019). (ii) Photographs (A) of the button-sensor, and schematic illustration showing (B) the assay
procedure (Wei et al., 2021).

micropatterned on a flexible polyimide substrate by a low-cost Saliva

and facile procedure. The working electrode was also integrated Saliva is a very attractive biofluid toward point-of-care non-
with chitosan glucose oxidase composites to achieve sensing of invasive monitoring applications as researchers found that
glucose. The unique structure and processing method endowed saliva collected from diabetics has higher glucose
the point-of-care device with a large detection range, remarkable concentration values (Liu et al., 2015; Zhang et al., 2015).
amperometric response to glucose, fast response, high linearity, Additionally, the simple non-invasive process of saliva
and high sensitivity (Figure 5). collection and the needlessness of sample pretreatment make it
Although plenty of research studies have been made for sweat possible for saliva’s extensive application in wearable point-of-
glucose sensing, several challenges prevent wearable point-of-care care sensors (Arakawa et al., 2016). However, in several cases,
sweat glucose sensors from being applied in daily life besides saliva needs to be treated by either filtration or dilution (Ji and
the sampling problems. The skin can act as a contamination Choi, 2015). Besides convenience, saliva is a challenging biofluid
source, leading to the contamination of sweat samples, and for electrochemical measurements. Saliva is a kind of ultrafiltrate
new sweat can be mixed and contaminated by the old sweat of blood and contains mostly water (Czumbel et al., 2020). As a
(Liu et al., 2020). Moreover, a huge change in sweat pH result, the concentration of biomarkers is always much low in
(between 4.5 and 7.0) and the active analyte channels that saliva, which is the most significant shortcoming of saliva as a
exist in eccrine glands will make a skew of glucose detection biofluid (Chiappin et al., 2007; Miočević et al., 2017).
concentration in sweat (Heikenfeld, 2016). Moreover, the specific confounds by the oral cavity also

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FIGURE 7 | showing the distinct layers of smart contact lens structure placed
onto an eyeball. The dashed region highlights the method of gold-mediated
mechanical exfoliation for the fabrication of monolayer MoS2. (B) Images of the
sensor structure and serpentine electrode. (C) Photograph of a dome-shaped
PDMS substrate with the sensor layer on it. (D) Photograph of an artificial eye
with the sensing system attached to it. (E) Schematic diagram illustrating the
smart contact lens and the sensors placed on the eyeball (Guo et al., 2021).
(iii) On-demand drug delivery applying an f-DDS. (A) Schematic diagram
displaying the construction process of f-DDS. (B) Photographic image of
f-DDS. (C) SEM images of f-DDS before and after the gold electrochemistry
experiment. Scale bar, 250 μm. (D) Confocal fluorescence microscopic im-
ages of rhodamine B dye released from drug reservoirs. Scale bars, 300 μm
(left) and 500 μm (right). (E) Change of current for the f-DDS. (F) Released
levels of genistein in a pulsatile manner. (G) Normalized content of genistein
released from the reservoirs (n
6) in comparison with the initial loading
content (Keum et al., 2020).

influences saliva as the point-of-care monitoring biofluid

(Miočević et al., 2017). Researchers are trying their best to
dissolve these problems.
For example, Castro et al. developed a microfluidic paper-
based wearable sensor for glucose monitoring (de Castro et al.,
2019). The reported device integrated microfluidic paper-
based devices (μPADs), the 3D printed holder, and the
silicone mouthguard for the realization of salivary
diagnostics. A mixture of 4-aminoantipyrine (AAP) and
3,5-dichloro-2-hydroxybenzenesulfonic acid (DHBS) as a
chromogenic solution was used in μPADs, and μPADs were
fabricated through simple and low-cost technologies. The 3D-
printed holder made insulation between the mouth and the
reagents, which eliminated the risk of the water-soluble
chemical assay reagents in these wearable sensors to the
health of patients. Without any pretreatment process, this
low-cost and partially recyclable wearable sensor represented
a major step forward in the field of point-of-care testing
devices [Figure 6(i)].
Apart from colorimetric measurements (Tian et al., 2016;
de Castro et al., 2019), the non-enzymatic electrocatalytic
reaction based on the metal–organic framework (MOF) is
another stable way for glucose sensing, which displays higher
sensitivity (Ling et al., 2020; Wang et al., 2020). In particular,
Wei group has made significant progress toward non-
enzymatic quantitative detection of glucose (Wei et al.,
2021). The team developed a cobalt metal–organic
framework–modified carbon cloth/paper (Co-MOF/CC/
paper) hybrid button-sensor as the simple and portable
FIGURE 7 | (i) Wireless representation circuit on the substrate. (A)
Schematic diagram illustrating the wireless display circuit. The stretchable, electrochemical analytical chip. Co-MOF was an artificial
transparent AgNF-based antenna and interconnects are in an elastic area, nanozyme featuring low cost, easy production, and high
while the LED and rectifier are located in the reinforced area. (B) Relative environment tolerance and was an ideal succedaneum of
change in transmitted voltage by antenna versus the applied strain. (C) the commonly used enzyme in glucose detection. In
Characterizations of Si diode on the hybrid substrate by using 0 and 30% in
tensile strain. (D) Rectified properties of the constructed rectifier. (E) Optical
addition, the flexible Co-MOF/CC sensing interface of this
image of wireless display circuit on the hybrid substrate. Scale bar, 1 cm. (F) reported sensor, which was effectively integrated with the
Photos (left, off-state; right, on-state) of operating wireless display with patterned paper, provided adequate catalytic sites and a high
lens shape located on the artificial eye. Scale bars, 1 cm (Ruan et al., 2017). (ii) specific area [Figure 6(ii)]. Compared to the glucose detected
Design of the structure of a smart contact lens with ultrathin MoS2 in serum, this portable button-sensor shows a comparable
transistor–based serpentine mesh sensor system. (A) Schematic diagram
(Continued )
accuracy to that of a commercial glucometer and presents a
promising platform for wearable POCTs.

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Tears personal health-care and medical devices with a combination

Recently, the glucose level in tears has attracted great of diagnosis and therapy at the same time in perspective view.
attention in wearable point-of-care glucose sensors. It is The most significant challenge for the tear glucose sensors is
confirmed that tears participate in the metabolism of the power supply. As the human eye is delicate, the power supply
glucose in the human body, and the glucose concentration device must be soft, and the external power supply applied in
in tears is a positive correlation with the glucose level in blood most research studies nowadays will bring great discomfort for
(Chen et al., 1996; Chatterjee et al., 2003). Besides, myopia users (Bandodkar and Wang, 2014). Although ascorbate (Falk
nowadays has become a global health issue and the prevalence et al., 2013) and lacrimal glucose (Falk et al., 2012) have been
is remarkably high, especially in east Asia (Morgan et al., demonstrated as usable energy supplies in biofuel cells, further
2012). Wearing contact lenses is one of the most favorite ways studies need to be performed for future applications.
to correct vision. As a result, the smart contact lens with the
ability to collect tears and then monitor the glucose in tears Interstitial Fluid
has become a welcome wearable point-of-care device for Interstitial fluid is found between the cells of the body that
glucose detection (Yao et al., 2011; Elsherif et al., 2018; Lin provides much of the liquid environment of the body. Since
et al., 2018; Park et al., 2018). the interstitial fluid (ISF) contains a higher glucose concentration
Ruan et al. reported the fabrication of an attached lens based value, through related technologies, a non-invasive blood glucose
on a gelated colloidal crystal for point-of-care tear glucose sensor based on the interstitial fluid (ISF) can obtain higher
detection (Ruan et al., 2017). The novel glucose sensor was sensitivity and accuracy (Potts et al., 2002; Bandodkar et al., 2015;
made by embedding a crystalline colloidal array in a matrix of Lee et al., 2018; Lipani et al., 2018). Therefore, it is also a very
hydrogel and amounted on the rigid gas permeable lens attractive biofluid toward point-of-care non-invasive monitoring
[Figure 7(i)]. With the change in the glucose level in tears applications.
from 0 to 50 mM, the sensing contact lens could diffract Nightingale et al. proposed a fully integrated wearable
visible light with distinct wavelengths from 567 to 468 nm microfluidic sensor (Nightingale et al., 2019). This sensor
accordingly and thus showed different colors from reddish could provide accurate, high-resolution real-time continuous
yellow to blue. This novel point-of-care sensor exhibited a low measurement in a small wearable software package, and
detection limit of 0.05 mM, and with the assistance of the contact researchers could monitor the glucose and lactate levels in
lens, the device also showed superior portability and healthy volunteers in real time by the sensor. The sensor could
biocompatibility. not only use droplets as in situ chemical analysis of the
In Guo et al., a multifunctional smart contact lens based on microreactor but also provide accurate, precise, and robust
MoS2 transistors were developed (Guo et al., 2021). On the PDMS flow sampling and control. In the future, when it is used in
lens substrate, there was a glucose sensor based on MoS2 combination with physical sensors, physical characteristics and
nanosheets for the direct detection of the glucose biochemical data can be obtained at the same time. This rich,
concentration in tear, a photodetector to receive optical high-quality, and multimodal data will help in the development of
information, and a temperature sensor based on Au to accurate and personalized medical care (Figure 8).
monitor the potential corneal disease. This serpentine mesh However, as the interstitial fluid is hard to access as compared
structure enabled the sensor to contact with tears and was with other biofluids and the collection must be invasive, it needs
mounted on the contact lens directly so that the sensing further research to be applied practically. The application of
sensitivity would be increased and blinking or vision would microneedles is a promising method to minimize the needle
not be interfered [Figure 7(ii)]. Moreover, the following tests wound. The poor adhesion and hydrophilicity of traditional
demonstrated the remarkable biocompatibility of the lens, and porous polymer microneedle hinder it from further
thus, this smart contact lens showed great potential as the next- application. In Liu et al., a mild and simple poly(ethylene
generation point-of-care wearable soft device for personal glycol) (PEG) and polydopamine (PDA) coating method was
health care. developed to fabricate polymer microneedles for dermal ISF
The recent research direction toward the point-of-care tear extraction (Liu et al., 2021b). Owing to the anti-adhesion and
glucose sensors is not only to diagnose diabetes and related hydrophilicity of PEG, the microneedle exhibited little target
complications but also to assist with therapy. In Keum et al., a molecular adhesion, high fluid extraction speed, and excellent
smart lens device was attached to a polymer with excellent hydrophilicity. This research paved the way for microneedle-
biocompatibility (Keum et al., 2020) [Figure 7(iii)]. This based off-line analysis in POCT and has demonstrated that the
point-of-care device consisted of ultrathin soft circuits and a glucose concentration in the interstitial fluid extracted by the
microcontroller for the detection of glucose concentration in porous PDA@PEG-coated microneedles and the value
tears, drug delivery, data transmission, and wireless power determined with a glucometer in venous blood had no
supply. It was demonstrated that the concentration of tear discernible difference.
glucose detected by the contact lens was validated by blood
glucose, and drugs could be triggered to deliver for the Urine
diabetic retinopathy therapy. This work first constructed a Glucose concentration in urine is also a significant indicator of
contact lens with the capability of biometric analysis in diabetes. Because urine glucose monitoring is non-invasive and
combination with drug delivery and paved the way for for elder patients with diabetes, glycosuria may occur with the

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Zhang et al. Wearable Point-of-Care Glucose Sensor

FIGURE 8 | Schematic illustration of the operation of the point-of-care device (Nightingale et al., 2019).

FIGURE 9 | Schematic diagram illustrating the circuit illustration of the alarm glucose monitoring system and components of the wearable urine glucose biosensor
system (Zhang et al., 2021a).

complications of kidney disease, monitoring glucose levels in generate electricity was also integrated with the sensor to power
urine also attracts reasonable attention (Chen et al., 2019; Ghosh the whole system. Additionally, a power management system
et al., 2020). (PMS) was connected with an EBFC with a power density of
In Zhang et al., a wearable biosensor with the ability to detect 220 μWcm−2 to store the power generated and a light-emitting
glucose in urine was integrated with the diaper (Zhang et al., diode to indicate the concentration of glucose in urine. As a result,
2021a). An enzymatic biofuel cell (EBFC) with the ability to this biosensor system displayed satisfactory anti-interference

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Zhang et al. Wearable Point-of-Care Glucose Sensor

TABLE 1 | Summary of wearable glucose sensors in point-of-care testing.

Biofluid Wearable glucose sensor Sensing method Advantages Refs

Blood Wearable non-enzymatic glucose sensor Non-enzymatic electrocatalytic • High selectivity Hekmat et al. (2021)
reaction • Acceptable repeatability
• Long-term stability
Non-invasive continuous serum glucose device Short near-infrared (NIR) • Non-invasive Joshi et al. (2020)
spectroscopy • Precise
• Cost-effective

Sweat Flexible spliced self-powered sensor Colorimetric measurements • Self-powered Zhang et al. (2018a)
• Facile
• No need for other instruments
Cloth-based electrochemical sensor Enzymatic electrocatalytic • Prominent stability Zheng et al. (2021)
reaction • Reproducibility
• Selectivity
• Continuous monitoring
Cotton thread/paper-based microfluidic sensor Colorimetric measurements • Single use Xiao et al. (2019b)
• Excellent compatibility
AI/ML-enabled 2-D-RuS2 nanomaterial–based Impedance change • High speed and accuracy Veeralingam et al.
multifunctional sensor measurements • Prominent reusability and stability (2020)
• Continuous monitoring
• Excellent calibration
• Wide sensing range and low
detection limit
Patch-based strip-type disposable sensor Enzymatic electrocatalytic • Effective Lee et al. (2017)
reaction • Closed-loop
• Streamlined structure
Nanostructured rGO-based sensor Enzymatic electrocatalytic • Large detection range Xuan et al. (2018)
reaction • Fast response
• High sensitivity and linearity

Saliva Microfluidic paper-based sensor Colorimetric measurements • No pretreatment steps Tian et al. (2016)
• Easy to produce
• Partially recyclable
Co-MOF/CC/paper hybrid button-sensor Non-enzymatic electrocatalytic • Easy to produce Wei et al. (2021)
reaction • High environment tolerance
• Good sensitivity

Tears Glucose sensor based on gelated colloidal crystal Colorimetric measurements • Superior portability and Ruan et al. (2017)
biocompatibility
Glucose sensor based on MoS2 nanosheet Enzymatic electrocatalytic • Facile fabrication process Guo et al. (2021)
reaction • Mechanical stability
• Remarkable biocompatibility
Smart contact lenses for both continuous glucose Enzymatic electrocatalytic • Remarkable biocompatibility Keum et al. (2020)
monitoring reaction

ISF Fully integrated wearable microfluidic sensor Colorimetric measurements • High resolution Nightingale et al.
• High accuracy (2019)
• Real-time monitoring

Urine Integrated with EBFC, PMS, and an LED Enzymatic electrocatalytic Self-powered Zhang et al. (2021a)
reaction

Note: AI/ML: artificial intelligence/machine learning; Rgo: reduced graphene oxide; co-MOF/CC/paper: cobalt metal–organic framework modified carbon cloth; ISF: interstitial fluid; EBFC:
enzymatic biofuel cell; PMS: power management system; LED: light-emitting diode.

capability and provided a novel way for the urine glucose sensor CONCLUSION
to be applied for wearable point-of-care health-care devices
(Figure 9). Wearable sensors toward point-of-care monitoring of glucose in
However, urine cannot be obtained continuously, so it is biofluids attract great attention of researchers as point-of-care
hard to achieve the continuous characteristic for a wearable testing is generally easy to use, portable, inexpensive, and non-
point-of-care urine glucose sensor. As a result, there are fewer invasive and thus causes less discomfort for users and patients. In
research studies addressing this, and further studies are needed. this review, they are discussed according to six detection targets,

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Zhang et al. Wearable Point-of-Care Glucose Sensor

such as blood, sweat, saliva, tears, interstitial fluid, and urine, and In the future, with the development in the material, power
are tabulated in Table 1. The detection of glucose in blood is the supply, and data transmission area, the wearable point-of-care
most promising method to diagnose and monitor diabetes. Blood glucose sensors will be more miniaturized, accurate, and self-
is the only recognized biofluid that is applied to detect glucose in powered. With the help of these wearable point-of-care glucose
daily life and is regarded as the “gold standard” for glucose sensors, the traditional blood glucose test used most widely
measurement. Therefore, the technique is well developed, and nowadays will be replaced, and because of the non-invasive
there exist a large number of studies on wearable blood glucose characteristic of the novel test, patients will have less
sensors. Most of them are still invasive, thus leading to discomfort reluctance toward the glucose test. Besides the comfort,
for users as well as adding the risk of being infected. There exists a long-term monitoring of glucose can be achieved, and the
work reported by Joshi et al. onthe non-invasive wearable point- obtained data will be transmitted to clinical institutions as
of-care sensor for the detection of glucose in blood. However, as soon as possible so that patients with diabetes can get alert
the sensor is based on near-infrared (NIR) spectroscopy, accuracy and obtain professional advice from clinical personals on
will be not as good as invasive glucose detection in blood and time. Moreover, users can have the right of choice toward the
glucose detection in other biofluids, for example, sweat, saliva, kinds of detection biofluid in the future. For example, users
tears, and interstitial fluid. Research studies toward sweat are the with myopia can choose a sensor based on contact lenses,
most among all six biofluids as sweat is easy to access and will while users with tooth disease can use a saliva-based glucose
cause no discomfort. Besides, research studies toward glucose sensor.
detection in tears are increasing because some important
advancements have been made to develop the wearable and
point-of-care tear glucose sensor based on soft contact lens AUTHOR CONTRIBUTIONS
which causes less discomfort and is welcoming for people with
myopia. The wearable point-of-care sensors toward the SZ, CL, and LF did most writing for the manuscript and literature
measurement of glucose in saliva need further studies and study. JZ and LF assisted in partial writing and literature
cannot be applied widely as the collection of saliva is in the searching. SZ supervised the manuscript process.
mouth and will cause discomfort. Furthermore, in some cases,
saliva needs pretreatment of filtration or dilution. Besides comfort
and convenience, saliva is a challenging biofluid for FUNDING
electrochemical measurements as the concentration of
biomarkers is always much low in saliva and the composition This research was funded by the National Natural Science
of saliva is variable in distinct cases. The research of the wearable Foundation of China (No. 51805469), the Natural Science
point-of-care sensor toward the measurement of the glucose in Foundation of Zhejiang Province of China (No.
interstitial fluid and urine is in the initial stage and needs more LQ20E090008), and the Science and technology plan
studies because interstitial fluid is hard to obtain and urine cannot project of drug regulatory system of Zhejiang Province
be obtained continuously. (No. 2020016).

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Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 14 December 2021 | Volume 9 | Article 774210