Trends in Analytical Chemistry 122 (2020) 115701

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Trends in Analytical Chemistry

journal homepage: www.elsevier.com/locate/trac

Trends in miniaturized biosensors for point-of-care testing

Dan Liu a, *, Junxia Wang b, Lingling Wu c, Yishun Huang b, Yuqian Zhang a,
Mingyang Zhu a, Yang Wang b, Zhi Zhu b, **, Chaoyong Yang b, c
a
School of Biomedical Sciences, Huaqiao University, Fujian, 362000, China
b
The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory of Chemical Biology of Fujian Province, State Key Laboratory
of Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemical Biology, College of
Chemistry and Chemical Engineering, Xiamen University, Fujian, 362000, China
c
Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

a r t i c l e i n f o a b s t r a c t

Article history: The popularization of point-of-care (POC) testing is of great importance in healthcare diagnostics and
Available online 17 October 2019 other fields in the developing world, especially in resource-limited settings. To date, there are still great
challenges in the development of simple, quick, affordable, yet highly effective and selective biosensors
Keywords: for POC testing. To meet the increasing need for POC testing, researchers need to consider biosensor
Miniaturized biosensor miniaturization. In this review, we focus on recent advances in miniaturized biosensors for POC testing.
Point-of-care testing
We first review the miniaturization strategies, including handheld instruments and microfluidics-
Handheld instrument
assisted miniaturized biosensing systems. Recent progress in recognition biosensing interactions for
Microfluidic platform
Integration
miniaturized biosensing systems is then summarized. We further describe how POC testing applications
Automation can be realized based on developments in integration, automation and multiplexing. Finally, the future
Multiplexing prospects and remaining challenges of miniaturized biosensors for POC testing are discussed.
© 2019 Elsevier B.V. All rights reserved.

1. Introduction fields of biomedical analysis, food safety assessment, environ-

A biosensor is an analytical device for the detection of a specific
target by converting a biomolecular recognition event into an
amplified measurable physicochemical signal [1]. Biosensors are
mainly composed of biological recognition and transducer com-
ponents. The biological recognition elements are designed to
directly interact with the specific target upon biomolecular recog-
nition. Biosensing interactions can be generally classified as anti-
body/antigen, nucleic acid/DNA, enzyme/substrate, ligand/
receptor, cellular structure/cell, etc. The interaction is subsequently
converted and amplified by the transducer, which gives a
measurable output signal proportional to the target concentration.
The most common types of transducers applied in biosensors
include electrochemical [2], optical [3], electronic [4], and mass-
sensitive [5] devices.
Over the past years, a variety of biosensors for highly sensitive
and specific detection have been developed and applied in the
* Corresponding author.
** Corresponding author.
E-mail addresses: liudan@hqu.edu.cn (D. Liu), zhuzhi@xmu.edu.cn (Z. Zhu).
mental monitoring, etc. Nevertheless, there are still great chal-
lenges in the development of simple, quick, affordable, yet highly
effective and selective biosensors for point-of-care (POC) testing.
The popularization of POC testing is of great importance in
healthcare diagnostics and other fields in the developing world,
especially in resource-limited settings [6]. The ideal POC device is a
portable ‘sample-in-answer-out’ system, which is generally
accomplished by biosensors. To meet the increasing need for POC
testing, researchers need to consider device miniaturization [7,8].
For the most part, existing biosensing systems require sophisti-
cated laboratory instruments or can detect only a single target,
thereby limiting the application scenarios of POC testing.
In recent years, miniaturized biosensors based on existing
handheld devices or microfluidic systems have been developed for
POC testing (Fig. 1). Many simple and handheld devices have been
broadly applied in measuring classical physical parameters, such as
thermometers, pressure meters, and pH meters. New signaling
strategies combined with the above miniaturized devices have
been pursued for simple and portable POC testing without bulky
external instrumentation. On the other hand, microfluidic systems
are often likened to miniaturized forms of biological and chemistry
laboratories. They can realize a series of analytical processes, such

https://doi.org/10.1016/j.trac.2019.115701
0165-9936/© 2019 Elsevier B.V. All rights reserved.
2 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701
Fig. 1. Miniaturized biosensors based on existing handheld devices or microfluidic systems for POC testing. Target recognition determines the specificity of the biosensor, and the
transducer and amplifier determine the sensitivity of the biosensor.
as sample transfer, reagent mixing, reagent separation, biological
reaction, and signal output. Since microfluidic technology has
enabled the construction of miniaturized systems, portability can
be implemented for the POC testing applications. Therefore, sensor
specificity has been determined by target recognition, which is a
critical component in miniaturized biosensors, as it transforms the
handheld device or microfluidic platform to detect various targets.
Another important consideration is sensitivity, which is signifi-
cantly influenced by the transducer and amplifier, which translate
molecular recognition into a measurable signal.
In this review, we focus on recent advances in miniaturized
biosensors for POC testing. We first review the miniaturization
strategies of biosensors, including handheld instruments and
microfluidic platform-assisted miniaturized biosensing systems.
Recent progress and development of recognition interactions for
miniaturized biosensing systems are then summarized. We further
describe how POC testing applications can be realized based on
developments in integration, multiplexing and automation of
miniaturized biosensors. Finally, the future prospects and remaining
challenges of miniaturized biosensors for POC testing are discussed,
especially the barriers in reproducibility and commercialization.
2. Miniaturization strategies of biosensors for POC testing
Miniaturized biosensors for POC testing can be classified into
different categories in terms of the miniaturization formats. This
review highlights the recent developments in miniaturized bio-
sensors for POC testing applications, including handheld in-
struments and microfluidic platform-assisted miniaturized
biosensing systems.
2.1. Handheld instrument-assisted strategies
Many commercial and handheld devices are currently available
to the public, including pressure meters, thermometers and pH
meters. These simple devices are easy to use and can measure the
corresponding physical parameters with excellent sensitivity. For
example, pressure meters can measure the pressure ranging from
0 to 3000 kPa, with sufficient sensitivity to detect pressure changes
as low as 0.01 kPa. However, most of these devices can measure
only a specific physical parameter, such as pressure, temperature or
pH. By combining these handheld devices with new biological
recognition and amplified transducer components, miniaturized
biosensors for highly sensitive detection of various disease targets
have been developed. Herein, we will summarize recent in-
novations in handheld instrument-assisted miniaturized bio-
sensors, focusing on the strategies of signal transduction and
amplification.
2.1.1. Pressure meters
Common gas-generation reactions in sealed containers can lead
to substantial pressure increases, which can be readily read out by a
portable pressure meter. With the advantages of signal amplifica-
tion and portability, the pressure-based signaling system is an ideal
strategy for portable quantitative analysis. A pressure meter-based
biosensor for POC testing can be designed by linking a biological
recognition event with a pressure signal output by gas generation.
Many examples of gas-generation reactions have been used in
pressure meter-based biosensors.
Yang's group initially used a hand-held pressuremeter for highly
sensitive bioanalysis [9]. As shown in Fig. 2A, the biosensor
employed a catalyst, such as enzyme catalases or Pt nanoparticles
(PtNPs), and was tagged with detection antibody to form a sand-
wich enzyme-linked immunosorbent assay. Upon the introduction
of substrates, a rapidly catalyzed breakdown of H2O2 to O2 occurs,
leading to significant pressure change in the sealed container,
which can be easily detected by the portable pressure meter.
Further, many pressure meter-based biosensors have been devel-
oped for various targets, such as small molecules [10], ions [10e12],
 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701
Fig. 2. Handheld instrument-assisted miniaturization strategies. A). Principle of hand-held pressure meter for biomolecule sensing (Reprinted with permission from Ref. [9]). B).
Principle of Pt staining strategies by coating AuNPs with Ag and Pt bimetallic shells (Reprinted with permission from Ref. [20]). C). Scheme of flexible pressure sensor with digital
multimeter (Reprinted with permission from Ref. [22]). D). Principle of biosensor for thrombin detection by electronic balance (Reprinted with permission from Ref. [23]).
microRNA [13], telomerase activity [14], protein markers
[12,15e17], and pathogens [18,19].
With the advantage of excellent catalytic gas production capa-
bility, PtNPs have been widely used as catalysts in pressure-based
bioassays. However, in many cases, PtNPs are easily poisoned in
the atmosphere, adversely affecting their catalytic activity and
practical applications. To overcome this limitation, Yang's group
reported a Pt staining strategy by coating AuNPs with Ag and Pt
bimetallic shells [20]. As shown in Fig. 2B, 16-nm AuNPs were first
conjugated with detection antibodies by physical adsorption,
which were then applied to form sandwich immunosorbent assays.
AgNO3 and hydroquinone solutions were subsequently introduced
as Ag precursor and reducing agent respectively, to form silver
shells (Au@AgNPs) as a sacrificial layer for Pt staining. Finally,
H2PtCl6 and ascorbic acid solutions were introduced and applied as
Pt precursor and reductant, respectively, to form Ag and Pt bime-
tallic shells. Stained Pt exhibits long-term stability and low non-
specific adsorption, making the pressure meter-based biosensor
practical in POC settings.
Apart from oxygen gas, hydrogen gas has also been used in
pressure meter-based studies. Wang's group reported a portable
device for sensitive detection of cancer cells with a pressure meter
[21]. Folate modified CuO/Co3O4 catalysts were applied to spe-
cifically recognize folate receptor-expressing cancer cells. The
CuO/Co3O4 nanofibers efficiently catalyzed the decomposition
of the borane-ammonia complex to generate nontoxic H2, resulting
in a significant pressure increase.
2.1.2. Digital multimeters
Instead of using a hand-held pressure meter, a digital
multimeter-based biosensor was developed for pressure-based
POC testing [22], as shown in Fig. 2C This biosensor integrated a
traditional immunoassay as the pressure generator and a paper
electrode-based flexible pressure sensor as the signal output. The
paper electrode and flexible pressure sensor were connected
3
through syringe tubing to a single-break microplate. A sandwich
ELISA complex was first formed via a capture antibody, target of
carcinoembryonic antigen (CEA), and Pt nanoparticle-labeled sec-
ondary antibody on the microplate for gas generation. When gas
production results in a pressure increase, a compressive deforma-
tion occurs to enhance the contiguous area between the two paper
electrodes leading to more conductive sites. The resulting resis-
tance change is readily measured by a digital multimeter.
2.1.3. Electronic balance
Electronic balance readout is another strategy for gas
generation-based biosensors. Lin's group first utilized an elec-
tronic balance as a biosensor readout in a novel aptasensor for
protein detection, by converting the pressure signal to an ampli-
fied weight signal [23]. As shown in Fig. 2D, aptamer-modified
PtNPs were applied to recognize targets by forming sandwich
aptamer complexes. The PtNPs subsequently catalyzed the
decomposition of H2O2 to O2, producing a large volume of gas. In a
drainage device, the pressure increase caused by the continuous
gas generation can force out a certain amount of water. Therefore,
the pressure signals were successfully converted to an amplified
weight signal, which could be easily measured by an electronic
balance.
2.1.4. Thermometers
Digital thermometers, the most significant analytical tools in
personal healthcare, are generally available, simple and cheap
clinical devices for temperature determination. In order to apply a
thermometer to detect a wide range of targets, a link between
measurable temperature signal and target concentration is needed.
The thermometer as a signal readout was first developed by Li's
group through nanoparticle-mediated photothermal biosensing,
using antibody-tagged iron oxide nanoparticles to form a sandwich
enzyme-linked immunosorbent assay [24]. To generate a strong
photothermal effect, iron oxide nanoparticles were reacted with
4 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701

potassium ferrocyanide and transformed into Prussian blue nano-
particles (NPs). The formed Prussian blue NPs served as a photo-
thermal probe to translate the assay signal into heat through a near-
infrared (NIR) photothermal effect, allowing quantitative biomol-
ecular analysis with a thermometer. However, the conversion of
iron oxide NPs to Prussian blue NPs complicated the biosensor. Li's
group further reported new photothermal probes with simpler
design and broader applications to advance the thermometer-
based biosensor [25]. Based on the iron oxide NP-mediated TMB-
H2O2 colorimetric system, they developed an NP-mediated TMB-
H2O2 photothermal immunoassay platform for POC biomolecule
detection using a thermometer as the transducer [25]. The
colorimetric-based photothermal immunoassay does not require a
complicated NP conversion process and exhibits great advantages
for simple biomolecule quantitation.
New photothermal nanomaterials of plasmonic copper selenide
nanocrystals (Cu2
xSe NCs), as good representatives of chalco-
genide copper compounds, were also prepared to develop a
thermometer-based biosensor [26]. As shown in Fig. 3A, Cu2
xSe
NCs with high photothermal conversion efficiency were loaded into
liposomes to form photothermal soft nanoballs, which greatly
amplified the photothermal effect by encapsulating a large amount
of Cu2
xSe NCs. The heat released from the photothermal soft
nanoballs under near-infrared irradiation led to a temperature in-
crease in the substrate solution, which was measured with a
thermometer and linked quantitatively to target concentration.
2.1.5. pH meters
pH meters are simple and portable devices for monitoring pH.
They are available and broadly applied in a variety of areas,
including laboratory tests and environmental detection. pH meters
generally measure the hydrogen ion concentration in a solution
with an outstanding accuracy. In order to employ a pH meter to
detect various biological targets, a link between hydrogen ion
concentration response and target concentration must be estab-
lished. Enzyme-mediated hydrogen ion generation and Loop-
mediated isothermal amplification (LAMP)-based hydrogen ion
products have been used to demonstrate the feasibility of pH
measurements for sensitive bioanalysis.
Jeon's group proposed the use of pH meters to link an acetic
acid-generating reaction by acetylcholinesterase hydrolysis to
detection of the cardiac marker troponin I [27]. They applied
acetylcholinesterase-tagged detection antibody to form sandwich-
type immunocomplexes. Introduction of the substrate acetylcho-
line initiated acetic acid generation by enzymatic hydrolysis, lead-
ing to a decrease in pH for sensitive readout with a pH meter. By
acetylcholinesterase-catalyzed hydrolysis, Ju's group further
designed a pH-responsive colorimetric strategy with DNA-
triggered nonenzymatic cascade amplification for highly sensitive
DNA detection using pH paper strips [28].
The use of a pH meter or pH test strips was also proposed by Li's
group to link an ammonia-generating reaction catalyzed by urease
to the detection of microbial pathogens [29]. They coupled an RNA-
cleaving DNAzyme with urease, which can hydrolyze urea into
ammonia, thus leading to a significant change in pH. Later on, by
using urease for signal transduction and amplification, many pH-
meter-based biosensors for POC testing have been developed for
various targets, such as uranyl ion [30], aflatoxin B1 [31,32], exo-
somes [33], and telomerase activity in cancer cells [34]. Recently,
urease was first inactivated with silver ions and printed onto paper

Fig. 3. Handheld instrument-assisted miniaturization strategies. A). Principle of photothermal immunoassay of Aflatoxin B1 with a homemade thermometer (Reprinted with
permission from Ref. [26]). B). Detection principle of CeC mismatched single nucleotide polymorphisms using a portable pH indicator (Reprinted with permission from Ref. [35]). C).
Scheme for screening thrombin inhibitors and detection of thrombin using a handheld pH meter (Reprinted with permission from Ref. [43]). D). Scheme of amino acid analysis using
a personal glucose meter (Reprinted with permission from Ref. [54]).
 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701
test zones [35]. As shown in Fig. 3B, urease was bound with Ag(I)
(black circle) to fully inactivate the enzyme. Addition of cytosine-
cytosine mismatched DNA displaced the Ag(I) and reactivated the
urease enzyme. Activated urease then hydrolyzed substrate urea to
ammonia, leading to a pH change for pH indicator readout. Glucose
oxidase is another efficient enzyme which can convert glucose to
gluconic acid, resulting in a decrease in pH. Based on glucose oxi-
dase signal amplification, various biosensors have been developed
for POC testing combined with a handheld pH meter [36e41]. In
addition to enzyme-mediated Hþ-amplification, a loop mediated
isothermal amplification method for measuring the released
hydrogen ions has also been reported as pH meter-based bio-
sensors [42].
In addition to measuring the concentration of hydrogen ions
during biological reactions, pH meters can also detect the photo-
voltage difference between two electrodes and act as a promising
photoelectrochemical signal detector. Wu's group recently reported
a light-addressable photoelectrochemical sensor employing pH
meter readout for high-throughput screening of thrombin in-
hibitors [43]. As shown in Fig. 3C, the sensor was constructed by
effectively immobilizing thrombin-cleavable and biotin-labeled
peptides on eight identical sensing zones of a single gold-film
working electrode. The incubation of thrombin with each peptide
sensing zone resulted in the reduction of binding sites for
streptavidin-labeled fullerene photoelectrochemical bioprobes,
which actually reflected thrombin activity by the decreased pho-
tovoltage, and thereby allowed screening of thrombin inhibitor
drugs using a simple pH meter.
2.1.6. Glucose meters
The personal glucose meter is one of the most successful
commercialized biosensors for in vitro diagnostics. However, the
application is still limited, because it detects only glucose. The
existing glucose meters are commonly designed for monitoring
blood glucose with a dynamic range of 0.6e33 mM based on the
electrochemical signals generated by redox reaction of either
glucose oxidase or dehydrogenase [44e46]. The key to detecting
non-glucose targets by glucose meters is establishing a link be-
tween measurable glucose signal at the mM level and target con-
centration at much lower concentration in the sample. Non-glucose
target detection was first developed by Lu's group by linking the
binding of aptamers to targets with the enzyme invertase, which
can catalyze the hydrolysis of sucrose to a large amount of glucose
[47]. By invertase-catalyzed glucose generation, a series of glucose
meter-based biosensors were developed for a variety of analytical
targets, such as drugs [47], biological cofactors [47], disease
markers [47e49], toxic metal ions [47,50], DNA [51,52], and mel-
amine in milk [53]. Recently, Kim's group developed a bioassay to
quantitatively analyze amino acids using a personal glucose meter
[54]. The scheme is shown in Fig. 3D. To link the amino acid con-
centrations with glucose detection, the reaction mixture for cell-
free protein synthesis was programmed with DNA encoding bac-
terial invertase, which catalyzes the hydrolysis of sucrose to
glucose. The invertase synthesized upon addition of amino acids is
related to the amount of glucose converted from sucrose, which can
be precisely detected by the glucose meter.
In addition to invertase, many other enzymes, such as amylase
[55,56] and alkaline phosphatase [57], can be utilized to catalyze
glucose generation as signal transduction and amplification. In
addition, Park's group developed a label-free and wash-free strat-
egy for ATP detection [58]. Cascade enzymatic reactions promoted
by hexokinase and pyruvate kinase were utilized to link the ATP
level to glucose that can be detected by the glucose meter.
Glucose is endogenously present in clinical samples, and high
background levels of glucose can affect glucose-based quantitative
5
analysis. To overcome this problem [59], Lu's group reported that
commercially available glucose meters can be directly used to
quantitate the reduced form of nicotinamide adenine dinucleotide
(NADH) as well as glucose. The enzyme hexokinase was employed
to remove the background glucose signal by catalyzing the con-
version of glucose to glucose-6-phosphate, which shows no inter-
ference with the NADH signal.
In terms of amplified transducer components, the above hand-
held instrument-assisted strategies have relative merits. Pressure
meters, digital multimeters and electronic balance are all based on
a catalytic gas-generation reaction, leading to signal amplification
for sensitive detection. For gas-generation-based measurements,
the performance of catalysts with excellent catalytic activity and
time stability may still need to be further improved in future. In
thermometer-based biosensor, the key design concept is trans-
lating molecular recognition into a temperature signal. One limi-
tation is that NIR laser source may be still relatively expensive in
resource-constrained settings. For pH meter-assisted strategies, a
link between hydrogen ion signal and target concentration is
needed. In addition to hydrogen ion amplification, pH meter itself is
also critical as it directly determines the biosensor sensitivity. Un-
like the other handheld devices, glucose meter itself is a commer-
cialized biosensor for monitoring blood glucose with a range of
0.6e33 mM. By conversion of non-glucose target recognition to
glucose signal, the feasibility of quantification for various targets
have been demonstrated. One concern is that glucose meter at the
mM level would limit the sensitivity. Therefore, handheld glucose
meters with higher sensitivity should be developed for detection of
target at a much lower concentration.
2.2. Microfluidic platform-based miniaturized biosensing systems
Micro-scale/micron-scale manufacturing techniques provide
opportunities to enhance miniaturized sensing devices. Consid-
ering sensing and miniaturization, they require precise micro-
fabrication, ease of use, high integration and low cost. As material
properties are mostly related to these requirements, the following
descriptions of miniaturized biosensors are classified by the ma-
terial types and their corresponding performances.
2.2.1. Capillary-based paper devices
Up to now, capillary-based paper devices have been widely
applied in diagnostic biosensors owing to easy-fabrication, high-
portability, low-cost and excellent capillarity of the paper. Micro-
fluidic paper-based analytic devices, as one type of paper-based
diagnostic tool, were first introduced by the Whitesides group
through simple visual color intensity detection. However, color
intensity-based paper microfluidic devices may not be precise,
because differences in color intensity are difficult to distinguish
without instrumentation.
Alternatively, distance-based microfluidic devices, which
display a readable scale of visible length corresponding to sensing
information, have been developed. With explicit readout, distance-
based paper microfluidic devices are highly integrated, user-
friendly miniaturized biosensors. Classical distance-based paper
microfluidic devices rely on the principle of capillary action or
diffusion action, in which the strip becomes more visible or elon-
gated based on a precipitation reaction or polymerization reaction
[60,61]. Nanoparticles or metal enzymes (e.g. oxidoreductase and
hydrolase) are sometimes involved to transduce a molecular signal
to a distance signal. For example, horse radish peroxidase (HRP)
provides free radicals for chromogenic polymerization [62,63].
Yang's group has proposed a 2D paper microfluidic device using a
glucose-encapsulated aptamer-crosslinked hydrogel with an
enzymatic cascade reaction catalyzed by glucoamylase, glucose
6 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701

oxidase (GOx) and HRP, ending in brown poly-DAB (3,30 -dia-
minobenzidine) [poly (DAB)] distance strips [63]. Furthermore, to
strengthen signal amplification, they introduced invertase into the
above cascade reaction, proposing an invertase-GOx-HRP-DAB
enzymatic reaction. In terms of new strips, researchers spread
chromogenic reactant onto the channels, for reaction with the
target molecule, ending with longer or shorter strips. Bakker's
group performed distance-based potassium ion analysis based on
an ion-selective capillary sensor [64]. As shown in Fig. 4A, the
concept involved two sequential steps: first, selective replacement
of analyte ion with ionic dye, followed by detection of the dye on
paper with distance-based readout.
Although distance-based microfluidic devices are simple and
quantitative, the dependence on diffusion within a microchannel in
heterogeneous filter paper can lower the precision of the results. To
overcome this limitation, “Dip-and-read” distance-based paper
devices were developed by color screening [65]. As shown in
Fig. 4B, a colorimetric indicator deposited onto a paper by inkjet-
printing undergoes a target-dependent colorimetric response.
The colorimetric response is then converted to a distance signal by
overlaying a color filter with a continuous color intensity gradient
and matching the color of the developed indicator line. The assay
format eliminated the capillary flow-based analyte depletion step
and demonstrated improved precision for Ni detection.
2.2.2. Glass-based microfluidic devices
When it comes to miniaturized biosensors, glass has the ad-
vantages of diverse and highly accurate processing methods, leak-
proofness and high-transparency. In terms of signal output,
distance-based readout is perhaps the most common strategy in
glass microfluidics. One representative work is the volumetric bar-
chart chip (V-Chip), developed by Qin's group [66]. V-Chip presents
a measurable ink bar whose length increases with the advance of
ink by oxygen generated from hydrogen peroxide catalyzed by
antibody-conjugated-catalase. The advantages of this innovative
biosensor are low cost, portability, rapid operation and straight-
forward readout. Yang's group further innovated a target-
responsive aptamer-crosslinked hydrogel with V-Chip, which was
characterized by target-induced hydrogel decomposition, release of
embedded Au@PtNPs and gas production catalyzed by nano-
particles [67], which exhibited two orders of magnitude higher
catalytic efficiency compared to catalase. Yang's group has
expanded V-Chip for many applications. By changing the constit-
uents of the hydrogel with various types of aptamers and DNA-
zymes, uranium [68], cocaine [67], and aflatoxin B1 [69] could be
detected. Moreover, the binding affinity measurements of aptamers
against targets has also been achieved by an affinity measurement
chip (Afi-Chip) [70]. Furthermore, nanoporous glass with nano-
structures have been developed and utilized in V-Chip by Qin's
group, increasing the number of binding sites for antibody and
enabling lower detection limits [71]. Recently, the V-Chip was
developed as a portable platform for circulating tumor cell (CTC)
detection [72]. The target CTCs were labeled with aptamer-
conjugated nanoparticles and analyzed by V-Chip via quantifica-
tion of the oxygen generated by the catalytic reaction between
nanoparticles and hydrogen peroxide. The released oxygen resulted

Fig. 4. Microfluidic platform-based miniaturized biosensing systems. A). Scheme of the distance-based analysis of potassium ions with microfluidic paper-based capillary sensor
(Reprinted with permission from Ref. [64]). B). Scheme and photograph of “Dip-and-read” paper-based analytical device using distance as readout with color screening (Reprinted
with permission from Ref. [65]). C). Scheme for visual quantitative detection of CTCs with single-cell sensitivity using a portable microfluidic device (Reprinted with permission
from Ref. [72]).
 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701
in movement of an ink bar by a concentration-dependent distance
for visual quantitative readout. This method was sensitive enough
for single cell detection (Fig. 4C).
2.2.3. PMMA-based microfluidic devices
Due to the advantages of low-cost and mass production,
polymethyl methacrylate (PMMA) has been widely applied in
many industries such as hot embossing and injection modeling.
With high optical transparency, good biocompatibility as well as
excellent dielectric and mechanical stability, PMMA is particu-
larly suitable for micro-biosensors. To reach high resolution of
channel pattern, technologies of computerized numerical con-
trol millings and laser ablation are adopted [73]. Yang's group
focused on highly integrated quantitative PMMA biosensors
based on distance-readout. A simple-fabricated distance-based
disposable Shake&Read PMMA microfluidic Chip was developed,
which was designed with a sample reservoir, hydrogen peroxide
reservoir and dye reservoir, followed by a slender, scaled
channel [74]. For operation, reagents can be shifted to the
adjacent reservoir and mixed with other reagents simply by
hand-shaking. After gas generation and volumetric expansion of
dye, visual quantitative detection for cancer biomarker PSA was
realized.
2.2.4. PDMS-based microfluidic devices
Polydimethylsiloxane (PDMS) is also broadly applied in
microfluidic devices due to its moderate optical clarity, superior
biocompatibility and good gas permeability. For miniaturized
biosensing systems, PDMS-based devices are usually designed in
a power-free format. Tang's group described an autonomous
PDMS time sensor recording temporal information driven by
diffusion reaction without any external power. Two timing re-
agents (potassium chromate and lead nitrate) diffused from two
sides of the chip, met and precipitated each other, finally formed
a visible band [75]. Maeda's group proposed a power-free PDMS
chip by storing energy and utilizing it into laminar flow-assisted
dendritic amplification (LFDA)-based microRNA detection. Once
stored energy exposed to atmosphere, a pressure difference
would push sample into the channel to accomplish power-free
liquid flow [76]. Furthermore, Lee's group designed a self-
powered biosensor by integrating a vacuum battery into a
PDMS chip. With amplification initiator loading, plasma loading
and in-situ digital nucleic acid amplification, the microfluidic
chip provides a portable and low-cost solution for on-site
quantitative nucleic acid detection [77]. For PDMS-based
microfluidic devices, one concern is that the chip manipulation
generally relied on soft lithography by pouring PDMS materials
onto a silicon mold, which usually takes long time for whole
process, and the sensors are hardly mass produced.
3. Target recognition interactions for miniaturized
biosensors
Target recognition interactions are central to miniaturized bio-
sensors since they determine the sensor selectivity. Antibody/an-
tigen interactions, functional nucleic acid/target interactions and
other target recognition interactions have been employed in
miniaturized biosensors.
3.1. Antibody/antigen interactions
Antibody/antigen interactions with high affinity and selectivity
are the most popular affinity-recognitions used in biosensors [78].
In most miniaturized biosensors, antibody-based sandwich
[9,22,24,48] and competitive immunoassays [31,48] are used
7
extensively to capture or release enzyme labels for further signal
transduction and amplification. A detailed description is not pre-
sented here since several reviews have described the progress of
antibody/antigen interactions in biosensors for POC testing
[79e81].
3.2. Functional nucleic acid interactions
Functional nucleic acids, including aptamers, DNAzymes, and
derived aptazymes, are novel recognition elements in the design of
biosensors [82e84]. Functional nucleic acids are generated by an
in vitro process called Systematic Evolution of Ligands by Expo-
nential Enrichment (SELEX) [85,86]. A variety of species, such as
small molecules, proteins, cells, and tissues can serve as targets
[87]. The response of the functional nucleic acid can be tailored for
recognition-based binding or recognition-based catalysis. To reach
the goal of precise POC detection of specific targets, functional
nucleic acids-based biosensors have been designed as portable
devices. Recent developments indicate that functional nucleic acids
are mainly incorporated in the miniaturized biosensors using two
signal transducing platforms: magnetic bead separation and DNA
hydrogels.
Lu's group first proposed the transduction of non-glucose target
signals to glucose signal by the introduction of functional nucleic
acids and invertase into the magnetic bead-separation platform
[47]. The complex is hybridized with the DNA on the surfaces of the
beads to act as the sensing unit [88]. Moreover, Yang's group
developed a simple Afi-Chip platform to allow rapid evaluation of
aptamer affinity by the bead-based separation method (Fig. 5A)
[70]. The catalase
aptamer
bead complex initiated a rapid gas-
generation reaction, leading to significant ink movement for dis-
tance readout. Various pathogens can be detected by V-Chip
through the introduction of different aptamers against specific
pathogens in the beads-based separation method [89]. Hg2þ can be
detected by the sequence recognition of T-Hg-T in the bead-based
separation platform (Fig. 5B) [11].
Hydrogels are crosslinked hydrophilic polymer networks.
Functional nucleic acid hydrogels can be tailored for desired ap-
plications [90e92]. For example, an aptamer sequence can be used
as the linker of a DNA-grafted polymer to form hydrogels [55].
Many aptamer hydrogel-based POC biosensors have been devel-
oped for various targets, such as ochratoxin A [93], aflatoxin B1
[69], glucose [94], etc. In addition, DNAzyme hydrogels have been
reported for portable detection. Yang's group first reported a uni-
versal DNAzyme hydrogel for Pb2þ quantitative detection [95]. The
hydrogel can be modified for specific detection of various targets,
such as UO22þ [68] and Ln3þ [96], by replacing the DNAzyme
sequence.
The sensitivity of bulk hydrogels is low because many target
molecules are required for the gel-to-sol transformation. To solve
this problem, Li et al. [97]. recruited a sensitive capillary self-driven
regulator sensor, to detect small changes in the hydrogel. As shown
in Fig. 5C, the process included hydrogel preparation in a capillary
under high temperature, uniform gel-film formation, and the target
test. The small amount of target resulted in obvious change in the
internal structure of the hydrogel and influenced the permeability,
leading to different flow velocities of the sample solution in the
capillary. Sensitive detection of cocaine with a low detection limit
(1.17 nM) was achieved through this proposed method under ultra-
trace DNA hydrogel.
3.3. Other target recognition interactions
Although the majority of miniaturized biosensing systems
rely on antibody/antigen or functional nucleic acid/target
8 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701
Fig. 5. Functional nucleic acid-incorporated portable platforms. A). Binding affinity evaluation between aptamer and its target based on bead-based separation platform (Reprinted
with permission from Ref. [70]). B). Sequence recognition of T-Hg-T for Hg2þ detection (Reprinted with permission from Ref. [11]). C). Capillary-coupled hydrogel to achieve highly
sensitive detection (Reprinted with permission from Ref. [69]).
interactions for recognition, other target recognition assays
have been developed. Ligand/receptor interactions have been
reported for detection of cancer cells by portable pressure
meter (Fig. 6A) [21,98]. An ion exchange reaction was used in
microfluidic paper-based analytical devices for visual speciation
analysis of ions (Fig. 6B) [64,99]. Enzyme/substrate interactions
have been applied in miniaturized biosensing systems. For
instance, Park's group developed a label-free and wash-free
assay for ATP detection using a personal glucose meter [100].
As shown in Fig. 6C, cascade enzymatic reactions promoted by
hexokinase and pyruvate kinase were adopted to link the
amount of target ATP to glucose. To eliminate background
glucose interference, Iyer's group discovered that paracetamol
or catechol compounds can perturb the glucose meter reading.
As shown in Fig. 6D, they synthesized the enzyme substrates of
paracetamol- or catechol-bearing compounds. When exposed
to their respective enzymes, the released paracetamol or
catechol could be detected using a glucose meter. This inno-
vative strategy could rapidly detect enzymes, viruses, and
bacteria [101].
4. Trends in miniaturized biosensing system for POC testing
Researchers have sought to develop miniaturized biosensors for
POC testing with simple detection methods based on existing
handheld devices or microfluidic systems. Besides the re-
quirements of high sensitivity and specificity, an appropriate
miniaturized biosensor should also be capable of integration,
automation and multiplex detection for use in areas without well-
trained personnel.
4.1. Integration
Since microfluidic systems can realize a series of analytical
processes, including sample transfer, reagent mixing, reagent sep-
aration, biological reaction, and signal output, many integration
strategies have been developed based on microfluidic systems.
Immunoassay is a widely used approach in POC due to its high ac-
curacy and sensitivity. But the tedious and laborious processing is
not favorable for rapid field testing. Therefore, there is great need to
solve these problems for a simple way without manual work. Qin's
group integrated sample preparation into a previously reported V-
Chip to simplify ELISA by providing precise flow control [102].
Yang's group also developed a fully integrated sample-in-answer-
out ELISA-Chip with PtNP-catalyzed oxygen distance readout
based on a stationary multiphase [103]. In Fig. 7A, The ELISA-Chip
was composed of several circular reservoirs for aqueous reagents
and washing buffer separated by elliptical reservoirs of mineral oil.
The above flow-based or stationary multiphase microsystems
needed careful control of interfacial properties, and exhibited
relatively bead retention during surface tension-gated movement.
To overcome such limitations, a more recent report demonstrated
the use of a single-phase and pneumatically gated microfluidic
communicating vessel chip to facilitate the manipulation of mag-
netic beads and streamline assay workflow [104]. The hydrostatic
pressure caused by the different liquid levels between two
communicating vessels generates a counter flow to wash the beads
during movement. The washed beads are moved across the washing
vessels without incubation to expedite the immunoassay (Fig. 7B).
In addition, great effort has been dedicated to developing a fully
integrated miniaturized biosensing system with lateral flow
 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701 9

Fig. 6. A). Receptor folic acid-conjugated tube-in-tube CuO/Co3O4 heterojunction nanofibers for detection of cancer cells (Reprinted with permission from Ref. [95]). B). Visual
analysis of Ag(I) and AgNPs due to a cation exchange reaction (Reprinted with permission from Ref. [96]). C). Cascade enzymatic reactions and glucose meter-based detection of ATP
(Reprinted with permission from Ref. [97]). D). Cleavage of paracetamol-bearing compounds into paracetamol by the target enzyme for glucose meter readout (Reprinted with
permission from Ref. [21]).

Fig. 7. A). Stationary multiphase ELISA chip with sample-in-answer-out capability (Reprinted with permission from Ref. [99]). B). Integrated microfluidic communicating vessel chip
for immunomagnetic assays (Reprinted with permission from Ref. [100]). C). Integration of solution-based assays onto lateral flow device for one-step quantitative testing by
glucose meter (Reprinted with permission from Ref. [102]). D). Lateral flow device for sample processing integrated with a pressure meter for rapid quantitative detection
(Reprinted with permission from Ref. [103]). E). Schematic procedure for implementing RPA assay on an active matrix EWOD device (Reprinted with permission from Ref. [107]).
10 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701

devices. For example, Yang's group used a lateral flow device for
sample processing and integrated it with a pressure meter to
develop a rapid detection approach for disease-related protein
(Fig. 7C) [105,106]. Lu's group integrated multistep target binding
and enzymatic reactions in solution in a lateral flow device in a
single step based on glucose detected by the glucose meter (Fig. 7D)
[107]. The complete integration of target recognition, signal
amplification, and distance signal output based on a 3D paper
microfluidic analytical device was also reported [108].
4.2. Automation
Another trend of POC testing is automation, which can greatly
save manual labor and lower the requirements for operators.
However, most of the automated operations must be handled in a
centralized laboratory with complex instrumentation or strict
environmental requirements, which are not feasible for POC ap-
plications. Digital microfluidics (DMF) is an emerging fluid-
handling technique, based on the principle of electrowetting-on-
dielectric (EWOD), to manipulate discrete droplets in an array of
electrodes [109]. By applying a series of electrical potentials to
these electrodes, droplets can be controlled to move, merge, split,
and dispense from reservoirs in a full range manner [110]. Due to
programmable control, an automated process could be realized on
a DMF chip. With the advantages of miniaturized assay volume and
programmable fluid handling ability, DMF is an attractive platform
for automated POC applications. Recently, the emergence of DMF
has provided a new concept of automated operation and has been
widely applied in immunoassays. For example, Morgan's group
described a novel active matrix EWOD platform with 16,800 elec-
trodes and a built-in impedance sensor for real-time droplet posi-
tion and size sensing [111]. It is ideally suited for POC testing, as it
provided a highly flexible and customizable platform capable of
manipulating droplets of various volumes. Using this system,
recombinase polymerase amplification (RPA) was applied for rapid
and sensitive detection of blaCTX-M-15 antimicrobial resistance
gene within 15 min (Fig. 7E). To realize fully automated operation,
sample preparation was integrated on DMF. The flexibility and
programmability of DMF for droplet handling could address a wide
range of problems in bioanalysis. And the portability and low-cost
of the device make DMF an ideal platform for POC applications.
However, there are still some limitations to be overcome, such as
on-chip reagent storage, miniaturization and integrated signal
output [112].
4.3. Multiplexing
POC multiplex testing shows the potential for extracting the
most information by simultaneous detection of various target
analytes. To date, some miniaturized biosensing systems capable of
multiplex target detection have been reported. A microfluidic
paper-based analytic device is widely used to promote multiplexed
target analysis. For instance, a paper-based microfluidic device that
enables multiplex LAMP-based detection of malaria in blood was

Fig. 8. A). The layout of the multiplex paper device (Reprinted with permission from Ref. [109]). B). Multiplex detection of nucleic acids using a low-cost microfluidic chip and a
personal glucose meter (Reprinted with permission from Ref. [110]). C). V-Chip for POC detection of multiple myocardial infarction biomarkers (Reprinted with permission from
Ref. [98]). D). Multiplexed instrument-free bar-chart SpinChip for visual quantitative detection of multiple pathogens (Reprinted with permission from Ref. [86]).
 D. Liu et al. / Trends in Analytical Chemistry 122 (2020) 115701
recently developed [113]. Within the distribution channel, the
sample was split into three spots for detection of three different
genes. (Fig. 8A).
In addition, a simple assay for multiplex DNA detection has been
developed using a microfluidic chip and a personal glucose meter
[114]. As shown in Fig. 8B, the chip was composed of three pieces of
inexpensive polystyrene plates. Since each branch channel allowed
a complete assay for target detection, this microfluidic chip could
be used for the detection of at least two targets simultaneously.
Qin's group developed an integrative V-Chip for quantitative
multiplex detection of MI biomarkers CK-MB, troponin I and
myoglobin [102]. As shown in Fig. 8C, four individual wells for
multiplex detection were used for negative control and detection of
CK-MB, troponin I and myoglobin. Based on the similar Bar-Chart
SpinChip, Li's group used a “spinning” mechanism to achieve
multiplexed bar-chart detection [89]. As shown in Fig. 8D, intro-
duction of the spin unit not only enabled convenient sample
introduction from one inlet to multiple separate channels, but also
elegantly solved the pressure cross-interference problem in the
multiplexed V-Chip.
5. Conclusions and future perspectives
This paper has provided a review of state-of-the-art de-
velopments in miniaturized biosensors for POC testing over the
recent 3 years. The review has described various handheld
instrument-assisted miniaturization strategies, such as pressure
meter, digital multimeter, electronic balance, glucose meter, ther-
mometer and pH meter. Microfluidic platform-assisted miniatur-
ized biosensing systems which focus on distance-based
microfluidic devices have been further described. Moreover, recent
progress of antibody/antigen, functional nucleic acid and enzyme/
substrate interactions proposed in the literature for miniaturized
biosensing system were summarized.
Besides the requirement of high sensitivity and specificity, an
appropriate miniaturized biosensor should also be capable of
integration, automation and multiplex detection for use in areas
where well-trained personnel may not be available. Although
many studies have reported the integration of miniaturized bio-
sensors, it remains challenging to develop a fully integrated de-
vice in a robust, and user-friendly format, especially for the
integration of sample pretreatment. Even though multiplex
detection has been introduced in several studies, the process
takes place primarily in multiple operation steps. With the
advantage of miniaturized assay volume and programmable fluid
handling ability, DMF is an attractive platform for automated POC
applications. There are still some limitations to be overcome, like
on-chip reagent storage and miniaturized signal output
integration.
The cost of miniaturized biosensors is also a major consider-
ation. For handheld instrument-assisted strategies, the simple de-
vices are mainly commercial to the public, and obviously
inexpensive compared to bulky analytical instruments. Although
the accessories used in miniaturized biosensors account for a
fraction, the costs of some components also need to be considered.
For instance, the template cost of “gas-tight container” component,
which is used in pressure meter-based biosensor, are about 30 US
dollars upon small amount of production. For commercial appli-
cation and cost reduction, stable mass manufacturing is important
and encouraging. With regard to microfluidic platform-based bio-
sensing systems, device costs can be reduced by the low-cost ma-
terial utilization, small-volume reagent requirement and mass-
scale device production. When establishing a new miniaturized
biosensor, the cost per test should be taken into account, which is
very significant for developing POC platforms.
11
Significant challenges are yet to be addressed to translate the
developed miniaturized biosensors to commercialization for POC
testing. The problems of consistency and reliability are still prob-
lematic with some of these miniaturized biosensors. To increase the
consistency and reliability of miniaturized biosensors, further ef-
forts will be required before practical applications are feasible, such
as improvement of stable signal transducer components and par-
allel production of microfluidic chips. Moreover, it should be noted
that despite the progress we have witnessed in technologies,
commercialization of POC platforms are also facing many chal-
lenges such as customer acceptance, market adoption, and limited
funding in resource-limited settings. Although the commerciali-
zation of such miniaturized biosensors for POC testing faces some
challenges, future development of portable, integrated, and auto-
mated biosensing technologies is an emerging area that may
greatly streamline healthcare and improve clinical outcomes for
people in resource-limited settings.
Acknowledgements
We thank the Science and Technology Project of Quanzhou
(2018C081R), the National Natural Science Foundation of
China Grants (21435004, 21775128, 21735004, 21521004), the Sci-
entific Research Funds of Huaqiao University (Z18Y0052) and the
National Students' Platform for Innovation and Entrepreneurship
Training Program (201910385015) for their financial support.
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