Analytica Chimica Acta 1033 (2018) 1e34

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Analytica Chimica Acta

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Review

Recent advances in electrochemical non-enzymatic glucose sensors e

A review
Dae-Woong Hwang a, 1, Saram Lee b, 1, Minjee Seo a, Taek Dong Chung a, c, *
a
Department of Chemistry, Seoul National University, Seoul, 08826, South Korea
b
Seoul National University Hospital Biomedical Research Institute, Seoul, 03082, South Korea
c
Advanced Institute of Convergence Technology, Gyeonggi-do, 16229, South Korea

h i g h l i g h t s g r a p h i c a l a b s t r a c t

This review summarizes the latest

progress in non-enzymatic electro-
chemical sensors.

The review encompasses funda-
mental principles of electrochemical
glucose detection.

The merits and demerits of various
electrode materials are discussed.

The authors critically evaluate
numerous aspects concerning cur-
rent research.

The prospect of clinical application of
non-enzymatic glucose monitoring is
described.

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

Article history: This review encompasses the mechanisms of electrochemical glucose detection and recent advances in
Received 31 January 2018 non-enzymatic glucose sensors based on a variety of materials ranging from platinum, gold, metal alloys/
Received in revised form adatom, non-precious transition metal/metal oxides to glucose-specific organic materials. It shows that
23 April 2018
the discovery of new materials based on unique nanostructures have not only provided the detailed
Accepted 18 May 2018
Available online 19 May 2018
insight into non-enzymatic glucose oxidation, but also demonstrated the possibility of direct detection in
whole blood or interstitial fluids. We critically evaluate various aspects of non-enzymatic electrochemical
glucose sensors in terms of significance as well as performance. Beyond laboratory tests, the prospect of
Keywords:
Non-enzymatic
commercialization of non-enzymatic glucose sensors is discussed.
Glucose sensor © 2018 Elsevier B.V. All rights reserved.
Glucose oxidation
Nanomaterial
Nanoporous
Electrochemical sensor

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

* Corresponding author. Department of Chemistry, #503-221, Seoul National

University, Seoul, 08826, South Korea. Tel.: þ82 2 880 4362; fax: 82 2 887 4354.
E-mail address: tdchung@snu.ac.kr (T.D. Chung).
1
These two authors contributed equally to this work.

http://dx.doi.org/10.1016/j.aca.2018.05.051
0003-2670/© 2018 Elsevier B.V. All rights reserved.
2 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

1.1. Diabetes and blood glucose monitoring device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.2. Glucose detection by enzymatic method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.3. Glucose detection by non-enzymatic method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Background knowledge for non-enzymatic glucose electrochemical detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1. Mutarotation of glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. Direct glucose oxidation via metallic redox centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.3. Nonfaradaic detection via association with glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.4. Nanostructures for glucose detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3. Materials and structures of non-enzymatic glucose sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1. Platinum-based sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.2. Gold-based sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.3. Metal alloy- and adatom-based glucose sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.4. Non-precious transition metal-based glucose sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.5. Selective binding-based glucose sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5. Outlook for non-enzymatic glucose sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

1. Introduction days using a small sensor attached on the arm. The recorded in-
formation can be scanned and downloaded by a doctor as medical
1.1. Diabetes and blood glucose monitoring device records. Above all, this device does not require fingersticks and is
relatively cheaper compared to other devices [13,14].
Diabetes is a disease caused by the inadequate production of
insulin by the pancreas, or the inability to effectively utilize insulin.
Its incidence have steadily increased in the recent decades [1,2]. 1.2. Glucose detection by enzymatic method
Since low-income countries, in particular, tend to show a greater
rate of increase in the incidence of diabetes and the quality of care The most important component of a blood glucose monitoring
varies largely from country to country, diabetes has been desig- device is the detection technology that measures the concentration
nated by the world leaders as one of four non-communicable dis- of glucose. Much effort has been made to improve the performance
eases that must be resolved [3,4]. According to the International of this technology in the last 40 years, since the invention of the
Diabetes Federation (IDF), the number of diabetic patients first enzyme electrode in 1962 by Clark and Lyons [15]. Most
increased from 151 million in 2000 to 382 million in 2013, and 415 commercial blood glucose monitors use an enzyme-based elec-
million in 2015, implying that 8.8% of adults between the ages of 20 trochemical method. There are many reports on the evolution of
and 79 years are diabetic [5]. The IDF also predicted that the blood glucose sensors [16e18]. Current blood glucose sensors, all of
number of diabetes patients would increase to 642 million in 2040, which employ enzymes, are commercialized and marketed by the
accounting for 10.4% of the world's population, and that diabetes aforementioned global corporations. Glucose oxidase (GOx) and
would be the seventh-leading cause of mortality [3,5]. Much in- glucose dehydrogenase (GDH) are the most commonly used en-
terest is focused on the effective management of diabetes, as it is a zymes in this technology [19,20]. While GOx is highly selective
chronic disease that leads to many comorbidities such as vision towards glucose molecules and more stable than other enzymes, it
loss, renal failure, retinopathy, and strokes. Studies have shown that quickly loses its activity below pH 2 or above pH 8 and can be
strict sugar control can improve the survival of diabetes patients irrevocably damaged at temperatures over 40  C. It is sensitively
and prevent complications related to type 1 and type 2 diabetes affected by surfactants, sodium-dodecyl sulfate at a low pH and
[6e11]. As such, blood sugar monitoring devices are commonly hexadecyl trimethyl ammonium bromide at a high pH. Exposure to
used as medical devices in the management of diabetes. The main unstable humidity can seriously influence the sensors based on
players in the market are Abbott Laboratories, Roche Diagnostics, GOx. Its relatively low activity leads to the dependence on the ox-
LifeScan, Medtronic, and Dexcom [12]. A typical example of a self- ygen concentration of its surroundings [21]. In order to overcome
monitoring device is the Accu-Check Guide, released by Roche in these shortcomings, studies have been conducted on GOx with
August 2016. It features a newly devised strip with an improved lower activity towards oxygen [22,23].
blood injection area and leak-proof function. It also provides GDH is generally used in conjunction with cofactors such as
wireless monitoring and management. Among blood glucose flavin adenine dinucleotide (FAD) and pyrroloquinoline quinone
monitoring devices, the continuous glucose monitoring (CGM) (PQQ). It has a relatively higher activity than that of GOx and is,
system offers a more thorough understanding towards glucose therefore, most commonly used in blood glucose monitoring sys-
levels and trends than those of traditional monitors through 24-h, tems [19]. However, blood glucose monitors using GDH-PQQ can be
real-time monitoring of interstitial glucose levels. The CGM system affected by maltose or galactose, requiring caution in any potential
is also applicable to both type 1 and type 2 diabetes patients and drug interaction before use. Blood glucose monitors using GDH-
can help juvenile diabetic patients who fear fingersticks. Real-time FAD are neither sensitive to oxygen nor reactive to maltose, but
CGM in the Dexcom G4 Platinum Professional, Medtronic iPro2 they respond to xylose, another form of sugar with similar activity
Professional CGM, and FreeStyle Libre Pro System from Abbott are to glucose. GDH systems reportedly show bias in the measured
the three models currently approved by the Food and Drug glucose level due to reactivity towards sugars other than glucose
Administration (FDA). The FreeStyle Libre Pro System by Abbott such as maltose and xylose, which has not been reported in GOx
measures the interstitial glucose level every 15 min for up to 14 systems [24,25]. Incorrect measurements of glucose can lead to the
decision of prescribing more insulin than needed, leading to
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
potentially life-threatening hypoglycemia.
Researchers worldwide are working to overcome the interfer-
ence effect of GDH systems. Efforts in engineering and screening for
GDH-FAD that are less reactive towards xylose are particularly
notable [26e28]. The Sode group has been dedicated to the
screening and engineering studies, as well as structure research of
bacteria from which GDH-FADs are extracted. GDH-FAD screening
based on genome information has led to the discovery of various
structural genes of GDH-FAD. In particular, Aspergillus flavus GDH-
FAD (AfGDH), with a primary structure similar to that of A. oryzae
that is widely used for commercial self-monitoring of blood glucose
(SMBG) sensors, has been the key solution in overcoming the
aforementioned problems. The second most suitable substrate for
AfGDH is xylose, with an activity to xylose around 20% of that to
glucose. Another interesting GDH-FAD (AnGDH) was discovered in
the genome of A. niger. While other GDH-FADs, including AfGDH,
shows xylose reactivity over 20% of that of glucose reactivity, the
AnGDH shows a xylose reactivity of less than 10% of the glucose
reactivity. Recently, a new fungus-derived GDH with low xylose
reactivity and low glucose enzyme selectivity, AnGDH, was intro-
duced. Several studies utilizing AnGDH on screen-printed carbon
electrodes showed that AnGDH is superior to other GDH-FAD de-
rivatives [29,30].
1.3. Glucose detection by non-enzymatic method
The commercial glucose sensors have gradually evolved from
photometric sensors to enzymatic electrochemical detectors, as
photometric devices require the exclusion of interfering bio-
materials such as red blood cells and relatively larger blood sample
volume [18]. Enzyme-based sensors per se monopolize the current
glucose sensor industry. Nonetheless, ongoing research efforts on
non-enzymatic glucose sensors are active in the hopes of
improving the above-mentioned drawbacks of the traditional
enzymatic sensors.
Most commercialized disposable glucose sensors are manufac-
tured by making use of highly optimized cocktails. Many enzyme
immobilization methods including direct adsorption, sol-gel
adsorption, cross-linking, etc. have been reported and utilized in
line with the cocktail methodology [31,32]. Another well-known
method is to capture enzymes during electro-polymerization in
solutions containing enzymes, monomers, and cross-linking agents
[33,34]. This method is attractive in terms of one-pot-immobiliza-
tion of the enzyme and the electrochemical control of the enzyme
layer thickness. However, since the sensitivity of glucose sensors
largely depends on the activity of the immobilized enzyme,
reproducibility remains an important issue in quality control. All
types of enzyme-based sensors necessitate complicated enzyme
fixation and thus inevitably suffer from the uncertainty of artifi-
cially engineered biological substances regardless of the type of the
enzymes. In contrast, most non-enzymatic sensors without bio-
logical functional units can be advantageous in terms of structural
simplicity and quality control for mass production.
More importantly, non-enzymatic sensors are free from oxygen
limitation. For most enzyme electrodes, low or high oxygen con-
centrations may modulate the sensor signals, causing deviation
from signals measured in the normal range of oxygen. Oxygen
deficiency cause nonlinear and less sensitive response towards
glucose concentration in the absence of mediator. In the presence of
mediator, oxygen act as scavengers that intercept electrons from
the redox site of enzyme. Even elaborately designed electron relay
systems, which can reportedly suppress oxygen dependence, are
insufficient to completely rule out the competition with dissolved
oxygen at the electron-binding site. Glucose sensors that generate
electrical currents by directly oxidizing glucose on the surface of
3
the electrode should be able to eliminate the concerns regarding
the oxygen limitation. The thermodynamic reduction potential of
oxygen is more positive than glucose oxidation, and the reduction
reaction of the oxygen molecule is electrokinetically slow at most
electrode surfaces, so that applying an appropriate potential should
negate such interference.
The most common and serious concern is the stability issue of
enzyme sensors, stemming from the intrinsic characteristics of
enzymes. Enzyme-based glucose sensors are hardly free from
thermal or chemical deformations during its manufacture, storage
and use. As mentioned earlier, temperatures above 40  C or below
pH 2 and above pH 8 can cause severe damages to the sensor. High
or low humidity can seriously damage stored or in-use sensors. In
this respect, non-biological electrode materials have been attract-
ing significant attention as an alternative to biosensors. In partic-
ular, fueled by the rapid advance in nanotechnology, various
nanostructures constantly offer new opportunities for non-enzy-
matic sensing. Especially, non-enzymatic glucose sensors based on
nanoporous platinum can be liberated from constraints such as
temperature, humidity, solvent, and processes in manufacturing.
Therefore, it should be easier to establish reliable mass production
processes such as injection, photocuring, thermosetting, vapor
deposition, and polymer coating. Importantly, whereas conven-
tional subcutaneous enzymatic glucose sensors require sterilizing
the whole manufacturing line, non-enzymatic blood glucose sen-
sors can be sterilized just before packaging, leading to reduced
manufacturing costs. It is expected that such merits of enzyme-free
sensors can cut the unit price of CGM system substantially, and thus
expand its market to target both type 1 and 2 diabetes.
In these respects, non-enzymatic sensing is a fascinating strat-
egy that offers a number of opportunities to material scientists.
Discussions on non-enzymatic sensors can be proceeded in diverse
views depending on the material or mechanism used in sensing.
This review article summarizes the latest progresses in non-enzy-
matic electrochemical glucose sensors since our previous review
published in 2006. The content encompasses a brief history,
mechanism, recent advancements, and critical evaluation of the
current non-enzymatic electrochemical glucose sensors.
2. Background knowledge for non-enzymatic glucose
electrochemical detection
2.1. Mutarotation of glucose
The naturally occurring D-glucose is an aldohexose with five
different isomers (see Fig. 1 (a)). In aqueous solutions, the open-
chain aldehyde structure, g-glucose, rapidly cyclize through
hemiacetal bond formation via an acid-catalyzed hydrolysis,
resulting in a five-membered ring, furanose, or a six-membered
ring, pyranose. Depending on the cis-trans arrangement of the
hydroxyl group attached to C-1, the two cyclic glucoses can be
distinguished into a and b anomers. Their abundance ratio in
aqueous solution at equilibrium is known to be approximately a-
glucopyranose: b-glucopyranose: glucofuranose (a and b): g-
glucose ¼ 38: 62: <1.0: <0.1, although the values may slightly vary
depending on the research [35]. The a and b pyranoses, which
compose the majority of glucose solution, equilibrate by acid-
catalyzed hydrolysis through an open-chain structured g-glucose
intermediate, a process known as mutarotation. The mutarotation
is a rather slow process that takes up to 2 h to reach equilibrium at
room temperature [35,36], and its equilibrium and isomeric ratio
are strongly affected by the physico-chemical environment, such as
pH [37], temperature [35,38], and the coexisting ions [39]. For
instance, the composition of D-glucose solution equilibrated for
5 h at 2  C, is as follows; a: b ¼ 56: 44 at pH 1.0, a: b ¼ 27: 73 at pH
4 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

Fig. 1. (a) Molecular structures of various D-glucose isomers. The numbers in parentheses represent the composition ratio of aqueous glucose solution at equilibrium under standard
temperature and pressure. The functional groups at carbon atom 1 (C-1) are highlighted for emphasis on stereochemistry. (b) Overall process of glucose oxidation. The reaction
proceeds from D-glucose into D-glucono-d-lactone via slow hydrogen abstraction and oxidation, followed by fast hydrolysis into D-gluconic acid.

7.0, a: b ¼ 22: 78 at pH 13 [37]. In the non-enzymatic glucose
oxidation, abstraction of the hydrogen atom at C-1 is the rate
determining step, where the abstraction from b-glucopyranse is
highly preferred rather than from the a counterpart. This tendency
is similar to those of glucose oxidizing enzymes such as GOx and
GDH. The hydrogen atom of C-1 is easily activated due to the high
acidity of the hydroxide group at C-1 (pKa ¼ 12.3), which is higher
than that of aliphatic alcohols (pKa ¼ 16). Moreover, the b-gluco-
pyranse has a relatively more accessible axial H atom than the
equatorial hydrogen of the a form [37]. Regardless of the anomeric
forms, the dehydrogenated glucose is quickly oxidized into glu-
cono-d-lactone, and further oxidized to gluconic acid through rapid
hydrolysis with a rate constant of 103 s1 at pH 7.5 [37,40]. The
general non-enzymatic glucose oxidation process is depicted in
Fig. 1 (b).
2.2. Direct glucose oxidation via metallic redox centers
Most electrocatalytic processes occur through adsorption where
reactant molecules adsorb onto active sites of the electrode.
Various factors including favorable electronic states of the redox
center, unfilled d-orbitals at transition metal centers, or abundant
defects in non-metal-based catalysts affect the adsorption mecha-
nism. Adsorption of the reactant is followed by bond breaking and
formation of intermediates. As the oxidation state of the redox
center is changed, the interaction between the product and elec-
trode weakens, leading to desorption of the reaction product from
the electrode surface. Such process involving adsorption-desorp-
tion of reactants on the electrode is generally known as the
chemisorption model [41,42]. In the chemisorption-based glucose
oxidation, the chemical interaction of C-1 and its hydrogen atom
with the electrode surface increase as the glucose molecule ap-
proaches the electrode, causing C-1 dehydrogenation and adsorp-
tion onto the electrode surface (see Fig. 2 (a)). Subsequently, the
electro-oxidation of the adsorbates occurs, producing glucono-d-
lactone, which is further oxidized into gluconic acid through
various reaction pathways depending on the pH [40,43e47].
The surface bound reactive hydroxide species (OHads) generated
during electrocatalysis also has a large influence on the redox re-
actions of small organic molecules, where surface hydroxide radi-
cals directly oxidize the reactants. This incipient hydrous oxide/
adatom mediator (IHOAM) model proposed by Burke and his co-
workers [48] complementarily explains the complex electro-
catalytic process along with the chemisorption-based
electrocatalysis model [41] (see Fig. 2 (b)). According to this
description, the reactive OHads premonolayer formed on the metal
sites of low-lattice coordination number mediates the various
redox reactions, as is evidenced by the concurrence of the onset
potential of these redox reactions with the OHads formation po-
tential [48]. Other researches on glucose oxidation using various
metal electrodes confirmed the involvement of the reactive OHads
[40,49e51].
Since the chemisorption and the IHOAM models basically as-
sume noble metal electrodes such as Pt and Au, these explanations
are not fully applicable to numerous transition metals or metal
oxide-based electrodes. Instead, the redox reaction of the transition
metal centers can explain the glucose oxidation on such materials,
for instance Ni [52,53], Cu [54,55] and Co [56,57]. Under an anodic
bias, the metal oxide layer with a lower oxidation number (lower
oxide) oxidizes into the metal oxide with a higher oxidation
number (higher oxide). The higher oxide itself has oxidative power
strong enough to create surface bound OHads radicals that are
capable of oxidizing organic reactants near the surface. The premier
step in the oxidation of glucose is the C-1 hydrogen atom
abstraction, followed by further oxidization of reaction in-
termediates into glucono-d-lactone through yet unclear processes
that involve surface hydroxyl radicals, hydroxide ions or solvent
molecules in the reaction solution. The hydrogen abstraction is
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
Fig. 2. (a) The chemisorption mechanism of glucose oxidation. The reactant (glucose) is chemically adsorbed first, through concerted process of hydrogen abstraction and
chemisorption of reactive intermediate onto the metal electrode surface, before it is further oxidized. (b) Incipient hydrous oxide/adatom mediator model. The presence of reactive
hydrous oxide (OHads) layer on the electrode is believed to promote fast electro-oxidation of glucose into glucono-d-lactone. Redrawn from Ref. [42].
regarded as the rate determining step as in the case of the noble
metals, but the actual adsorption process of the reactants is largely
unexplained [52,54e57] or is considered to involve unconventional
reaction mechanisms [53]. Most researches utilize voltammetric
methods, especially amperometric techniques, when studying the
direct oxidation of glucose on electrodes. The reaction conditions in
these glucose oxidation are usually neutral or alkaline and rarely
acidic, due to favorable reactive OHads formations in alkaline con-
ditions, the instability of transition metal/metal oxide-based elec-
trode materials in acidic conditions, and finally, the dominance of
easily oxidizable b-glucopyranoses at higher pH because of
mutarotation.
2.3. Nonfaradaic detection via association with glucose
Glucose sensor technologies utilizing biomaterials such as
glucose-oxidizing enzymes (GOx and GDH), glucose-binding lectins
(concanavaline A), and glucose-specific dextrans are based on se-
lective intermolecular interactions between glucose molecules and
the active sites. Attempts to detect saccharides using electro-
chemical methods with artificially synthesized materials instead of
biomolecules initiated in the early 2000s [58e60], and can be
classified into two categories: materials involving boronic acid
functional groups, and molecularly imprinted polymers with
amines, hydroxyl and carboxylic groups as major functionalities.
Boronic acid consists of a central boron atom with two hydroxyl
groups and an alkyl or aryl group, which form a trigonal planar
structure through sp2 hybridization. The vacant p-orbital of the
central boron atom is labile to the incoming nucleophiles. Unlike
the carboxylic acid, the eOH groups are hardly deprotonated.
Instead, the boron center acts as a Lewis acid and thus form a Lewis
acid-base pair with nearby nucleophiles, releasing Hþ as a result
(see Fig. 3 (a)). Boronic acid can reversibly form a diester with 1,2-
diol and 1,3-diols, and has a strong affinity towards polyols such as
carbohydrates, making it a promising chemical moiety in saccha-
ride detection [61,62]. Selective detection of glucose is problematic,
however, due to their intrinsic affinity towards all types of diols.
5
The boronic acid related functionalities generally have comparable
reactivity towards most saccharides. Furthermore, the boronic
diester formation does not correspond to electrochemical signals,
particularly to faradaic signals. For this reason, the utilization of
boronic acid moieties for sensing mostly adopt colorimetry, fluo-
rescence, and absorbance rather than electrochemical methods
[63e65].
In order to make use of the boronic diester formation as a
functional electrochemical glucose sensor, three strategies have
been proposed. The first is to use potentiometry - monitoring the
potential of boronic acid functionalized electrodes. Boronic acid is
incorporated on conducting polymer [59,66] or gold nanoparticle
[67] electrodes, and the change in the equilibrium potential caused
by chemical binding of glucose on the functionalized electrodes is
measured, allowing electrochemical detection of glucose even in
the absence of redox reactions. The second is to introduce a redox
marker that repels away from the boronic acid functionalized
electrode upon the formation of the gluco-boronate ester, leading
to diminishment of its electrochemical signal [68e70]. Many of the
commonly used redox markers are negatively charged, for instance
[FeCN6]3/4, so that they are electrostatically pushed away from
the negatively charged boronate ester on the electrode surface.
Thus, higher glucose concentration triggers larger change in elec-
trochemical signals, e.g. drop of redox current from the marker,
augmentation of surface resistance or difference between anodic
and cathodic peaks. The third strategy is to record the redox cur-
rents from boronic acids coupled to conducting polymers or redox
markers, using voltammetric techniques such as differential pulse
voltammetry [71,72]. Boronate ester formation result in structural
changes of the conducting polymer/redox marker functionalized
electrodes, leading to changes in reduced redox current or redox
peak shifts. This method prefers electrochemical techniques such
as differential pulse voltammetry (DPV) as it mitigates the over-
oxidation of labile substrates such as conducting polymers.
Molecularly imprinted polymer (MIP) is a polymeric structure
with various types of functional moieties that can preferentially
bind to the targeted analyte. Its applications were attempted to
6 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
Fig. 3. (a) The possible equilibria of bor(on)ic acid and diols in aqueous solution. The boronic and related compounds easily form diesters 1,2- and 1,3-diols. Summarized and
redrawn with permission from Refs. [61,62]. Copyright 2014, 2012 Elsevier. (b) Schematic representation of molecular imprinting by non-covalent interactions between the analyte
and functional monomers. The molecularly-imprinted polymer selectively rebinds to molecules matching the imprinted binding sites, analogous to the binding sites of biomolecules
such as enzymes and receptors. Summarized and redrawn from Ref. [74].
detect a wide range of biomolecules including proteins, neuro-
transmitters, and DNA, as well as various organic molecules like
toxins, drugs and pollutants [73e75]. The monomers functional-
ized with moieties such as amines, carboxylic acids, hydroxyl, and
aryl groups, are blended with the target analyte, then polymerized
or “imprinted” in the naturally bound state. This results in a mold
that can specifically recognize and bind even to the most complex
structures (see Fig. 3 (b)). The versatility and selectivity of MIPs
have intrigued many researchers to develop optical sensors based
on fluorescence and absorbance, as well as electrochemical sensors.
There are, however, only a handful of papers concerning the
detection of small and simple molecules such as glucose due to the
intrinsic difficulties associated with the electrochemical detection
of glucose such as slow response time and delicate equilibrium
conditions (pH, temperature, ions).
The strategies used in boronic acid-based sensors, such as
potentiometry [76,77], use of redox markers [60,78,79], impedance
spectroscopy [60,80], and direct oxidation [81], have also been
applied to electrochemical detection of glucose using MIPs. Some
recent results showed significant advancements in selective
detection of glucose [76,77].
2.4. Nanostructures for glucose detection
Recently published papers on electrocatalysis [82e89], energy
applications [82,84e93], and sensors (including glucose sensors)
[94e98] introduced various nanostructures such as nanoparticles,
nanowire, nanorod, nanotube, nano/mesoporous particles and
films. We can view the catalytic effects of those nanostructured
electrode materials in terms of three aspects, i.e. generation of
electrocatalytic active sites, enlargement of surface area, and for-
mation of nano-space enclosed by conducting surfaces. As dis-
cussed in Section 2.2, the glucose oxidation involves surface
adsorption sites and/or reactive OHads radical species, both of
which play the roles of facilitating kinetically sluggish electro-
chemical oxidation of glucose. High indexed planes, edges, and
adatoms more prevalent on nanoparticles, nanowires, etc. would
serve as active sites that enhances electrocatalysis on the electrode
surface. Beside the surface morphology, nanomaterials such as
quantum dots and plasmonic gold nanoparticles have been known
to show remarkable differences in the electronic band structure or
the surface energy [99]. Such electrocatalytic active sites on the
nanostructured surface may assist electrocatalytic oxidation of
glucose.
On the other hand, nanomaterials on a flat substrate naturally
possess rougher surfaces, thus leading to wider electrode area that
can participate in electrochemical reactions. Most nanostructured
electrodes have electrochemically active surface area (ECSA) that is
greatly enlarged, generating correspondingly large currents.
Therefore, nanostructured electrodes are generally advantageous in
terms of sensitivity for sensing. This, however, does not necessarily
lead to better selectivity as background signals including capacitive
current also increases with the wider electrode surface. Nano-
structured surfaces would be worthless for most glucose sensing
purposes unless the generated catalytic active sites and/or the
enlarged ECSA can amplify the glucose signals selectively. For this
reason, Auxiliary functionalities or methods that enable specific
recognition of glucose or exclusion of interferents are usually
required to selectively oxidize glucose on the electrode surface. In
this regard, it is intriguing that a simple nanoporous electrode
without any active site introduced shows an improvement in not
only the glucose sensitivity but also in the selectivity [100,101]. The
nano-spaces created by the porous structure account for such
enhancement, and the electrochemistry involved in this phenom-
enon will be explained in further discussion.
The confined space formed inside the nanopores triggers
physico-chemical changes in reactant-surface interactions or sol-
vation properties, eventually generating an environment favorable
for catalysis. Heterogeneous nanoporous catalysts such as zeolite or
carbon nanotubes are renowned for their superior catalytic activity
towards numerous organic molecules [102,103]. When it comes to
electrocatalysis, the electric field applied to the nanoporous elec-
trode creates a field gradient inside the nanopores on the scale
comparable with the Debye length, which is the characteristic
thickness of the electric double layer. Such field gradient is a sen-
sitive function of the electrolyte concentration in mesoporous
electrodes as demonstrated by the dioxygen reduction [104]. Once
the pore size and the electrolyte concentration fulfill the condition
that the entire surface of nanoporous electrode participates in the
faradaic reaction, we could determine the pore size that provides
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34 7

the maximal ECSA-to-apparent area ratio. Smaller pores than the
thickness of electric double layer, several nm in most biological
fluids, should require significantly higher overpotential to drive
glucose oxidation. Larger pores than that would be less efficient in
terms of ECSA-to-apparent electrode area ratio to raise sensitivity.
The sensitivity of glucose oxidation increases as pore size decreases
and reaches the maximum at a certain pore size. The ECSA-to-
apparent electrode area ratio is not only a function of pore size but
of the thickness of nanoporous electrode. Obviously, thicker
nanoporous electrode can provide higher ECSA-to-apparent elec-
trode area ratio. Since interfering molecules such as ascorbic acid
and 4-acetamidophenol are oxidized much faster than glucose,
even lower concentration of such interfering reactants can generate
as high current as glucose does. We should see overwhelmingly
large currents not from glucose but from interfering molecules at a
flat Pt electrode due to their fast kinetics. The interfering currents
are saturated at a flat electrode, while the current of sluggish
glucose oxidation keeps increasing as the ECSA-to-apparent elec-
trode area is enlarged. Considering far higher concentration of
glucose than any other electroactive potential reactants in blood,
diffusion controlled (saturated) current of both glucose and inter-
fering molecules means predominant contribution of glucose cur-
rent to the signal output, i.e. glucose-selective sensing ultimately.
Park et al. [100] compared the kinetics of glucose oxidation
between a electrodeposited mesoporous Pt electrode (roughness
factor (RF) ¼ 72) and a well-polished Pt rod electrode (RF ¼ 2.6).
They observed that the sensitivity towards glucose enhances at the
nanostructured electrode, while oxidizable substances with fast
electrokinetics gave unchanged current responses. At sufficiently
high potentials that make the system diffusion-controlled, any
reactant undergoing fast electrochemical oxidation should be
depleted inside the nanoporous electrode within a few millisec-
onds. As all reactants are oxidized as soon as they reach the
outermost surface of the nanoporous electrode, the currents from
flat and nanoporous electrodes are indistinguishable from each
other. They confirmed that the faradaic current coming from
interfering molecules with fast electrokinetics are not proportional
to the ECTA but to the apparent geometric area [105]. On the other
hand, unreacted glucose can diffuse into deeper region in the pores
before eventually being oxidized to generate faradaic current. A
further study [101] reported similar results, supporting this inter-
pretation. In this study, the faradaic current densities of O2 and
H2O2 reduction (a diffusion-controlled system) reach a plateau at
thicker nanoporous electrodes, i.e. higher RF, while the current
density of glucose oxidation continuously rise (see Fig. 4). Even-
tually, an excessively thick nanoporous electrode gives saturated
current from glucose, as determined experimentally. It is worth
noting that the experiments mentioned so far were conducted in
phosphate buffered saline (PBS; phosphate buffer þ NaCl or KCl)
solutions, containing chloride ions, which are considered as one of
the major interference in electrocatalysis that use noble metal
electrodes such as Pt and Au. Thus, these studies show the capa-
bility of nanoporous electrodes in enhancing anti-interference.
The experimental results published to date can not be fully
reasoned by factors such as the catalytic active sites and the ECSA-
to-apparent electrode area ratio. The current of glucose oxidation at
mesoporous electrodes, especially those with small pores sizes
close to microporous electrodes, is higher than predicted from the
ECSA. There seems to be another factor accelerating sluggish elec-
trochemical reactions including glucose oxidation [106e111]. Such
enhanced performance observed only at small mesopores allegedly
originates from the nano-space formed by surrounding electrode
surfaces, in which reactants are expected to experience unique
conditions, e.g. different dielectric properties of solvent, strong
electric field gradient, extremely confined dynamic diffusion and so
on. There remains much fundamental research associated with the
electrocatalytic enhancement in nanostructures.
3. Materials and structures of non-enzymatic glucose sensors
3.1. Platinum-based sensors
Platinum is one of the most widely used electrocatalytic elec-
trode material owing to its excellent catalytic performance and
decent stability. A great deal of literature concerning glucose
oxidation reaction on the Pt-based electrodes suggest oxidation

Fig. 4. (a) Schematic cross-sectional view of Pt films with Rf (roughness factor) < 10 (1 and 5), 3D-nanoporous Pt films (3D-npPt) with 10 < Rf < 40 (2 and 6), 40 < Rf < 300 (3 and 7),
and high Rf (>300) (4 and 8). With the increase in Rf, i.e. film thickness, the reactants with fast electron transfer kinetics (O2 or H2O2 reduction) are diffusion-controlled and thus
unable to penetrate and diffuse into the thick nanoporous layer before undergoing faradaic reaction, showing a plateau in current density at high Rfs (b). The open circles represent
cathodic current density of O2 reduction at þ0.1 V vs. Ag/AgCl (3 M KCl) and the solid circles represent cathodic current density of H2O2 reduction at 0 V, all conducted in 0.1 M PBS
(pH 7.4) with 3D-npPt. On the other hand, reactants with sluggish electron transfer kinetics (glucose oxidation) are kinetically-controlled, and can penetrate deeper into the
nanoporous layer, thus showing higher relevance towards increasing Rf (c). The solid circle represents anodic current density of glucose oxidation using 3D-npPt and open circle
represents that of 1D-npPt. The experiments in (c) were conducted in 0.1 M PBS (pH 7.4) containing 6 mM glucose at þ0.4 V vs. Ag/AgCl (3 M KCl). Reprinted with permission from
Ref. [101]. Copyright 2010, Elsevier.
8 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
mechanisms at various chemical environments. In the cyclic vol-
tammogram of glucose, three distinct oxidative regions are found
during the anodic sweep. The potential region 0.15 Ve0.3 V vs. RHE
(reversible hydrogen electrode) is called the hydrogen region,
where the dehydration reaction of organic species including
glucose occurs [112]. In this region, the hemiacetal C-1 hydrogen is
abstracted and the resulting dehydrogenated glucose intermediate
adsorbs onto the electrode. This hydrogen abstraction process is
considered as the rate-determining step in glucose oxidation.
0.40 Ve0.80 V vs. RHE is denoted as the double layer region [112],
where reactive OHads species are formed on the Pt electrode sur-
face. In this region, the adsorbed glucose goes through further
oxidation reaction into glucono-d-lactone, possibly at potentials
lower than the thermodynamic oxidation potential of glucose as
predicted by the IHOAM model. The potential region more positive
than 0.8 V vs. RHE is the oxide region [113], where the Pt surface is
oxidized into PtO. The glucose oxidation becomes diffusion
controlled, suggesting direct oxidation of the bulk glucose on the
oxide film, rather than undergoing a surface bound reaction [113].
In noble metal electrodes such as Pt [112], Au [114] and Pd [115], a
large oxidative current is observed at the double layer region dur-
ing the cathodic scan. Similar anodic current during the cathodic
scan commonly appears in cyclic voltammograms of many other
organic species, especially alcohols [116e118]. Numerous efforts to
interpret this unexpected behavior revealed that the oxidative
current depends on the concentration of glucose [119,120], pH
[121], temperature [43], upper limit potential [122], surface crys-
talline facet [45,47,123], and adsorbates on the electrode [123,124].
The cause of this phenomenon is associated with the reduction of
the metal oxide layer along with desorption of adsorbed species,
exposing a fresh metal surface accordingly. The reactants in the
solution quickly adsorb and reinitiate oxidation at the renewed
metal surface, resulting in the anodic faradaic current.
Despite the long and intense research of glucose oxidation on Pt
electrodes, intrinsic characteristics of the material impede the
research progress of Pt-based glucose sensors. Due to the
outstanding reactivity of the Pt surface, various oxidizable species
coexisting in blood, such as ascorbic acid and uric acid, adversely
affect the oxidative signals of glucose [122,124]. Even common

anions such as HPO2- 4 [43,44] and Cl [125] create massive com-
plications in applying Pt in glucose detection, owing to their strong
tendency to adsorb on the Pt surfaces. In order to overcome such
drawbacks, researchers have made many attempts of nano-engi-
neering the Pt surface, controlling the porosity, the crystalline facet,
and synthesizing nanocomposite structures. Table 1 lists all Pt-
based non-enzymatic glucose sensors described in this section.
Morphology, electrochemical environment, and sensor perfor-
mances are briefly summarized for comparison of various sensors.
Nanoporous Pt electrode is a 2D or 3D porous film structure
with nanometer-sized pores, which are usually synthesized by
methods such as selective dealloying [126] and surfactant-tem-
plated electrodeposition [127]. Since the pioneering work of Park
et al. [100] in 2003, which showed the potential of nanoporous Pt
electrodes as non-enzymatic glucose sensors, various forms of
nanoporous Pt film electrodes have been reported
[110,119,128e131]. The closest approach towards a commercial
application of non-enzymatic glucose sensors was reported in 2012
[130]. The nanoporous Pt electrode consisted of a surfactant-tem-
plated nanoporous Pt film formed on a Pt-Ir wire on which multi-
layered polymer protective films were coated (see Fig. 5). The
protective layer was composed of a negatively-charged Nafion
layer, Nafion and Kel-F (polychlorotrifluoroethylene) polymer
mixture layer, and positively-charged MPC polymer (poly(2-
methacryloyloxyethyl phosphorylcholine)) layer, where each layer
repelled interferents with the same charge and excluded large
biomaterials. The combination of multiple protective polymer
layers was crucial in efficient detection of glucose and effectively
kept out large components in blood or extracellular fluids including
cells and proteins, contributing to its high selectivity towards
glucose. The interferences from molecules such as ascorbic acid and
4-acetamidophenol were minimized by the mechanism explained
in Section 2.4. The nanoporous Pt film withstood various chemical
interferences in blood, and displayed high stability for up to 30
days. This is the first non-enzymatic sensor that showed consecu-
tive blood glucose measurement in virtually undiluted human
whole blood and serum. It suggests the possibility of continuous
glucose monitoring systems, such as non-enzymatic sensors
implantable underneath human skin. In further studies, mass-
producible nanoporous Pt on a disposable strip-type screen printed
carbon electrode was reported [131]. It successfully detected
glucose in virtually undiluted whole blood. Xu et al. [119] selec-
tively dissolved Cu from Pt-Cu alloy to create nanoporous Pt elec-
trodes, which showed enhanced resistance against molecular
interferences. In an experiment comparing the current response of
glucose and various interferences in 0.1 M phosphate buffer (pH
7.0), the nanoporous platinum electrode exhibited a huge increase
in sensitivity towards glucose compared to a flat platinum disk
electrode. The ratio of normalized current response of glucose
(2 mM) to ascorbic acid (0.1 M) on a flat Pt electrode was 1:45,
whereas the current response ratio on the Pt electrode increased to
1:0.45. The authors attributed such selective catalytic enhancement
of glucose oxidation to the nanoporous structure.
The high-index crystalline facet of a metal surface exhibits
highly enhanced catalytic properties compared to the low-index
counterpart. This mainly arises from the changes in adsorption
property, enhanced local electrical field and electron transfer rate
[132,133]. In this regard, various nanostructures such as nanocube
[134], nanoflower [135] and nanopetal [136] were studied as cat-
alysts for glucose sensors. For example, Guo et al. [135] used a ul-
trasonic electrodeposition technique to synthesized submicron
sized platinum nanoflowers on a polished gold electrode. The XRD
analysis revealed that (111), (200), (220) crystalline facets were
dominant. In an experiment in 0.2 M phosphate buffer (pH 7.0)
solution, the Pt nanoflower showed excellent selectivity towards
glucose against various interference molecules of physiological
concentrations. The nanoflower electrode also exhibited a good
linear response in the range of 1e16 mM and excellent reproduc-
ibility, where 10 different electrodes showed only 1.5% standard
deviation.
Constructing nanocomposite structures is another most popular
ways to improve catalytic efficiencies in nanoparticle-based ma-
terials, especially for noble metals. Nanocomposite formation is not
only economic, but it also maximizes electrocatalytic activities by
evenly distributed nanoparticles on substrate materials with high
electrical conductivity and large surface area. For the substrate
materials, a number of candidates were proposed such as graphene
[137e139], carbon nanotubes [137,140,141], carbon nanofibers
[142,143], mesoporous carbons [144] and metal foams [128,134].
Chang et al. [138] hydrothermally synthesized 22 nm Pt nano-
clusters on graphene oxide using polyvinylpyrolidone (PVP) as a
polymeric surfactant. The experiments were conducted in 0.1 M
phosphate buffer solution (pH 7.4), and the fabricated nano-
composite showed excellent performance with a wide linear range
(1e25 mM), very fast response time (~3 s), good reproducibility,
and anti-interference. Rathod et al. [145] hydrothermally synthe-
sized Pt nanoparticles (20 w/w%) on various carbon substrates
(activated carbon, multi-walled carbon nanotube (MWCNT), carbon
nanofiber)), and compared their performances in glucose detection.
On average, the size of the nanoparticles were 2e4 nm, and XRD
analysis revealed (111) as the dominant crystalline facet. In the
Table 1
List of Pt-based electrochemical non-enzymatic glucose sensors

Ref Catalyst Morphology Substrate/Electrodeb Binderc Chemical Real Sample Linear Range LOD Sensitivity (mA cm2 Selectivityf Long-term Repeatabilityh Reproducibilityh
a
Environmentd Teste (mM) (mM) mM1) Stabilityg

[130] Pt np Film Pt-Ir wire Nafion/Kel- PBS (0.1 M, pH HWB (undiluted) 2.5e22 N/A N/A AA, AP, NaCl 30 d (Whole N/A Good (n ¼ 8)
F/MPC 7.4) Blood)
[110] Pt np Film Si wafer e PBS (0.1 M, pH e 1e10 50 10 AA, AP, DA, AS, Ch, N/A N/A <5% (n ¼ 5)
7.4) Ep, NaCl
[131] Pt np Film SPCE PVA PBS (0.1 M, pH HWB (undiluted) 0e30 N/A 0.0054 N/A; Stable in whole N/A N/A Good (n ¼ 100)
7.4) blood
[119] Pt np Film GCE Nafion PB (0.1 M, pH 7.0) BS (diluted) 0.01e8.14 7.75 N/A AA, AP, UA 30 d (PB, 90%) 3.5% (n ¼ 10) 2.4% (n ¼ 10)
[128] Pt np Film Cu foam e PB (0.1 M, pH 7.4) Mouse Blood 1e11 385 9.62 UA, Fru N/A N/A N/A
(diluted)
[129] Pt np Film Pt disk e PBS (0.1 M, pH Human Blood 1e10 800 5.67 AA, UA, NaCl N/A N/A N/A
7.4) (diluted)

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

[134] Pt NC Cu foam Nafion PBS (0.1 M, pH e N/A N/A N/A AA, AP, UA, DA, KCl N/A N/A N/A
7.4)
[135] Pt NFw Au disk e PB (0.2 M, pH 7.0) e 1e16 48 1.87 AA, AP, UA, Fru, 30 d (PBS, 90%) 3.0% (n ¼ 30) 1.4% (n ¼ 10)
EtOH
[136] Pt NP Pt disk e PBS (0.01 M, pH DMEM N/A N/A 2.9 N/A; Stable in N/A N/A N/A
7.4) DMEM
[137] Pt NFw MWCNT/G/GCE e PB (0.1 M, pH 7.4) e 1e7 387 11.06 AA, UA, NaCl N/A Stable (n ¼ 3) N/A
[138] Pt NP GCE e PB (0.1 M, pH 7.4) IV sol’n (diluted) 1e25 30 1.21 AA, AP, UA 20 d (air, 95%) N/A 4.2% (n ¼ 5)
[139] Pt NFw GO/GCE Nafion PBS (0.05 M, pH IV sol’n (diluted) 0.002e10.3 10.3 2 0.64 AA, UA, NaCl 14 d (PBS, 6.3% (n ¼ 5) 7.6% (n ¼ 6)
7.4) e20.3 73.4%)
[140] Pt NP MWCNT/GCE Nafion NaOH (0.1 M, pH e 0e2.4 N/A 106 AA, AP, UA, Fru 7 d (90%) N/A N/A
13 ca.)
[141] Pt NP MWCNT/Si MN array/ e PBS (0.01 M, pH e 3e20 N/A 17.73 N/A N/A N/A N/A
Si wafer 7.4)
[142] Pt NP C NF /GCE Nafion NaOH (0.1 M, pH Calf BS (diluted) 0.3e17 33 2.03 AA, UA N/A N/A N/A
13 ca.)
[143] Pt NP C NF /GCE Nafion PBS (0.01 M, pH e 0e10 0.42 22.7 N/A N/A N/A N/A
7.4)
[144] Pt NP mp C NP on GCE Nafion NaOH (0.1 M, pH e 0e7.5 3 8.52 AA, UA 20 d N/A 3.9% (n ¼ 5)
13 ca.)
[145] Pt NP AC or MWCNT or C NF Nafion PB (0.1 M, pH 7.4) e 2e20 N/A 1.10 1.07 0.52 AA, UA, Fru, Gal, Xyl N/A N/A N/A
on GCE
[146] Pt mp Film Au on stainless steel Nafion PBS (0.1 M, pH in-vivo test 0e36 50 1.62 N/A 3 d (in-vivo) N/A N/A
MN 7.4)
a
np ¼ nanoporous, mp ¼ macroporous, NP ¼ nanoparticle, NC ¼ nanocube, NFw ¼ nanoflower
b
SPCE ¼ screen-printed carbon electrode, GCE ¼ glassy carbon electrode, AC ¼ activated carbon, GO ¼ graphene oxide, MWCNT ¼ multi-walled carbon nanotube, C ¼ Carbon, NF ¼ nanofiber, G ¼ graphene, MN ¼ microneedle,
m-C ¼ mesoporous carbon
c
Kel-F ¼ polychlorotrifluoroethylene, MPC ¼ poly(2-methacryloyloxyethyl phosphorylcholine), PVA ¼ polyvinyl alcohol
d
For proper comparison, calculated pH of NaOH solution is presented (indicated as ca. after the pH value). The references only gave any information about concentration, not pH. PBS ¼ phosphate buffered saline,
PB ¼ phosphate buffer
e
HWB ¼ human whole blood, BS ¼ blood serum, IV sol’n ¼ intravenous glucose injection solution, DMEM ¼ Dulbeco’s modified Eagle’s Medium (contains salts, amino acids, minerals, and vitamins)
f
The chemicals in this column are those resisted by the sensor. AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, AS ¼ acidum salicylicum, Ch ¼ cholesterol, Ep ¼ ephedrine, EtOH ¼ ethanol,
Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose
g
In the parenthesis, chemical environment of storage or consecutive measurements, and percentage of electrode signal after the tested period compared to the initial signal are presented. d ¼ day, w ¼ week, m ¼ month
h
Relative standard deviation (R.S.D) are shown in percentages. When they were not available, words such as stable or good are presented instead. In the parenthesis, number of tests or electrodes are presented.

9
10 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

Fig. 5. (a) Schematic illustration of multilayered structure of nanoporous Pt film (npPt) covered with protective membranes. (b) Cross-sectional SEM image of npPt/naf/naf þ kelF/
mpc film on Au/Si wafer. (c) TEM image of bare npPt on Pt/Ir wire. (d) Amperometric measurement of glucose concentration in whole blood using the fabricated film (circle)
compared with results obtained from a conventional blood glucose analyzer (solid line with unfilled square) (YSI 2300 STAT Plus, YSI Life Science, USA). (e) Sensitivity changes
during the 30-day long-term test. Data points were consecutively acquired and the fabricated film was incubated in a whole blood sample (4  C) in between the measurements.
Reprinted with permission from Ref. [130]. Copyright 2012, Elsevier.

electrochemical experiments, active carbon and MWCNT showed
the best catalytic performances in 0.1 M PBS (pH 7.4), and had good
anti-interference ability against easily oxidizable species such as
ascorbic acid and uric acid, and monosaccharides such as fructose,
galactose and xylose.
Recently, a noticeable result in non-enzymatic glucose sensing
have been reported using conventional materials as the electrode.
Lee et al. [146] used patch-type Pt black-coated stainless steel/Au
microneedle for minimally invasive continuous glucose moni-
toring. The Pt black microneedle showed wide linear range
(0.05e36 mM), good anti-interference, and good stability (6 days)
in 0.1 M PBS (pH 7.4). A Nafion-coating was added to prevent pro-
tein fouling, and the coated microneedle was subjected to 5 days of
continuous glucose monitoring in-vivo, using guinea pig, rat and
rabbit. When compared with the results from a commercial blood
glucose analyzer, comparable results were obtained on the 1st and
the 3rd day, while severe bio-fouling degraded the result on the 5th
day.
Possibly the most significant advantage of using Pt as the elec-
trode material for glucose sensing is its good catalytic performance
in neutral pH environments. The ability to operate in vivo, or in a
real sample (whole blood or interstitial fluid) is the primary
requirement for a competitive glucose sensor. In most academic
researches, however, the performance of non-enzymatic glucose
sensors are tested in alkaline solutions, even the Pt-based sensors,
due to the innate catalytic enhancement in alkaline solution. The
reasons for such bias include the instability of many electrode
materials composed of metal/metal oxide due to corrosion at low
pH, the feasibility of reactive OHads formation at higher pH, and the
increased equilibrium ratio of b-glucopyranose at higher pH. In
addition, metal-based electrodes are negatively charged at high pH
conditions, making them resistant to common interfering species
such as chloride, sulfate, phosphate, ascorbic acid and uric acid, all
of which are naturally repelled from the electrode surface owing to
their negative charge. Even more seriously, the concentrations of
the interfering species used in most studies are far from the range
that is truly required, probably because the physiological concen-
trations of interfering substances are tens of times smaller than the
blood glucose level. For example, sensors working in alkaline
conditions require several 10 s or even up to 1000 fold-dilution of
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
real samples (blood or serum) in NaOH or KOH before sampling
glucose signals. The performance of such sensors tends to be
claimed “good”, presenting linear response in the concentration
range encompassing the physiological blood glucose level
(3e8 mM). This may mislead readers because the actual linear
range needed to determine glucose levels in diluted samples are
much smaller than the physiological concentrations. To date, there
are only few examples that show the experimental results in un-
diluted whole blood, serum or interstitial fluid [130,131,146,147].
The major disadvantages of Pt are deactivation by halides and
interferences from concurrent electrochemical reactions, which
can be mitigated by nano-engineering. Some nanostructured Pt
maintain good stability and performance even with the use of
phosphate buffered saline (PBS) with 0.1 M of NaCl or KCl, a typical
electrolyte concentration. Many researchers confusingly abbreviate
phosphate buffer (PB) solution without salts as PBS. This needs
caution because the absence or presence of salts, particularly
chloride, is likely to give rise to critical difference, sometimes
leading to totally different conclusions. Many nanostructures of Pt
are known to improve anti-interference as favorable electrode
materials in glucose sensor applications.
3.2. Gold-based sensors
Gold is a well-studied electrode material, which gives high
glucose oxidation current in neutral or alkaline conditions
compared to other noble metals [49,148]. Like Pt, Au has been the
representative electrode material in glucose oxidation for several
decades, and intensively investigated in the fields of glucose fuel
cell. Despite the great amount of works, however, the oxidation
mechanism is still unclear and necessitates further studies. During
the anodic scan in cyclic voltammogram of Au, no hydrogen region
is observed while only the double layer region and Au oxide region
are present [50,51,114,120,121,149,150]. As in Pt, many researches
concede that the hydrogen abstraction of C-1 is the rate-deter-
mining step in Au electrodes. Some rotating disk electrode (RDE)
experiments showed smaller current density at higher rotation
rates in spite of the enhanced mass transfer, indicating the possi-
bility of the dehydrated glucose intermediate being very weakly
bound to the electrode surface, unlike Pt [114,149]. Although the
exact mechanism is yet undefined, it is certain that the surface state
of Au is greatly influential on the glucose oxidation. The glucose
oxidation at the Au oxide region is not as effective as in Pt [44].
Furthermore, the glucose oxidation takes place primarily in the
double layer region where surface OHads layers are formed
[44,50,114,149,150]. Other findings assert that the faradaic current
rises sharply at higher pH [44,49,121] and the oxidative current is
only observed at potentials higher than the oxide region at low pH
(<3) [48,49]. All these evidences consistently indicate the high
correlation between glucose oxidation and the presence of surface
oxides such as Au(OH)x or AunOm. Like Table 1, Table 2 lists all Au-
based non-enzymatic glucose sensors described in this section.
Numerous nanoporous Au samples have been synthesized by a
variety of methods such as templated electrodeposition [151e153],
selective dissolution [154e156], electrochemical etching [157e160]
and thermal annealing [161]. As in the case of Pt, the nanoporous
structure alleviate the adversities caused by anionic substances
such as Cl, SO2-
4 or molecular interferences from ascorbic acid and
uric acid. Chen et al. [155] synthesized nanoporous Au film with a
series of pore sizes of 18e50 nm by selective dissolution of Ag from
AuAg alloy. Although KCl had radical influences on oxidation effi-
ciency, the nanoporous Au film showed fair performance (linear
range: 1e18 mM, sensitivity: 20.1 mA cm-2 mM-1) in 0.1 M phos-
phate buffer solutions (pH 7.4) including 0.1 M KCl. The effects of
0.1 mM ascorbic acid and 0.05 mM uric acid were minimal. The
11
interferences diminished further in higher pH. Han et al. [161]
fabricated nanoporous Au film on FTO substrate by annealing
Au@BSA microspheres. The film suffered from negligible influence
upon addition of 0.15 M NaCl in the 0.2 M NaOH solution. Less than
4% current variation was observed in the mixed solution of 5 mM
glucose with 0.1 mM ascorbic acid, 0.1 mM acetamidophenol, and
0.1 mM uric acid as molecular interferences.
Although nanoporous structures assist in anti-interference
ability, some researchers have reported its limitations. Jeong and
Kim [162] prepared nanoporous Au films via electrochemical
etching to investigate the effect of Cl. The current decreased to 15%
of the original value when 0.1 M PBS (pH 7.0) including 0.1 M Cl
was used. Higher roughness factor (RF) improved the anti-inter-
ference ability, but to a limited extent. Lu et al. [154] synthesized a
porous self-supporting Au electrode by electrochemical alloying/
dealloying at elevated temperatures using ionic liquid and Zn2þ
ions. The glucose oxidative current was adversely affected by the
presence of interfering ions in the solution containing ionic liquid
species and NaOH. Xia et al. [158] used nanoporous Au electrode
made by electrochemical etching. They found that the electrode
showed good anti-interference against ascorbic acid and uric acid
in 0.1 M phosphate buffer solution (pH 7.4) with Na2SO4 as elec-
trolyte, while the presence of NaCl suppressed the current signal
from glucose and greatly increased those of ascorbic acid. Thus, the
glucose oxidation behavior and anti-interference abilities vary with
the synthetic methods of nanoporous Au electrodes, possibly due to
the difference in surface crystallinity [150] and trace amount of
adatoms or alloys [163e166].
A number of Au nanostructures with diverse morphologies were
employed for glucose detection [167e172]. Chang et al. [170]
electrodeposited different sized Au nanoparticles on a glassy car-
bon electrode, and tested the glucose oxidation performance in
0.1 M NaOH solution. They found that bigger nanoparticles showed
better catalytic activity, and that the optimal nanoparticle size was
40 nm in diameter. The electocatalytic performance was decent as
supported by the linear range of 0.1e25 mM, limit of detection
(LOD) of 0.05 mM, and sensitivity of 87.5 mA cm-2 mM-1. The anti-
interference effect was excellent as well, with strong resistance to
ascorbic acid, uric acid, 4-acetamidophenol and NaCl. This is not
surprising considering that the measurements were made in
alkaline solution, Hsu et al. [172] used photolithography to fabricate
hemispherical pattern arrays on a silicon wafer and sputtered Au
nanoparticles onto the film. The effective sensing area increased
10.2 times compared to that of planar Au electrode, resulting in low
detection limits (9 mM), acceptable linear range (0.06e14 mM) and
high sensitivity (749.2 mA cm-2 mM-1) in 0.1 M NaOH. The oxidative
current maintained its initial value after 20 potential cycles with
good anti-interference against ascorbic acid. Shu et al. [167] con-
structed dendrite-like gold structure on glassy carbon electrodes
via potentiostatic electrodeposition (see Fig. 6). Longer deposition
time added complexity to the dendrite structure, and this extension
of the dendrite network greatly augmented the glucose oxidation
current in the double layer region around 0.0 V vs. Ag/AgCl. The
linear sweep voltammetry (LSV) in 0.1 M phosphate buffer solution
(pH 7.4) showed good sensing performances (linear range:
0.1e2.0 mM and 2.0e25 mM, LOD: 50 mM, sensitivity: 180 mA cm-
2
mM-1), acceptable anti-interference against ascorbic acid, uric
acid and 4-acetamidophenol, accurate measurements in diluted
serum samples (less than 5% variation compared to commercial
sensors), and 15 days of shelf life.
Recently, bio-templated Au sensors have been actively investi-
gated [173e175]. Zhong et al. [173] used eggshell membrane as a
template, which is a well-known semi-permeable membrane. 3D
hierarchical porous Au networks were fabricated by electroless
plating and calcination. In 0.2 M NaOH, they observed good sensing
 12
Table 2
List of Au-based electrochemical non-enzymatic glucose sensors

Ref Catalyst Morphologya Substrate/ Binder Chemical Real Sample Linear Range (mM) LOD Sensitivity (mA cm2 Selectivitye Long-term Repeatabilityg Reproducibility
Electrodeb Environmentc Testd (mM) mM1) Stabilityf

[151] Au m-film Au-Si wafer e NaOH (0.1 M, pH 13 e 0.01e10 4.13 291.6 AA, UA N/A 15% (5000 s N/A
ca.) CA)
[152] Au Nanocoral SPCE e PB (0.1 M, pH 7.4) e 0.05e30 10 22.6 AA, UA N/A Stable (n ¼ 8) N/A
[153] Au mp film Au disk e PBS (0.1 M, pH 7.4) e 2e10 5 11.8 AA, AP, UA, KCl 2 d (PBS, N/A N/A
Stable)
[154] Au np Film Au wire e PB (0.05 M, pH 7.0) e N/A N/A N/A IL N/A N/A N/A
[155] Au np Film GCE Nafion PB (0.1 M, pH 7.4) e 1e18 3 20.1 AA, UA N/A 10% (n ¼ 500) N/A
[156] Au np Film GCE Nafion PB (0.1 M, pH 7.4) e 0e10 1 N/A AA, UA, Suc N/A N/A 8.15 (n ¼ 6)
[157] Au np Film ITO glass Nafion PB (0.1 M, pH 7.4) e N/A N/A N/A N/A N/A 95% (n ¼ 200) N/A
[158] Au np Film Au disk e PB (0.1 M, pH 7.4) e 0.01e11 8.7 66 AA (w/o Cl-), UA N/A 2.69% (n ¼ 5) N/A
[159] Au np Film Au disk Nafion NaOH (0.01 M, pH 12 HBS (diluted) 0.002e1.375 1.375e15 0.5 N/A AA, UA 30 d (r.t., 96%) N/A 2.72% (n ¼ 5)
ca.)
[160] Au np Film Au disk e PB (0.1 M, pH 7.0) e 0e15 10 35.3 AA N/A N/A N/A

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

[161] Au np Film FTO glass e NaOH (0.2 M, pH e 0.01e10 2 10.65 AA, AP, UA, NaCl 30 d (r.t., 98%) 5% (3 h CA) 2.2% (n ¼ 5)
13.3 ca.)
[162] Au np Film Au disk Nafion PB (0.1 M, pH 7.0) e N/A N/A 120 AA, Cl- N/A N/A N/A
[167] Au Dendrite GCE e PB (0.1 M, pH 7.4) IV Sol'n 0.1e25 50 190.7 AA, AP, UA 15 d (r.t., 7.06% 4.3% (n ¼ 5)
(diluted) 92.1%) (n ¼ 15)
[168] Au MP array Au/Si wafer e PBS (0.01 M, pH 7.4) e 0.5e9 60 13.2 AA, NaCl, KCl N/A 3.0% (n ¼ 10) 3.2% (n ¼ 5)
[169] Au NP film ITO glass e KOH (0.5 M, pH 13.7 HU (diluted) 0e11 5 23 AA, UA, NaCl N/A 6.0% (n ¼ 15) 6.9% (n ¼ 10)
ca.)
[170] Au NP GCE Nafion NaOH (0.1 M, pH 13 e 0.1e25 50 87.5 AA, AP, UA, NaCl 4 w (Stable) N/A N/A
ca.)
[171] Au NP ITO glass e NaOH (0.1 M, pH 13 IV Sol'n (N/A) 0.001e0.17 0.2e15 0.4 N/A AA, AP 20 d (r.t., 90%) N/A 3.5% (n ¼ 3)
ca.)
[172] Au NP film Si wafer e NaOH (0.1 M, pH 13 e 0.0556e13.89 9 749.2 AA 2m Stable N/A
ca.) (unspecified) (n ¼ 20)
[173] Au hp film GCE Nafion NaOH (0.2 M, pH HBS (N/A) 0.001e0.5 4.0e12 0.2 N/A AA, AP, DA, UA 21 d (r.t., 93%) 5% (n ¼ 10) 8.1% (n ¼ 5)
13.3)
[174] Au L-R GCE Nafion NaOH (0.1 M, pH 13 SB (diluted) 0.002e23 0.87 29 AA, UA N/A N/A N/A
ca.)
[175] Au NP Diatom biosilica e NaOH (pH 9) e N/A N/A N/A N/A N/A N/A N/A
[176] Au NP GO NR/CS Nafion PB (0.1 M, pH 7.0) e 0.0005e10 0.005e4.92 0.5/5 59.1, 31.4, 57.1 AP, UA N/A N/A 2.72% (n ¼ 6)
4.92e10
[177] Au NP MWCNT-CG/Au e NaOH (0.05 M, pH HBP (diluted) 0.001e1 0.5 27.7 AA, UA, DA, Cl- 60 d (r.t., 90%) 3.3% 1.2% (n ¼ 6)
disk 12.7 ca.) (n ¼ 525)
[178] Au NP PANI/GCE e PB (0.1 M, pH 7.0) e 0.3e10 100 N/A AA, AP, UA, Gal, Tyr 14 d (4  C, 95%) 2.5% (n ¼ 20) N/A
[179] Au NP PANI arrays/CC e KOH (0.5 M, pH 13.7 HBS (diluted) 0.01026e10 3.08 150 AA, AP, UA, Fru, Gal, 15 d (r.t., 95%) N/A 6.7% (n ¼ 5)
ca.) NaCl, KCl
[180] Au NP PPy NF/GCE Nafion PB (0.1 M, pH 7.4) e 0.2e13 N/A 1.003 AA, Urea N/A N/A N/A
[181] Au NP Cht/GCE e NaOH (0.1 M, pH 13 Rat BS 0.4e10.7 370 N/A AA 2 w (93%) 4.4% (n ¼ 10) N/A
ca.) (diluted)
a
np ¼ nanoporous, mp ¼ macroporous, hp ¼ hierarchical porous, NP ¼ nanoparticle, NC ¼ nanocube, NFw ¼ nanoflower, MP ¼ micropillar, L-R ¼ lamellar ridge-like
b
SPCE ¼ screen-printed carbon electrode, GCE ¼ glassy carbon electrode, ITO ¼ indium tin oxide, FTO ¼ fluorine doped tin oxide, AC ¼ activated carbon, GO ¼ graphene oxide, NR ¼ nanorod, MWCNT ¼ multi-walled carbon
nanotube, CNF ¼ carbon nanofiber, MN ¼ microneedle, m-C ¼ mesoporous carbon, CG ¼ cryogel, CS ¼ carbon sheet, Cht ¼ chitosan film, PANI ¼ poly(aniline),
c
PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer
d
HWB ¼ human whole blood, BS ¼ blood serum, HBP ¼ human blood plasma, IV sol’n ¼ intravenous glucose injection solution, DMEM ¼ Dulbeco’s modified Eagle’s Medium (contains salts, amino acids, minerals, and
vitamins)
e
AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, AS ¼ acidum salicylicum, Ch ¼ cholesterol, Ep ¼ ephedrine, EtOH ¼ ethanol, Fru ¼ fructose, Gal ¼ galactose, Tyr ¼ L-tyrosine, Xyl ¼ xylose
f
d ¼ day, w ¼ week, m ¼ month
g
Some repeatability tests consist of measuring chronoamperometry for a certain time. When only a single test was done, the measured time was presented. CA ¼ chronoamperometry, CV ¼ cyclic voltammetry.
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34 13

Fig. 6. (a) SEM image of dendrite-like gold nanostructure (DGN). (b) Chronoamperometry curve of DGN-modified glassy carbon (GC) electrode with successive additions of 1.0 mM
and 5.0 mM glucose in 0.1 M PBS, pH 7.4; applied potential ¼ 0.15 V. (c) Chronoamperometry curve of the DGN-modified GC electrode with successive additions of 1.0 mM glucose,
0.1 mM AA, 0.05 mM AP and 0.05 mM UA at a constant detection potential of 0.15 V. (d) Linear sweep voltammograms of the DGN-modified GC electrode in a 0.1 M PBS solution
containing 10 mM glucose, 1.0 mM AA, 1.0 mM AP, and 1.0 mM UA; scan rate ¼ 100 mV s1. Reprinted with permission from Ref. [167]. Copyright 2014, Elsevier. (For interpretation of
the references to color in this figure legend, the reader is referred to the Web version of this article.)

performance (linear range: 1e500 mM and 4.0e12 mM, LOD:
0.2 mM), good anti-interference, excellent stability (Oxidative cur-
rent after 21 days ¼ 93%), and accurate measurements of diluted
human serum. Guo et al. [174] adopted Morph butterfly wing as a
template to synthesize zig-zag shaped lamellar-ridge Au micro-
structure through electroless deposition and Nafion coating. They
reported favorable sensing performances in 0.1 M NaOH (linear
range: 0.002e23 mM, LOD: 0.87 mM, sensitivity: 29.0 mA cm-2 mM-
1
), acceptable anti-interference, and accurate measurements in 20-
fold diluted synthetic blood serum. While the calculated electro-
chemically active surface area (ECSA) of lamellar-ridge Au was 4.8
time that of flat Au disk electrode, the actual sensitivity increased
by 5.8 times, more than the increase in surface area. The authors
attributed the phenomenon on enhanced mass transport efficiency
caused by the thin-layer diffusion on multi-stacked lamellar
microstructure.
As for Au composite materials, many substrate materials have
been tested including graphene [176], carbon nanotube [177],
conducting polymer [178e180] and adhesive polymer film [181].
Ismail et al. [176] constructed polypyrrole-Nafion coated Au
nanoparticle-graphene oxide nanoribbon composite structure by
mixing and heat treating nanoribbons made from unzipping
MWCNT with Au nanoparticles (Ppy-Nafion/Au/GONR/CS). The Au/
GONR structure performed well in 0.1 M phosphate buffer solution
(pH 7.0), exhibiting adequate linear range (0.005e4.92 mM,
4.92e10 mM), detection limit (5 mM) and sensitivity (59.1 mA cm-
2
mM-1). Without the protective polymeric layer, however, the
structure completely lost the ability to oxidize glucose in presence
of 0.1 M KCl. Only with the help of protective layer, it could work
with good anti-interference. Kangkamano et al. [177] made porous
composite cryogel electrode through blending and freezing the Au
nanoparticle decorated MWCNT with chitosan solution mixture.
They applied the thawed cryogel to a flow-injection system.
Although the linear range was limited to the mM range
(0.001e1 mM), the cryogel electrode showed excellent detection
limit (0.5 mM) in 0.05 M NaOH. As this system was measured in
0.05 M NaOH solution, the dilution of real sample is a necessary
process for detecting, which can be easily done by employing an
automated flow-injection system. The sensor as prepared suc-
cessfully proved itself capable of determining glucose concentra-
tion in blood plasma samples by comparing 20 measurements with
the standard hospital hexokinase method.
The major benefit of using Au-based electrodes as glucose sen-
sors is the comparable or possibly higher current response
compared to Pt, leading to higher sensitivity, and its capability to
function in neutral pH. Unlike Pt, however, the oxidation efficiency
responds sensitively to the surface state of Au, especially to the
presence of surface OHads. Hence, the glucose oxidation is greatly
activated in basic solutions, leading to most studies being con-
ducted in alkaline solutions. While the alkaline environment pro-
vide enhanced sensing performances in laboratory works, it is not
practical to apply such conditions to real samples unless exploiting
an automated flow system as shown in the works of Kangkamano
et al. [177]. This limitation intensifies when it comes to continuous
in vivo blood glucose monitoring. Furthermore, Au-based elec-
trodes suffer from severe poisoning from various anions including
14 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

chloride and phosphates. Lastly, the lack of selectivity against easily
oxidizable interferents such as ascorbic acid remains unsolved.
3.3. Metal alloy- and adatom-based glucose sensors
Alloys and adatoms are a long addressed topic with regard to
surface catalysis [163e166,182e185]. Heteroatoms inside alloys
and adatoms provide new binding sites or reaction pathways that
can dramatically influence the binding energy or the activation
energy of the reagent and the intermediate, possibly leading to a
new reaction pathway and reduced overpotential. Owing to the
emergence of computational chemistry, new multi-metallic sys-
tems of alloys and adatoms based on general electrode materials
such as Pt, Au and Pd have been extensively addressed in order to
enhance their catalytic efficiency, anti-interference and stability.
Similarl to the preceding tables, Table 3 lists all alloy and adatom-
based non-enzymatic glucose sensors described in this section.
A combination of noble metal catalysts such as Au-Pt, Pt-Pd, Pt-
Ir, and Pt-Ru are the most examined bimetallic systems for glucose
oxidation [186e195]. Alloys and adatoms of Au and Pt are popular
bimetallic systems, usually made by electrodeposition or selective
dealloying. Jia et al. [191] electrodeposited Pt nanoparticles onto

Table 3
List of alloy and adatom-based electrochemical non-enzymatic glucose sensors

Ref Catalysta Morphology Substrate/ Binder Chemical Real Linear LOD Sensitivity Selectivitye Long- Repeatabilityg Reproducibility
a
Electrodeb Environmentc Sample Range (mM) (mA cm2 term
Testd (mM) mM1) Stabilityf

[186] Pd- Thin film CD-R e PB (0.1 M, pH HBS (N/ 1e33 5 0.25 AA, UA 30 d (r.t., 4.1% (n ¼ 5) 4.7% (n ¼ 6)
npAu 7.4) A) 92%)
[187] Pt-npAu SM film Au disk e PBS (0.1 M, e 0.5e10 0.6 145.7 AA, AP, UA 5 d (PBS, Stable (2 h) N/A
pH 7.4) 95%)
[188] Pt-Au np Film C-powder Nafion PBS (0.1 M, e 0.2e4.8 1.3 12.85 AA, DA, UA N/A Stable (2000 s N/A
/GCE pH 7.0) CA)
[189] Pt-Au np Film C-powder Nafion PBS (0.1 M, e 0.2e5.4 0.5 N/A AA, DA, UA 14 d (PBS, Stable (2000 s 2.97% (n ¼ 5)
/GCE pH 7.0) 97.5%) CA)
[190] Pt-Ru NP GCE e PBS (0.01 M, e 0.0001 0.3 31.3 AA, UA, Fru 30 d (PBS, N/A <5.0% (n ¼ 10)
pH 7.4) e4 95%)
[191] Pt NP d-Au /GCE e PB (0.1 M, pH IV Sol'n 1e14 10 239.49 AA, AP, UA 15 d (PBS, N/A 2.11% (n ¼ 5)
7.4) (diluted) 95.25%)
[192] Pt-Au NF BDD /Si e PB (0.1 M, pH e 0.01e7.5 6.5 N/A AA, AP, UA, NaCl 2 w (r.t., 3.6% (n ¼ 15) 3.2% (n ¼ 6)
wafer 7.4) 93%)
[193] Pt-Ir np Film Ti plate e PBS (0.1 M, e 0e10 N/A 93.7 AA, AP, UA, NaCl N/A N/A N/A
pH 7.4)
[194] Pt-Pd NP m-C/GCE Nafion PBS (0.1 M, e 1.5e12 120 0.11 AA, DA, UA 2 w (4  C, N/A 5.2% (n ¼ 5)
pH 7.4) 92.6%)
[195] Pt-Pd NP G NSd Nafion PB (0.05 M, e 0.5e24.5 N/A 1400 AA, AP, UA, NaCl N/A N/A N/A
/GCE pH 7.4)
[197] Pt-Cd np Film GCE Nafion PB (0.1 M, pH e 0e10 50 146.21 AA, AP, UA 1 m (N/A, 4.3% (N/A) 5% (n ¼ 5)
7.4) 90%)
[198] Ni-Cu Thin film GCE e NaOH (1.0 M, e 1e9 0.8 N/A N/A N/A Stable N/A
pH 14 ca.) (n ¼ 150)
[199] Pd-Cu- NC GCE Nafion KOH (0.1 M, e 1e10 1.29 553 AA, UA, Fru, Man N/A Stable N/A
Pt pH 13 ca.) (n ¼ 50)
[200] Pt-Cu NSd GCE Nafion PBS (0.1 M, HBS (N/ 0.1e19 25 23 AA, AP, UA, Fru, 30 d (PBS, 3.5% (n ¼ 20) 2.8% (n ¼ 5)
pH 7.4) A) NaCl 90%)
[201] Pt-Cu NCh GCE Nafion PBS (0.1 M, HBS 0.01e17 2.5 135 AA, AP, UA, Fru, 30 d (air, 3.8% 3.2% (n ¼ 5)
pH 7.4) (diluted) NaCl 98%) (n ¼ 100)
[202] Pt-Ni NCl MWCNT/ Nafion PB (0.1 M, pH HBS 0e15 0.3 940 AA, AP, DA, UA, 2 (N/A, 10% (2 m CA) 3.5% (n ¼ 5)
GCE 7.4) (diluted) Urea, Fru, Gal, Lac 99%)
[203] Pt-Pb NSt Au disk e PB (0.2 M, pH e 0e12 8.4 10.71 AA 50 d (PB, 5.4% (n ¼ 10) N/A
7.0) 90%)
[204] Pt-Pb NW array Pt disk e PB (0.1 M, pH e 0e11 8 11.25 AA 1m N/A N/A
7.4) (Stable)
[205] Pt-Pb NP MWCNT/ Nafion PB (0.01 M, e 0e5 7 18 AA, UA, Fru N/A N/A N/A
Ta plate pH 7.4)
[206] Pt-Te MT Pt disk e PB (0.1 M, pH e 0.1e1, 1 100 522.61, 62.45 UA, Fru, Sorb, N/A N/A 1.47% (n ¼ 3)
7.0) e29 Gal,Man, Arb,Xyl,
Fuc, Suc
[207] Co@Pt NP VC/GCE Chitosan PB (0.1 M, pH HBS 1e30 300 2.26 AA, AP, UA, Fru, 30 d (PB, N/A 4.7% (m ¼ 5)
7.0) (diluted) NaCl 96%)
[208] Pt-Bi Bi/Pt NP GCE Bi NaOH (0.1 M, e 0e0.3 0.43 23 AA, AP, UA 1m 1.27% (n ¼ 7) N/A
pH 13 ca.) (Stable)
a
np ¼ nanoporous, mp ¼ macroporous, hp ¼ hierarchical porous, MT ¼ microtube, NP ¼ nanoparticle, NC ¼ nanocrystal, NCl ¼ nanocluster, NCh ¼ nanochain, NF ¼ nano-
fiber, NSd ¼ nanostrand, NSt ¼ nanostructure, NW ¼ nanowire, SM ¼ submonolayer
b
GCE ¼ glassy carbon electrode, G ¼ graphene, MWCNT ¼ multi-walled carbon nanotube, d-Au ¼ dentrite-like Au, VC ¼ Vulcan carbon, C-powder ¼ carbon powder, m-
C ¼ mesoporous carbon, G NSd ¼ graphene nanostrand, BDD ¼ boron-doped diamond, CD-R ¼ compact disk-recordable
c
PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer
d
HWB ¼ human whole blood, BS ¼ blood serum, HBP ¼ human blood plasma, IV sol’n ¼ intravenous glucose injection solution, DMEM ¼ Dulbeco’s modified Eagle’s Me-
dium (contains salts, amino acids, minerals, and vitamins)
e
AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose, Man ¼ mannose, Suc ¼ sucrose, Sorb ¼ sorbitol,
Arb ¼ arabinose, Lac ¼ lactose
f
d ¼ day, w ¼ week, m ¼ month
g
CA ¼ chronoamperometry, CV ¼ cyclic voltammetry.
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34 15

dendrite-like Au film on glassy carbon electrode. Combination of
the two components synergetically enhanced the oxidative current
of glucose and improved anti interference compared with single
component systems such as Pt nanoparticle electrode or dendrite-
like Au film. Nantaphol et al. [192] electrodeposited Au and Pt
consecutively on a boron-doped diamond electrode to prepare Pt/
Au/BDD electrode. It performed best when the composition ratio of
Pt:Au was 1:1, displaying about 2-fold enhancement of anodic
current density in 0.1 M phosphate buffer solution (pH 7.4) con-
taining 0.1 M NaCl. In cyclic voltammetry, the combination of Pt and
Au gave rise to a substantial increase in the anodic current of
glucose while the concomitant currents from interferents such as
ascorbic acid, p-acetamidophenol and uric acid remained practi-
cally the same.
Bimetallic systems using transition metals were also extensively
investigated [189,196e208]. Zhao et al. [202] synthesized 3D
flower-like PtNi nanoparticle on MWCNT by electrodeposition (see
Fig. 7). In 0.1 M phosphate buffer solution (pH 7.4), the PtNi elec-
trode gave maximum anodic current when the ratio of Pt and Ni
was 3:7. The Pt3Ni7 electrode showed excellent catalytic perfor-
mance with linear range up to 15 mM, sensitivity of 940 mA cm-
2
mM-1, limit of detection of 0.0003 mM, and virtually complete
resistance towards various interferences including oxidizable spe-
cies and monosaccharides. Although the anti-interference ability
against anionic species such as Cl was not tested, it demonstrated
good performance in diluted serum and great stability in a month-
long consecutive measurement, retaining 90% of the initial current.
Guascito et al. [206] tested Pt-Te system fabricated by a drop casting
Te microtubes on a Pt-disk electrode. The presence of Te microtubes
on a Pt disk electrode inhibited the oxidative current entirely in the
hydrogen region at 0.6 ~ 0.3 V (vs. SCE), while greatly enhancing
the anodic peak at þ0.38 V. The amperometric tests verified sen-
sitive anodic response to glucose and great sensing efficiency
(linear range: 0.1e1.0 mM and 1.0 mMe29 mM, LOD: 0.1 mM,
sensitivity: 522.61 and 62.45 mA cm-2 mM-1 for each linear range).
Even high concentrations of interferents (1 mM) such as uric acid
and eight different mono/disaccharides brought about only minute
signals. Unfortunately, they presented no result on anti-interfer-
ence against some common interferents such as ascorbic acid and
4-acetamidophenol, and anions such as Cl. Many multi-metallic
systems still lack anti-interference data against anionic species
such as Cl, which is considered as one of the major adversities.
The multi-metallic system of alloys and adatoms has great po-
tential to synergetically facilitate electro-oxidation of glucose.
There are many reports claiming its superior sensing performance
than those of single component electrodes. Systems involving Pt or
Au provide glucose-sensing platforms that are operable in neutral
pH besides better current response and anti-interference. The cost
of such materials, however, remains problematic. Lower amount of
precious metals in actual composite electrode materials are not

Fig. 7. The schematic illustration of the synthetic process of Nafion-coated 3D PtxNi1-x/MWCNT (a) and its typical TEM image (b). (c) The calibration curve, representing the current
response vs. glucose concentration using a. Pt3Ni7/MWCNTs-Nafion, b. 3D Pt/MWCNTs-Nafion, c. 3D Ni/MWCNTs-Nafion and d. 3D Pt3Ni7/MWCNTs(0.001s)-Nafion electrodes
at 0.3 V vs. Ag/AgCl in 0.1 M phosphate buffer solution (pH 7.4). (d) Anti-interference test result using materials the same as (c). 1 mM of reagent was consecutively injected into
the 0.1 M phosphate buffer solution solution at 1 min interval and its current response was measured at 0.3 V vs. Ag/AgCl. Reprinted with permission from Ref. [202]. Copyright
2016, Elsevier.
Table 4

16
List of Ni / Ni oxide-based electrochemical glucose sensors

Ref Catalysta Morphology Substrate/ Binder Chemical Real Sample Testd Linear Range LOD Sensitivity (mA cm2 Selectivitye Long-term Repeatabilityg Reproducibility
a
Electrodeb Environmentc (mM) (mM) mM1) Stabilityf

[211] Ni NP rGO/ GCE e NaOH (0.1 M, pH 13 HBS (diluted) 0.00025e1.2 0.01 0.0025 mA mM1 AP, UA, EtOH 1 m (N/A, 1.9% (n ¼ 5) 2.2% (n ¼ 5)
ca.) 97.8%)
[212] Ni NP MWCNT/GCE e NaOH (0.1 M, pH 13 HBS (diluted) 0.001e1 0.5 1438 AA, DA, UA, Gal, Xyl 60 d (NaOH, 4.0% (n ¼ 8) 5.9% (n ¼ 5)
ca.) 90%)
[213] Ni 3D porous SPCE e NaOH (0.1 M, pH 13 Mice BS (N/A) 0.0005e4 0.07 2900 AA, AP, DA, UA, Fru, Gal, Lac 1 m (NaOH, Stable N/A
film ca.) 90%) (n ¼ 100 CV)
[214] Ni-Au Multi-layer Au/ITO e NaOH (0.1 M, pH 13 Urine (diluted) 0.00025e2.0 2.0 0.1 3372 1906 AA, UA, H2O2, Tyr 3 w (NaOH, N/A 3.6% (n ¼ 3)
NW ca.) e5.5 92%)
[215] Ni NP TiO2 NW array/ e NaOH (0.1 M, pH 13 e 0.001e7 0.18 50.97 AA, UA 60 d (Stable) Stable Stable (n ¼ 5)
Ti foil ca.) (n ¼ 500 CV)
[216] Ni NP Cht-GO/ SPCE e NaOH (0.1 M, pH 13 HU (diluted) 0e9 4.1 318.4 AA, UA, DA 2 w (r.t., 12.6% (n ¼ 5) 13.7% (n ¼ 5)
ca.) 84.9%)
[217] Ni Metal foam Self-supporting e NaOH (0.1 M, pH 13 HBS (diluted) 0.05e7.35 2.2 N/A AA, DA, UA, Sal, Cys 10 d (r.t., 96%) 3.5% (n ¼ 10) N/A
ca.)
[218] Ni NP Porous GF/ GCE Nafion NaOH (0.1 M, pH 13 e 0.015e6.45 4.8 207.3 AA, DA, UA, Fru, Lac, Man 10 d (4  C, 2.5% (n ¼ 6) 7.2% (n ¼ 5)

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

ca.) 95.2%)
[219] NiO Microfiber FTO glass e NaOH (0.1 M, pH 13 e 0.001e0.27 0.033 1785.41 AA, DA 30 d (r.t., 96%) 2.4% (n ¼ 8) 4.6% (n ¼ 6)
ca.)
[220] NiO Hollow MS GCE Nafion NaOH (0.1 M, pH 13 HBS (N/A) 0.00167e6.87 0.53 2390 AA, DA, UA, NaCl 10 d (NaOH, 5.2% (N/A) 3.7% (n ¼ 4)
ca.) 93%)
[221] NiO Hollow MS GCE Nafion NaOH (0.1 M, pH 13 e 0.005e0.364 2 288870 37820 AA, Urea, Leu, Pro, Lys, NaCl 3 d (Stable) N/A N/A
ca.) 2.96e7.46
[222] NiO Porous thin Si wafer and e NaOH (0.1 M, pH 13 Human blood 0e1 0.34 1680 AA, AP, UA, Fru, Lac, Suc, 2 m (r.t., N/A N/A
film ITO glass ca.) sample (N/A) NaCl Stable)
[223] NiO NS Ni foam e NaOH (0.5 M, pH HBS (N/A) 0.005e5.5 0.46 6657.5 AA, Fru, Lac, NaCl 10 d (N/A, 5.8% (n ¼ 6) 5.3% (n ¼ 5)
13.7 ca.) 92%)
[224] NiO Hollow cage GCE Nafion NaOH (0.1 M, pH 13 HBS (diluted) 0.1e5 0.1 2476.4 AA, DA, UA 2 m (NaOH, N/A <1.0% (n ¼ 15)
ca.) 95%)
[225] NiO-Pt NP rGO/ GCE e NaOH (0.05 M, pH HBS (N/A) 0.001e5.66 0.2 668.2 AA, AP, DA, UA, Gal, Lac 1 m (4  C, 32.16% 5% (n ¼ 5)
12.7 ca.) 90%) (2000 s CA)
[226] NiO-C NS Ti foil e NaOH (0.1 M, pH 13 e 0e2.6 2 582.6 N/A 60 d (N/A, N/A N/A
ca.) 93.6%)
[227] NiO Hollow MS GCE e NaOH (0.1 M, pH 13 e 0.002e0.01 0.05 0.3 N/A AA, DA, UA N/A 5.8% (n ¼ 5) N/A
ca.) e3.3
[228] NiO- NS/ MP GCE e NaOH (0.1 M, pH 13 e 0.0005e6.4 0.5 120 AA, DA, UA, NaCl N/A N/A N/A
ZnO ca.)
[229] NiO NP DNA-rGO/ GCE Nafion NaOH (0.1 M, pH 13 e 0.001e8 2.5 9 N/A N/A N/A N/A
ca.)
[230] NiO NP Graphite e NaOH (0.5 M, pH Juice (diluted) 0.001e0.11 0.16 43.9 AA, DA, KCl 1 m (r.t., 2.3% (n ¼ 5) 4.9% (n ¼ 5)
powder 13.7 ca.) Stable)
[231] NiO NFl FTO glass e NaOH (0.1 M, pH 13 e 0.01e0.8 1.2 8500 AA, Fru, Lac N/A N/A N/A
ca.)
[232] NiO NP rGO/ GCE e NaOH (0.1 M, pH 13 HU (diluted) 0.00313e3.05 1 1087 AA, UA, NaCl 10 d (r.t., 95%) 4.8% (n ¼ 16) 5.1% (n ¼ 5)
ca.)
[233] NiO NP MWCNT e NaOH (0.1 M, pH 13 HBS (diluted) 0.01e7 2 1768.8 AA, DA, UA, Fru, Lac, Cl ion N/A 9% (n ¼ 25) 5.1% (n ¼ 3)
ca.)
[234] NiO-Cu NS GCE Nafion NaOH (0.1 M, pH 13 e 0.0005e5 0.5 171.8 AA, UA, Fru 50 d (NaOH, 2.46% (n ¼ 5) 2.13% (n ¼ 5)
ca.) Stable)
[235] Ni(OH)2 Thin coating np Au film/Au e NaOH (0.1 M, pH 13 HBS (diluted) 0e7 0.73 3529 AA, UA, NaCl, SC, Na2SO4, 3 w (4  C, N/A 1.19% (n ¼ 6)
disk ca.) NaH2PO4, TFA 84.4%)
[236] Ni(OH)2 Nanobox GCE Nafion NaOH (0.1 M, pH 13 HBS (N/A) 0.0005e5 0.07 487.3 AA, DA 30 d (NaOH, 2.7% (N/A) N/A
ca.) 95%)
[237] Ni(OH)2 NP rGO/Au coated e NaOH (0.1 M, pH 13 e 0.02e30 15 11.4 AA, DA, UA 1 m (r.t., 98%) N/A 6.2% (n ¼ 4)
glass ca.)
[238] Ni(OH)2 NW Ni foam e e 0.1e6 1 1598 UA, Urea, Fru, Lac, NaCl, KCl N/A 5% (n ¼ 5)
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34 17

only true for fuel cells but also for glucose sensors. It should be

GCE ¼ glassy carbon electrode, G ¼ graphene, rGO ¼ reduced graphene oxide, GF ¼ graphene foam, MWCNT ¼ multi-walled carbon nanotube, ITO ¼ indium tin oxide, FTO ¼ fluorine doped tin oxide, VC ¼ Vulcan carbon, C-

AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose, Mal ¼ maltose, Man ¼ mannose, Suc ¼ sucrose, Sorb ¼ sorbitol, Arb ¼ arabinose, Lac ¼ lactose,
warned that this may lead to overlook or mislead the true reason

2.67% (n ¼ 5) 2.69% (n ¼ 5)
10 d (r.t., 95%) 3.4% (n ¼ 10) 2.9% (n ¼ 5)

2.9% (n ¼ 5)

6.4% (n ¼ 5)
underlying the observation. It is very probable that the break-
through of non-enzymatic glucose sensing will come from funda-

np ¼ nanoporous, mp ¼ macroporous, MP ¼ microparticle, NP ¼ nanoparticle, NFl ¼ nanoflake, NS ¼ nanosheet, NW ¼ nanowire, Inorg.Cplx ¼ inorganic complex, MOCP ¼ Metal-organic coordination polymer
N/A

mental understanding of the complex multi-metallic systems.

Nevertheless, the excellent performance of alloys and adatoms
<6% (n ¼ 60)
1.6% (n ¼ 7)

gives significant inspiration for the development of non-enzymatic

glucose sensing.
N/A

3.4. Non-precious transition metal-based glucose sensors

21 d (NaOH,
7 d (NaOH,

The research on economic glucose oxidation catalysts based on

30 d (r.t.,

8 w (air,
89.96%)

Stable)

Stable)

non-precious transition metals have gained enormous attention

>90%)
N/A

from material scientists [209]. As elucidated in Section 2.2, the

chemistry of glucose oxidation in transition metal catalysts in-
Cel ¼ cellulose Sal ¼ Salicylate, CA ¼ Citric acid, TFA ¼ trifluoroacetic acid, SC ¼ sodium citrate, Leu ¼ L-leucine, Pro ¼ L-proline, Cys ¼ L-cysteine, Lys ¼ L-lysine, Gly ¼ L-glycine
AA, DA, UA, Fru, Suc, CA, Cl

volves redox reactions between metal oxides with lower and higher
oxidation numbers (lower and higher oxides) [52e57,210]. In
AA, DA, Urea, Fru, Lac

nickel-based electrodes, for instance, the redox species Ni(II)(OH)2

AA, DA, UA, NaCl
AA, DA, UA, Sal

and Ni(III)OOH (often wrote as Ni(II)/Ni(III)) is considered to be the

AA, UA, Cys

reaction center of glucose oxidation. The catalytic NiOOH species is

reduced to Ni(OH)2 in the glucose oxidation process via hydrogen
abstraction of C-1 hydrogen atom. The dehydrogenated radical in-
powder ¼ carbon powder, C-paste ¼ carbon paste, m-C ¼ mesoporous carbon, IL ¼ ionic liquid, SPCE ¼ screen-printed carbon electrode, Cht ¼ chitosan

termediate is further oxidized into glucono-d-lactone and finally

into gluconic acid by hydrolysis. The coincidence of the anodic peak
of transition metal species and the glucose oxidation supports the
1

involvement of the transition metal center in this process [54e57].

36.9 mA mM

As glucose is added, the anodic current of the metal oxide at the

32790
2650

oxidation potential rises whereas the cathodic peak remains un-

N/A

N/A

HWB ¼ human whole blood, HBS ¼ human blood serum, BS ¼ blood serum, HBP ¼ human blood plasma, HU ¼ human urine

changed. This suggests that some of the higher metal oxides formed
during the anodic potential are readily reduced into lower oxides in
0.34

0.14

0.05
0.2

the presence of glucose, oxidizing it into gluconolactone. On the

1

other hand, the cathodic current remain the same because the total
amount of the higher metal oxide exposed on the surface is limited
0.0015e1.48
0.001e1.17

0.01e8.75

0.005e2.8

by the electrode surface area [53].

0.002e5

Among numerous transition metals, Cu-, Ni- and Co-based

metal and metal oxide electrodes have been main targets of
research motivated by their good catalytic performance. In partic-
ular, nickel is the most intensively examined transition metal
HBS (diluted)

HBS (diluted)

HBS (diluted)

catalyst, and comes in a various forms such as Ni [211e218], NiO

[219e234], Ni(OH)2 [235e239], and Ni metal-organic complex
[240,241]. Metal or carbon-based conductive substrates are often
used due to the low conductivity of many transition metal oxides.
e

As mentioned above, the redox couple of the Ni species is Ni(II)/

NaOH (0.1 M, pH 13

Chitosan NaOH (0.1 M, pH 13

NaOH (0.1 M, pH 13

NaOH (0.1 M, pH 13

NaOH (0.1 M, pH 13
NaOH (0.3 M, pH

Ni(III). Regardless of the initially synthesized form, the surface of

the electrode is eventually converted into the Ni(OH)2/NiOOH
13.48 ca.)

redox couple during the electrocatalysis. For example, widely used

NiO is activated by OH in the solution into the Ni(OH)2 form
ca.)

ca.)

ca.)

ca.)

ca.)

[52,53,242,243]. Ni-based catalysts give oxidative current from

PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer

Ni2þ/Ni3þ conversion between potentials þ0.2 ~ þ0.4 V (vs. Ag/

CA ¼ chronoamperometry, CV ¼ cyclic voltammetry.

AgCl), where glucose oxidation also take place [52,53,242,243].

Table 4 lists all Ni and Ni oxide-based non-enzymatic glucose
e

Porous Si MP/ C e

sensors described in this section.

MWCNT in IL

Ensafi et al. [244] fabricated an home-made Ni@Si rod electrode

rGO/ GCE

by synthesizing Ni@Si microparticles by electroless deposition of Ni

Ni foam
3D GF

paste

paste

on hydrogen fluoride-etched porous Si microparticles, followed by

d ¼ day, w ¼ week, m ¼ month

packing the particles and graphite powder mixture into a syringe. A

number of interesting fundamental electrochemical measurements
Inorg. Cplx.

were conducted using the Ni@Si electrode. The Ni(II)/(III) anodic

current increases and the anodic peak negatively shifts as pH rises,
NP

NP
[239] Ni(OH)2 NS

NS

as previously seen in previous researches [52,53,243]. The studies

on the pH dependence concluded that the Nernstian electro-
MOCP

[248] Ni-C

chemical reaction involves the transfer of two electrons rather than

[240] Ni-

[241] Ni

[244] Ni

one in a single Ni(II) to Ni(III) oxidation reaction. This phenomenon

was ascribed to the hyper-extended polymeric oxide species shown
a

g
b

f
c
d

below [245e247], and similar chemical species are expected to be

18 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

involved in the glucose oxidation.

[Ni(II)2(OH)6(OH2)3]2-
n þ 3nOH /
e
[Ni(III)2O3(OH)3(OH2)3]3-
n þ3nH 2O þ 2ne
2Ni(III) þ glucose / 2Ni(II) þ gluconolactone
The fabricated porous Ni@Si sensor displayed decent sensing
performance, response time and stability in 0.1 M NaOH. The sur-
face of Si particle contains negatively charged Si-O-, which
contribute to the good resistance against various interferents even
without Nafion protective films and accurate measurements in
diluted human serum. Zhang et al. [248] synthesized Ni@C/Ni-foam
by calcination of Ni-metal organic framework (Ni-MOF) formed on
Ni-foam (see Fig. 8). The Ni@C had monodisperse pore diameters of
10 nm with a platelet morphology, favorable to efficient mass
transport. Although the linear response range was in the mM region
(0.00015e1.475 mM), it exhibited extremely high sensitivity
(32794.4 mA mM-1 cm-2), low detection limits (0.05 mM), and
excellent anti-interference (even against Cl) along with good
stability in successive measurements lasting 21 days. The sensor
performed well in diluted human blood serum, comparable to
commercial glucose analyzers. The authors attributed this extreme
sensitivity to the enhanced mass transfer coming from the hierar-
chical structure of the extensive pore network formed on metal
foam skeleton.
Copper is also a widely studied transition metal. Like Ni, various
forms of Cu-based glucose sensors were developed, for instance, Cu
[249e254], Cu2O [255e260], CuO [261e272], and Cu@CuOxide
[273e278]. Reaction mechanisms similar to Ni can be applied to the
glucose oxidation on Cu-based electrodes, with Cu(II)/Cu(III) redox
couple (CuII(OH)2 or CuIIO, and CuIIIOOH) as the reaction center. The
cyclic voltammograms of Cu-based materials have a broad Cu(II)
oxidation peak around þ0.3 ~ þ0.5 V (vs. Ag/AgCl). The oxidation
peak of Cu(II), however, contain high background currents so that in
some cases the glucose oxidation peak is almost indiscernible.
Competitive reactions such as oxygen evolution reaction can
disturb the anodic signal from the glucose oxidation, causing
complications in quantitative glucose analysis. Table 5 summarizes
all Cu and Cu oxide-based non-enzymatic glucose sensors
described in this section.
Zhao et al. [277] reported hierarchical Nafion/Cu@Cu2O nano-
wire mesh electrode through hydrothermal oxidation and dry
oxidation of metallic Cu nanosheet and nanowire mesh. The
Cu@Cu2O electrode was inferior in terms of linear range
(0.0007e2.0 mM) to the Cu nanowire counterpart in 0.1 M NaOH
solution containing 0.15 M NaCl. However, it showed 3-fold higher
sensitivity (1420 mA mM-1 cm-2), 100-fold lower detection limit
(40 nM), and 80 times faster response time (0.0276 s), along with
strong anti-interference ability, high stability, and accurate mea-
surements in diluted human blood serum. The authors credited this
high performance to the enhanced mass transport due to the
hyperbranched structure of catalytically active Cu2O nanoneedle/
sheet formed on the Cu-mesh, and fast electron transfer from high

Fig. 8. (a) Schematic illustration of the synthetic process of Ni@C/Ni foam. (b) Typical SEM image. (C) CV of bare Ni foam and Ni@C/Ni foam with and without glucose in 0.1 M NaOH.
(d) Amperometic response with successive addition of 8 mM glucose into 0.1 M NaOH solution at 0.54 V vs. Ag/AgCl. (e) Anti-interference result tested with 2 mM dopamine (DA),
ascorbic acid (AA) and uric acid (UA) in 0.1 M NaOH at 0.54 V vs. Ag/AgCl. Repriduced with permission from Ref. [248]. Copyright 2017, Royal Society of Chemistry.
Table 5
List of Cu / Cu oxide-based electrochemical non-enzymatic glucose sensors

Ref Catalysta Morphology Substrate/ Binder Chemical Real Sample Linear Range (mM) LOD Sensitivity (mA cm2 Selectivitye Long-term Repeatabilityg Reproducibility
a
Electrodeb Environmentc Testd (mM) mM1) Stabilityf

[249] Cu Thin coating np Au film/ Au e NaOH (0.1 M, pH 13 HBS (diluted) 0e8.11 0.59 3643 AA, UA, NaCl, SC, Na2SO4, 3 w (N/A, 4.48% (n ¼ 6) N/A
disk ca.) NaH2PO4 91.81%)
[250] Cu MP Cu disk e NaOH (0.1 M, pH 13 HBS (diluted) 0e4.711 0.19 2432 AA, UA, NaCl, SC, Na2SO4, 4 w (N/A, N/A 4.22% (n ¼ 6)
ca.) NaH2PO4 85.33%)
[251] Cu Coating Sandpaper e NaOH (0.1 M, pH 13 HBS (diluted) 0.001e4.6 0.03 2149.1 AA, DA, UA, EtOH, Fru, Lac, 90 d (NaOH, 1.16% (n ¼ 8) 2.06% (n ¼ 8)
ca.) Mal,Sorb 96.4%)
[252] Cu np MP Carbon black/ Nafion NaOH (0.05 M, pH e 0.0006e3.369 2.6 33.75 AA, DA, UA, Fru, Mal, Suc 12 d (NaOH, N/A N/A
GCE 12.7 ca.) 87.14%)
[253] Cu NP ZIF-8/ SPCE Nafion NaOH (0.1 M, pH 13 Rat BS (N/A) 0e0.7 2.76 412 AA, DA, UA N/A 9.3% (n ¼ 35) 5.68% (n ¼ 5)
ca.)
[254] Cu NP N-doped e NaOH (0.1 M, pH 13 e 0.005e2.1, 2.6e10 5 223.6, 100.6 AA, DA, UA,H2O2 N/A N/A N/A
carbon/ GCE ca.)
[255] Cu2O NP VC/ graphite Nafion KOH (0.1 M, pH 13 e 0e6 2.4 629 AA, KCl 7 w (NaOH, 3.4% (n ¼ 5) 3.5% (n ¼ 3)
disk ca.) 90%)
[256] Cu2O Hollow NC GCE Nafion NaOH (0.1 M, pH 13 e 0.001e1.7 0.87 52.5 AA, UA N/A N/A N/A

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

ca.)
[257] Cu2O G/NC GCE Nafion KOH (0.1 M, pH 13 e 0e3.25 3.3 285 AA, DA, UA, NaCl N/A N/A N/A
ca.)
[258] Cu2O NP rGO/ GCE Nafion NaOH (0.02 M, pH e N/A 0.1 N/A AA, DA, UA N/A N/A N/A
12.3 ca.)
[259] Cu2O Porous NS rGO/ GCE Nafion KOH (0.05 M, pH e 0.01e6.0 0.05 185 AA, DA, UA N/A N/A N/A
12.7 ca.)
[260] Cu2O NP SWCNT/ GCE Nafion NaOH (0.1 M, pH 13 HBS (diluted) 0.0005e2.5 0.2 2143 AA, AP, DA, UA, NaCl 9 w (air, 90%) 3.5% (n ¼ 8) 4.5% (n ¼ 5)
ca.)
[261] CuO Porous film Pt film/ Si wafer e NaOH (0.1 M, pH 13 e 0.001e2.5 0.14 2900 AA, UA 1 m (NaOH, 3.35% 15.45% (n ¼ 9)
ca.) Stable) (n ¼ 10)
[262] CuO NP MWCNT/Ta foil e NaOH (0.1 M, pH 13 HBS (diluted) 0.0004e1.2 0.2 2596 AA, DA, UA, Fru, Lac, Suc, KCl 30 d (NaOH, 3.4% (n ¼ 9) 2.8% (n ¼ 5)
ca.) 90%)
[263] CuO NP GCE PQ11 NaOH (0.1 M, pH 13 HBS (diluted) 0.005e2.3 0.5 1397 AA, DA, UA 10 d (NaOH, N/A N/A
ca.) 95%)
[264] CuO NW array Cu foam e NaOH (0.1 M, pH 13 HBS (diluted) 0.0001e0.5 0.02 32330 AA, DA, UA, Fru, Lac,Mal, 12 d (NaOH, 2.55% (n ¼ 6) 4.47% (n ¼ 6)
ca.) Suc,Sorb, NaCl 94.1%)
[265] CuO NN/NFw GCE Nafion NaOH (0.1 M, pH 13 e 0.001e4 0.5 1322 AA, UA, NaCl N/A N/A N/A
ca.)
[266] CuO NFw Pt disk e NaOH (0.1 M, pH 13 e 0.9e16 20 9.02 mA mM1 AA, DA, UA 30 d (NaOH, N/A 2.5% (n ¼ 5)
ca.) 97.0%)
[267] CuO Microflower Graphite wafer Nafion NaOH (0.1 M, pH 13 e 0.004e8 4 709.52 AA, DA N/A N/A N/A
ca.)
[268] CuO Aggregated Carbon felt Nafion NaOH (0.1 M, pH 13 HBS (diluted) 0.00279e2.03 0.27 6476 AA, DA, UA, LA, GSH, NaCl 30 d (NaOH, N/A 1.53% (n ¼ 8)
NR ca.) 90.1%)
[269] CuO NW GCE Nafion NaOH (0.1 M, pH 13 e 0.0005e0.488, 0.988 0.045 64.1, 488 AA, UA 4 w (air, 94.3%) 1.9% (n ¼ 7) N/A
ca.) e5.488
[270] CuO NW GCE Nafion NaOH (0.05 M, pH HBS (diluted) N/A 2 648.2 AA, AP, Fru, Suc N/A 3.32% (n ¼ 6) 4.54% (n ¼ 5)
12.7 ca.)
[271] CuO NP N-G/ GCE Nafion NaOH (0.1 M, pH 13 HBS (N/A) 0.001e6 0.5 207.3 AA, DA, UA, NaCl N/A 18% (3500 s N/A
ca.) CA)

[272] CuO Nanospindle rGO/ GCE e NaOH (0.1 M, pH 13 HBS (diluted) 0.0004e3, 3e12 0.1 2221, 1004 AA, DA, UA 2 w (4 C, 5% (n ¼ 28) 3.7% (n ¼ 5)
ca.) 94.7%)
[273] Cu@Cu2O NS rGO/ GCE Nafion NaOH (0.5 M, pH HBS (N/A) 0.005e7 0.5 145.2 AA, UA, Fru, Lac 2 w (NaOH, 2.1% (n ¼ 7) 3.4% (n ¼ 5)
13.7 ca.) 95%)
[274] CuO Nano leaf ZnO NR/Cu e NaOH (0.1 M, pH 13 e 0.1e1 18 408 AA, UA, Urea, Lac N/A N/A N/A
sheet ca.)
[275] Cu2O MP GCE Nafion NaOH (0.1 M, pH 13 e 0.22e10.89 0.05 33.63 AA, UA 4 w (N/A, N/A <3% (n ¼ 5)
ca.) 97.4%)
(continued on next page)

19
 20 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

quality Cu@Cu2O heterojunction. Dong et al. [279] formed Cu2O

G ¼ graphene, rGO ¼ reduced graphene oxide, N-G ¼ N-doped graphene, GF ¼ graphene foam, SWCNT ¼ single-walled carbon nanotube, MWCNT ¼ multi-walled carbon nanotube, ITO ¼ indium tin oxide, FTO ¼ fluorine doped

AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose, Mal ¼ maltose, Man ¼ mannose, Suc ¼ sucrose, Sorb ¼ sorbitol, Arb ¼ arabinose, Lac ¼ lactose,
np ¼ nanoporous, mp ¼ macroporous, MP ¼ microparticle, NP ¼ nanoparticle, NC ¼ nanocrystal, NFw ¼ nanoflower, NFl ¼ nanoflake, NR ¼ nanorod, NS ¼ nanosheet, NW ¼ nanowire, GCE ¼ glassy carbon electrode,

tin oxide, VC ¼ Vulcan carbon, C-powder ¼ carbon powder, C-paste ¼ carbon paste, m-C ¼ mesoporous carbon, IL ¼ ionic liquid, SPCE ¼ screen-printed carbon electrode, Cht ¼ chitosan, ZIF ¼ zeolitic imidazolate framework
Repeatabilityg Reproducibility

nanoneedles on Cu-foam via anodization and chemical etching.

4.7% (n ¼ 10)
2.2% (n ¼ 5)

This electrode showed excellent sensitivity of 97.9 mA mM-1 cm-2

N/A
and very low detection limit of 5 nM in 0.1 M NaOH, as well as high

N/A
stability and good resistance to various interferents including NaCl.
According to the authors' discussion, the extremely high sensitivity
2.47% (n ¼ 5)

came from the enhanced mass transport caused by the enlarged

2% (2500 s

surface area of the nanoneedle structure, and improved electron

transfer due to the efficient heterojunction formed by the Cu2O
N/A

AA, UA, DA, Fru, Lac, Suc, Mal, 6 m (N/A, 88%) N/A

CA)

nanoneedle catalyst and Cu-foam current collector. Hou et al. [251]

reproducibly synthesized Cu-patterned sandpaper, where the pat-
AA, UA, Urea, Fru, Lac, NaCl 15 d (NaOH.
7 d (NaOH,
Long-term

terns were formed by Ag nanoparticle seeding on commercialized

Stabilityf

98.15%)

94.55%)
7 d (r.t.,

sandpaper through laser-direct scribing, followed by electroless

98.5%)

plating of Cu layer. The copper framework supported by sandpaper

Cel ¼ cellulose Sal ¼ Salicylate, CA ¼ Citric acid, TFA ¼ trifluoroacetic acid, NC ¼ sodium citrate, Leu ¼ L-leucine, Pro ¼ L-proline, Cys ¼ L-cysteine, Lys ¼ L-lysine, Gly ¼ L-glycine

showed great sensing ability (linear range: 0.001e4.6 mM, LOD:

0.03 mM, sensitivity: 2149.1 mA mM-1 cm-2), anti-interference, good
AA, UA, Cl and other ions

stability (90 days), and accurate measurements in diluted human

blood serum and tea.
AA, UA, AP, Fru, Suc

Cobalt-based catalysts are also popular as glucose sensor ma-

terials. The Co-based catalysts come in various forms such as Co
Sensitivity (mA cm2 Selectivitye

oxides [280e291]. The electrochemistry of Co is quite different

from the two previous transition metals, where diverse forms of
various oxidation state exist in alkaline solutions, including CoIIO,
Cel

CoII(OH)2, Co3O4 (II, III oxide; also written as CoO$Co2O3 or CoII-

CoIII III IV
2 O4), Co OOH, Co O2 [56,292]. That is why many redox peaks
62.29 mA mM1

involving transition of Co(0)/Co(II), Co(II)/Co(III), Co(III)/Co(IV) are

observed in the cyclic voltammogram of cobalt in alkaline solution
[292e297]. The most commonly used catalyst of the Co oxides is
mM1)

123.8
1420

97.9

the spinel structured Co3O4, in which one of the three Co atoms is in

HWB ¼ human whole blood, HBS ¼ human blood serum, BS ¼ blood serum, HBP ¼ human blood plasma, HU ¼ human urine

the 2þ state, and the other two are in the 3þ state. In principle, the
0.005

corresponding Co(II)/Co(III) redox peak should appear in the cyclic

(mM)

0.04

0.05
LOD

37

voltammogram. In literature, however, this oxidative peak is absent

or hardly discernable. It is probable that Co3O4 species are naturally
Real Sample Linear Range (mM)

oxidized into CoOOH under highly oxidative alkaline condition.

Some groups insist that the low intensity of the peak is caused by
the relative difficulty of oxidizing/reducing the Co2þ cation in the
0.05e6.75

0.0007e2

0.01e5.5

tetrahedral site of the spinel structure than in the octahedral Co3þ

HBS (diluted) N/A

[298,299]. On the contrary, others argue that the peak is broadened

by the numerous species of Co(II)- and Co(III)-containing surface
oxides, which go through diverse reaction pathways as the oxida-
tion potential varies [293,294]. The majority of glucose oxidation is
Testd

expected to proceed via the Co(III)/Co(IV) redox couple

e

[56,57,293e296]. Table 6 provides concise summary for all Co and

NaOH (0.1 M, pH 13

Nafion NaOH (0.1 M, pH 13

NaOH (0.1 M, pH 13
Nafion NaOH (0.05 M, pH

Co oxide-based non-enzymatic glucose sensors described in this

section.
Environmentc

Hoa et al. [286] produced Co3O4 nanoflower/reduced graphene

Binder Chemical

12.7 ca.)

oxide hydrogel composite by hydrothermal synthesis of Co3O4

nanoflower on 3D-graphene oxide hydrogel followed by a calci-
ca.)

ca.)

ca.)

nation/thermal reduction process. The composite had a large BET

PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer

surface area, reaching up to 260 m2 g1, a long linear range for a

CA ¼ chronoamperometry, CV ¼ cyclic voltammetry.
e

transition metal catalyst (0.25e10 mM), and high sensitivity

(492.8 mA mM-1 cm-2). In addition, they found an excellent anti-
Cu NW/ GCE

interference against high concentrations of ascorbic acid, uric acid

Electrodeb
Catalysta Morphology Substrate/

Cu sheet

Cu foam

and dopamine (5 mM each). Ibupoto et al. [300] synthesized Co3O4

with various morphologies (nanorod, nanoparticle and nanosheet)
GCE

by simply varying the amino acid used as the structure-directing

d ¼ day, w ¼ week, m ¼ month

agent. Since such nanostructures are commonly used in other re-

Nanothorn

searches, this work enables the examination of morphology effects

array

by indirectly comparing a series of morphologies fabricated from

NN
NP

[278] Cu@Cu2O NP
Table 5 (continued )

the same synthetic process. Their various nanostructures had

almost identical crystallographic structures, as evidenced by the
[276] Cu2O

[277] Cu2O

[279] Cu2O

XRD results. The aggregated nanoparticulate structure from L-

serine performed best in 0.1 M NaOH (sensitivity ¼ 4169.0 mA mM-
1
cm-2, linear range ¼ 0.01e20 mM, detection limit ¼ 0.001 mM,
Ref

a,b

good anti-interference and stability). In the intriguing work by Wu

d

g
e
c

f
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
et al. [301], two different nanostructures, Co3O4 nanocube exposing
only the {100} crystalline facet and Co3O4 octahedron with {111}
and {100} crystalline facets, were compared with each other as
glucose oxidation catalysts. It had been already known that the
exposed crystalline facet of Co3O4 catalysts greatly affects the cat-
alytic efficiencies in many reactions such as the methane oxidation
[302]. In this work, they investigated how it would influence
glucose oxidation. As previously mentioned, Co(II) at tetrahedral
sites in spinel Co3O4 is too stable to oxidize glucose. Instead, labile
Co(III) at octahedral sites can be expected to accelerate glucose
oxidation. The density of octahedral Co(III) exposed in {001} facet is
0.0611 CoIII,oct Å2, while the density is 0.1059 CoIII,oct Å2 for the
{111} facet. The octahedral structure with the {111} facet had higher
density of CoIII,oct, which generate in turn improved the glucose
oxidation efficiency than the {100}eexposed Co3O4 cube.
Numerous articles concerning other transition metal/metal ox-
ide catalysts such as Fe [147,303e307], Mn [308e313], Sn [314], Zn
[315], and their alloys or combinations [316,317], have been pub-
lished. Among the transition metal-based glucose oxidation cata-
lysts, Fe oxides showed decent performances in neutral pH
conditions [147,304,306,307]. Ahmand et al. [147] used field effect
transistor (FET)-based on Fe2O3 modified ZnO, and successfully
measured glucose concentrations in 0.1 M PBS (pH 7.4), mouse
whole blood, and serum. The sensor performance was as good as
the average of other transition metal-based sensors (linear
range ¼ 0.05e22 mM, detection limit ¼ 12 mM, sensi-
tivity ¼ 105.75 mA mM-1 cm-2, response time ¼ 10 s, good anti-
interference, good stability). Chen et al. [307] used poly(4-vinyl-
pyridine)-co-poly(acronitrile) (P4VP-co-PAN) protected Fe2O3
nanoparticle films as glucose sensor. They were able to obtain great
anti-interference in 0.1 M PBS (pH 7.4) against numerous interfer-
ents such as ascorbic acid, uric acid. Although the anti-interference
was claimed, the actual data for amino acids, carbohydrates and
common mineral ions (Naþ, Kþ, NH4þ, Cl, Ca2þ, Fe2þ, etc.) were not
shown. Both the positive charge in pyridine group in the P4VP-co-
PAN protective polymer [318] and negative charge from Fe2O3 were
claimed to give rise to this high selectivity. Table 7 covers all the
other transition metal and metal oxide, nitride, phosphide and
chalcogenide-based non-enzymatic glucose sensors described in
this section (other than Ni, Cu and Co oxide-based sensors).
Transition metal-based nitrides [319e323], phosphides
[324e328] and chalcogenides [329e333] are also commonly
applied catalyst materials for non-enzymatic glucose oxidation.
Although the actual catalysis occurs via the same oxide-based
redox couple as in transition metal/metal oxide-based catalysts, the
superior electrical conductivity of nitrides, phosphides and chal-
congenides over the hydroxide/oxide counterparts proved them-
selves as promising candidates for non-enzymatic glucose
oxidation catalysts. Liu et al. [324] fabricated CoP nanowire array
electrode by hydrothermally synthesizing Co(OH)2 on Ti mesh,
followed by chemical vapor deposition. The electrode had adequate
linear range (0.0005e1.5 mM) and excellent sensitivity
(5168.6 mA mM-1 cm-2) in 0.1 M NaOH, showing exceptional anti-
interference abilities against high concentrations (2 mM) of easily
oxidizable species such as NaCl and monosacharrides. It also
worked adequately in 10% diluted human blood serum and fruit
juice. Chen et al. [326] synthesized three-dimensional Ni2P nano-
sheet-type arrays on carbon cloth through chemical vapor depo-
sition of phosphorous onto the hydrothermally fabricated Ni(OH)2
nanoarrays on carbon cloth (see Fig. 9). The nanoarray showed
decent glucose sensing performances in alkaline conditions (linear
range ¼ 0.001e3 mM, detection limit ¼ 0.18 mM, sensi-
tivity ¼ 7792 mA mM-1 cm-2, response time ¼ 5 s in 0.1 M NaOH, pH
13). It was resistant to 5 mM interferents, stable up to 30 days of
successive measurements, fairly reproducible, and gave no
21
apparent morphological changes even after the repeated mea-
surements. Its performance was maintained in human blood
serum, commercial peach juice, and human whole blood, all diluted
to 10 v/v % in 0.1 M NaOH.
Transition metal-based glucose sensors have a number of ad-
vantages over other catalytic materials in that they are economic,
available in numerous nanostructures and morphologies, resistant
to interferents such as Cl, and highly selective towards glucose,
performing well in alkaline solution. Despite these merits, most
transition metal oxides have bad conductivity that require
conductive substrates, and ineffectual glucose oxidation abilities in
neutral conditions. Furthermore, they have narrow linear range
that falls short of the average blood glucose level (3e8 mM) and
need dilution in spite of the high sensitivity and low limit of
detection. The transition metal-based catalysts also show good
oxygen evolution reaction (OER) performance [334e336], which
cause high background current near the glucose oxidation poten-
tial, leading to possible misinterpretation of the electrochemical
results.
3.5. Selective binding-based glucose sensors
The biggest flaw of non-enzymatic glucose sensors in general is
the low selectivity towards glucose. Ion selective membranes such
as Nafion can improve selectivity, but the use of the protective layer
diminishes the current by blocking the active electrode surfaces.
Voltammetric and amperometric sensors are based on recording
the glucose oxidation current at anodic potentials where many
biomolecules such as ascorbic acid, uric acid, dopamine and urea
can be also oxidized, leading to biased interpretations. In order to
minimize the influence coming from mixtures of oxidative current,
many scientists conform to adopting complex fabrication processes
to prepare nanostructure electrodes. Another feasible strategy is to
utilize functional materials equipped with specific glucose binding
abilities such as synthetic molecules introduced in Section 2.3,
represented by boronic acid-related compounds and molecularly-
imprinted polymer (MIP). Table 8 summarizes all non-enzymatic
glucose sensors that utilize specific binding of glucose-binding
moieties such as boronic acid and MIP described in this section.
Boronic acid and its related compounds form boronate esters by
binding with nucleophiles using the vacant p-orbital of the boron
atom. They specifically bind to 1,2-diols or 1,3-diols, abundant in
carbohydrate, and this ability has caught the attention of many
organic chemists in developing optical saccharide sensors based on
fluorescence, absorbance, and reflectance. Various electrochemical
sensors using boronic acid-related compounds were also devel-
oped including potentiometric sensors [59,66,67,337e341], vol-
tammetric sensors using redox couples [68e70,342,343], FET-
based chemresistive sensors [344,345], and voltammetric sensors
using boronic acid-functionalized markers [71,72,346].
Since the development of poly(3-aminophenylboronic acid)
(usually abbreviated as PABA) by Shoji and Freund in 2001 [59,66],
many works involving PABA, 3-aminophenylboronic acid (mono-
mer of PABA) and their derivatives were investigated as candidates
for non-enzymatic glucose sensors. However, the lack of selectivity
among monosaccharides halted further development of carbohy-
drate-specific sensors into glucose specific sensors
[66,68,70,71,337,340,342,344,345]. Several noticeable efforts were
made to overcome this problem. Manseh et al. [346] developed
electrospun poly(vinylidene fluoride)-co-poly(-
aminophenylboronic acid) nanofibrous membranes. By adding 4-
acryloylamidobenzo-15-crown-5 in a glucose solution of 0.1 M
phosphate buffer (pH 7.5), they could substantially reduce amper-
ometric signals (<2% of normalized current response from glucose)
from galactose, mannose, fructose, and maltose. Such use of crown
 22
Table 6
List of Co / Co oxide-based electrochemical non-enzymatic glucose sensors

Ref Catalysta Morphology Substrate/ Binder Chemical Real Sample Testd Linear Range LOD Sensitivity (mA cm2 Selectivitye Long-term Repeatabilityg Reproducibility
a
Electrodeb Environmentc (mM) (mM) mM1) Stabilityf

[280] Co3O4 NCl bi-C e NaOH (0.1 M, pH 13 e 0.0887e7 26 1377 DA, UA, KCl, NaNO3, NaCl, 30 d (4  C, N/A 4.67% (n ¼ 6)
ca.) Gal 96.11%)
[281] CoOx Thin film np Au film/ Au e NaOH (0.1 M, pH 13 HBS (diluted) 0.002e2 0.094 2025 AA, UA, NaCl, Na2SO4, 3 w (NaOH, 7.31% 3.0% (n ¼ 5)
disk ca.) NaH2PO4, SC Stable) (n ¼ 10)
[282] Co3O4 NP bi-C/ GCE e NaOH (0.1 M, pH 13 HBS and HU (diluted) 0.00005e22 0.02 34.23 AA, UA, DA 2 w (air, 97.2%) 3.2% (n ¼ 5) 2.7% (n ¼ 6)

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

ca.)
[283] Co3O4 NFw GCE Nafion NaOH (0.1 M, pH 13 BS (diluted) 0.1e5 0.1 1.62 AA, UA, DA 6 w (air, N/A <1% (n ¼ 6)
ca.) Stable)
[284] Co3O4 NF GCE Nafion NaOH (0.1 M, pH 13 BS (diluted) 0e2.04 0.97 36.25 AA, UA N/A 3.99% (n ¼ 5) 9.73% (n ¼ 5)
ca.)
[285] Co3O4 NW 3D G/ Ni foam e NaOH (0.1 M, pH 13 FBS (diluted) 0e0.08 100 3.39 N/A N/A N/A N/A
ca.)
[286] Co3O4 NFw GOHG/ GCE Nafion NaOH (0.1 M, pH 13 horse and rabbit BS 0.25e10 N/A 492.8 AA, UA, DA, Fru, Lac, Suc N/A N/A N/A
ca.) (diluted)
[287] Co3O4 NP GCE e NaOH (0.1 M, pH 13 BS (diluted) 0.005e0.8 0.13 520.7 AA, UA, AP N/A N/A N/A
ca.)
[288] Co3O4 NN G/micropipette e NaOH (0.1 M, pH 13 HBS (diluted) 0.05e0.30 10 N/A N/A N/A N/A N/A
tip ca.)
[289] Co3O4 NW GCE Nafion NaOH (0.3 M, pH HBS (diluted) 0.005e0.57 5 300.8 AA, UA, DA 1 m (r.t, 93.2%) N/A N/A
13.48 ca.)
[290] Co3O4 NP np Au film/ Au e KOH (0.5 M, pH 13.7 HBS (diluted) N/A 0.005 12500 AA, UA, AP, Fru, Lac, Suc, 15 d (r.t., Stable (N/A) Good (N/A)
wire ca.) Mal,Man 99.5%)
[291] Co3O4 NP/ NN Ni foam e NaOH (0.5 M, pH HBS (diluted) 0.005e12 0.08 1440 AA, UA, Fru 1 m (air, 90%) 3.7% (n ¼ 5) 6.3% (n ¼ 4)
13.7 ca.)
[292] Co3O4 NP GCE Nafion NaOH (0.1 M, pH 13 HWB (diluted) 0.01e20 1 4169 AA, UA, Suc 1 m (air, 90%) N/A <3% (n ¼ 8)
aggregate ca.)
[301] Co3O4 NC e e KOH (6 M, pH 14.78 e N/A N/A 32.54 N/A N/A N/A N/A
ca.)
a,b
np ¼ nanoporous, NP ¼ nanoparticle, NFw ¼ nanoflower, NW ¼ nanowire, GCE ¼ glassy carbon electrode, G ¼ graphene, GOHG ¼ graphene oxide hydrogel, bi-C ¼ bio-inspired pyrolytic carbon.
c
PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer
d
HWB ¼ human whole blood, HBS ¼ human blood serum, FBS ¼ fetal bovine serum, BS ¼ blood serum, HU ¼ human urine
e
AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose, Mal ¼ maltose, Man ¼ mannose, Suc ¼ sucrose, Sorb ¼ sorbitol, Arb ¼ arabinose, Lac ¼ lactose,
SC ¼ sodium citrate
f
d ¼ day, w ¼ week, m ¼ month
g
CA ¼ chronoamperometry, CV ¼ cyclic voltammetry.
Table 7
List of other transition metal / metal oxide, nitride, phosphide and chalcogenide-based electrochemical non-enzymatic glucose sensors

Ref Catalysta Morphology Substrate/ Binder Chemical Real Sample Linear Range (mM) LOD Sensitivity (mA cm2 Selectivitye Long-term Repeatabilityg Reproducibility
a
Electrodeb Environmentc Testd (mM) mM1) Stabilityf

[147] Fe2O3 NP ZnO NR/ Si Nafion PBS (1 mM, pH 7.4) HWB (N/A) 0.05e18 12 105.75 AA, DA, UA, Glu, Fru, Lac, 10 w (PBS, N/A 2.56% (n ¼ 6)
wafer Mal,Man, Suc 97.5%)
[303] Fe3O4 NT array FTO glass e NaOH (0.1 M, pH 13 e 0.0001e0.125 0.125 0.1 673.3 71.2 9.58 N/A N/A Stable (N/A) N/A
ca.) e1 1e5
[304] Fe@ZnO NP SPCE e PBS (0.1 M, pH 7.4) e N/A 0.3 N/A AA, UA, DA N/A Stable (N/A) Good (N/A)
[305] Fe3O4 NR array Fe foil e NaOH (0.1 M, pH 13 HBS (diluted) 0.0005e0.766 0.766 0.1 406.9134.1 AA, UA, AP, DA, Fru,Man, 5- 45 d (NaOH, 5% (n ¼ 10) N/A
ca.) e3.67 HT 96%)
[306] Fe2O3 NW GCE e PBS (0.1 mM, pH HBS (diluted) 0.015e8 N/A 726.9 AA, DA, Fru, Lac, Mal 30 d (NaOH, N/A 3.4% (N/A)
7.5) 98%)
[307] Fe2O3 NP GCE P4VP-co- PBS (0.1 M, pH 7.5) Human blood 0.0025e0.58 0.58 1382.8 AA, UA Stable (N/A) 4.1% (n ¼ 6) 3.5% (n ¼ 6)
PAN (diluted)
1
[308] MnO2 Thin coating MWCNT/Ta foil e NaOH (0.1 M, pH 13 e ~28 N/A 33.19 mA mM AA, UA, DA N/A Stable (N/A) Good (N/A)
ca.)
[309] MnO2/ NS GO NP/ Cu wire PVA NaOH (0.2 M, pH e 0.5e4.4 53 N/A N/A N/A Stable (N/A) Good (N/A)
CuO 13.3 ca.)

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

[310] MnO2 NFl MWCNT/Ni e NaOH (0.5 M, pH HBS (diluted) N/A 0.5 3406.4 AA, UA, Fru 1 m (r.t., 90%) 2.7% (n ¼ 5) 3.5% (n ¼ 6)
foam 13.7 ca.)
[311] Mn3O4 NFl 3D GF e NaOH (0.1 M, pH 13 HBS (N/A) 0.1e8 10 360 AA, UA, AP N/A N/A N/A
ca.)
1
[312] Mn3O4 NP N-G/CPE e NaOH (0.1 M, pH 13 Urine (diluted) 0.0025e0.5295 1 0.1011 mA mM AA, UA, DA 7 d (r.t., 92.4%) N/A 6.9% (n ¼ 5)
ca.)
[313] Mn3O4 NP N-G/CPE e NaOH (0.1 M, pH 13 HBS (diluted) 0.001e0.3295 0.5 0.026 mA mM1 AA, UA, DA, NaCl 7 d (r.t., 93.7%) 5.6% (n ¼ 5) 5.4% (N/A)
ca.)
[314] SnO2 NP rGO/GCE Nafion NaOH (0.1 M, pH 13 HBS (diluted) 0.050e0.500 13.35 1930 AA, UA, Fru N/A N/A N/A
ca.)
[316] Mn-Cu NP MWCNT/GO/ e Alkaline solution BSA (N/A) 1e32 1 59.3 AA, UA, DA, Fru, Lac, Gal, N/A N/A N/A
GCE (pH 13) Urea
[317] NiCo2O4 Hollow NSp GCE e NaOH (0.2 M, pH HBS (diluted) 0.01e0.3 0.3e2.24 0.6 1917 703 AA, UA, DA, Suc, NaCl 7 d (4  C, 3.15% (n ¼ 5) 5.47% (n ¼ 3)
13.3 ca.) 96.67%)
[319] Fe2Ni2N NS array Ti mesh e NaOH (0.1 M, pH 13 HBS (diluted) 0.00005e1.5 0.038 6250 AA, UA, AP, DA, Fru, Lac, 1 m (r.t., N/A 6.2% (n ¼ 5)
ca.) Urea 95.5%)
[320] Fe3N- NW array Carbon cloth e NaOH (0.1 M, pH 13 HBS and HWB 0.0001e1 0.077 4333.7 AA, UA, DA, Fru, Lac, NaCl 1 m (r.t., N/A 4.8% (n ¼ 5)
Co2N ca.) (diluted) 88.7%)
[321] Co3N NW array Ti mesh e NaOH (0.2 M, pH HBS (diluted) 0.0001e2.5 0.05 3325.6 AA, UA, DA, Fru, Lac, NaCl, 1 m (air, N/A 4.3% (n ¼ 5)
13.3 ca.) Gal, urea 91.5%)
[322] Ni3N NS Ti mesh e NaOH (0.1 M, pH 13 HBS (diluted) 0.0002e1.5 0.06 7688 AA, UA, DA, Fru, Lac, urea 1 m (NaOH, N/A 4.7% (n ¼ 5)
ca.) 91.3%)
[323] Cu3N NW array Cu foam e NaOH (0.1 M, pH 13 HBS (diluted) 0.001e2 0.013 14180 AA, UA, DA, Fru, Lac,Gly NaCl 26 d (NaOH, N/A 3.4% (n ¼ 10)
ca.) 96.4%)
[324] CoP NW array Ti mesh e NaOH (0.1 M, pH 13 HBS (diluted) 0.0005e1.5 0.1 5168.6 AA, UA, DA, Fru, Lac, NaCl, 1 m (air, 92%) N/A 3.4% (n ¼ 5)
ca.) Urea
[325] CoP NR GCE Nafion NaOH (0.1 M, pH 13 e 0e5.5 9 116.8 AA, UA, DA N/A N/A N/A
ca.)
[326] Ni2P NS array Carbon cloth e NaOH (0.1 M, pH 13 HBS (diluted) 0.001e3 0.18 7792 AA, UA, DA, Fru, Lac 1 m (4  C, N/A 4.7% (n ¼ 10)
ca.) 82.5%)
[327] Cu3P NW Cu foam e NaOH (0.1 M, pH 13 HBS (diluted) 0.005e1 0.32 N/A AA, UA, DA, Fru, Lac, Gal, 25 d (4  C, 3.1% (N/A) 4.8% (N/A)
ca.) Urea 86.9%)
[328] NiCoP NS Ti mesh e NaOH (0.1 M, pH 13 HBS (diluted) 1e10 0.13 14586 AA, UA, DA, Fru, Lac 25 d (NaOH, N/A 3.4% (n ¼ 10)
ca.) 93%)
[329] Ni2FeS4 NS CS e NaOH (0.1 M, pH 13 e 0.01e1.85 2.35 1.6 0.71 0.14 AA, UA, DA N/A 4.2% (n ¼ 5) 3.8% (n ¼ 5)
ca.) e7.75
[330] CoSe NFl rGO/ GCE Chitosan NaOH (0.3 M, pH e 0e10 2.5 480 UA N/A 1.1% (n ¼ 5) 2.3% (n ¼ 5)
13.48 ca.)
[331] CoS NFw bi-C Nafion HBS (diluted) 0.01e0.96 2 697 AA, UA, DA 2.3% (n ¼ 8) 3.6% (n ¼ 4)
(continued on next page)

23
 24 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose, Mal ¼ maltose, Man ¼ mannose, Suc ¼ sucrose, Sorb ¼ sorbitol, Arb ¼ arabinose, Lac ¼ lactose,
np ¼ nanoporous, mp ¼ macroporous, MP ¼ microparticle, NP ¼ nanoparticle, NC ¼ nanocrystal, NFw ¼ nanoflower, NFl ¼ nanoflake, NR ¼ nanorod, NS ¼ nanosheet, NW ¼ nanowire, GCE ¼ glassy carbon electrode,
G ¼ graphene, GO ¼ graphene oxide, rGO ¼ reduced graphene oxide, N-G ¼ N-doped graphene, bi-C ¼ bio-inspired pyrolytic carbon, GF ¼ graphene foam, MWCNT ¼ multi-walled carbon nanotube, ITO ¼ indium tin oxide,
Repeatabilityg Reproducibility

N/A

N/A
N/A

N/A
Long-term

14 d (4  C,
Stabilityf

92.6%)
N/A

N/A

Cel ¼ cellulose Sal ¼ Salicylate, CA ¼ Citric acid, 5-HT ¼ glutathione, NC ¼ sodium citrate, Leu ¼ L-leucine, Pro ¼ L-proline, Cys ¼ L-cysteine, Lys ¼ L-lysine, Gly ¼ L-glycine
AA, UA, DA, AP, Fru
Sensitivity (mA cm2 Selectivitye

Fig. 9. The SEM image of Ni2P nanoarray in (a) low magnification and (b) high
AA, AP

magnification. Amperometric response of Ni2P nanoarray/Carbon cloth electrode to

successive addition of (c) glucose solution and (d) various interferents in 0.1 M NaOH at
0.5 V vs. S.C.E. Reprinted with permission from Ref. [326]. Copyright 2016, American
Chemical Society.
139.35 28.44

ether or other polymeric ethers was originally proposed by Alexeev

mM1)

271.8

et al. [347], who asserted that polyols such as crown ether or

poly(ethylene glycol) and cationic species in the solution assisted
HWB ¼ human whole blood, HBS ¼ human blood serum, BS ¼ blood serum, HBP ¼ human blood plasma, HU ¼ human urine

the formation of glucose-specific bis-bidentate glucose-boronic

(mM)

0.15
Linear Range (mM) LOD

0.005e1.1 1.2e10.2 1.5

acid complex. Chen et al. [338] made polymeric liquid membrane

electrode through which glucose is permeable by dint of glucose-
specific diboronic acid species. The diboronic acid is highly specific
to glucose forming stable 1:1 complexes [61,348,349]. The forma-
0.005e3.7

tion of negatively charged diboronic-glucose ester complex causes

potentiometric changes with minimal interference by anionic
interferents such as Cl, SCN and NO 3 . In the experiment with
three monosaccharides, the individual sugars gives rise to poten-
tiometric responses in order of glucose > fructose > galactose, as in
NaOH (0.1 M, pH 13 HBS (diluted)

NaOH (0.1 M, pH 13 HBS (diluted)

Real Sample

the previous result [350]. The potential difference from mixtures of

glucose with either fructose or galactose appears to be negligible,
Testd

implying good anti-interference against monosaccharides.

Molecularly-imprinted polymer (MIP) is an artificial mold,
NaOH (0.1 M, pH 13

chemically mimicking the host-guest molecular interactions found

Environmentc

FTO ¼ fluorine doped tin oxide, SPCE ¼ screen-printed carbon electrode

in many biomolecules such as substrate-enzyme or receptor, and

antigen-antibody. MIP-based glucose sensors contain many func-
Chemical

tional moieties such as amine, carboxyl, hydroxyl, or boronic acid

ca.)

ca.)

ca.)

groups. Monomers with these moieties are bound to glucose, and

then polymerized, resulting in a polymeric mold specific to the
PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer
Binder

analyte. These MIP films are usually polymerized on the electrode

CA ¼ chronoamperometry, CV ¼ cyclic voltammetry.

as the glucose-recognition film, where the electrode sense the

e

physico-chemical changes when glucose is bound. MIPs are

intrinsically more selective towards glucose compared to methods
Electrodeb
Catalysta Morphology Substrate/

using boronic acid alone. Despite the advantages, however, only a

handful (~10) of papers have reported MIP-based glucose sensors.
GCE

GCE

Yang et al. [81] used photo-crosslinkable copolymer with amine,

d ¼ day, w ¼ week, m ¼ month

hydroxyl, benzyl, aliphatic alkyl functionalities to form MIP films on

gold electrode. They reported its excellent selectivity towards
glucose in 0.1 M NaOH solution containing 0.5 M KNO3, and its good
NFw

NFw
Table 7 (continued )

performance as a glucose sensor (linear range: 0.5e8 mM, LOD:

a

0.05 mM, stable for 30 days). Kim et al. [77] produced potentio-
[333] Ni7S6

metric sensors by preparing Au nanoparticle decorated screen-

[332] CoS

printed carbon electrode, onto which polymerization of MIP films

containing amine, carboxylic acid, and phenylboronic acid func-
Ref

tionalities (see Fig. 10). The MIP film on the Au/SPCE electrode had
a,b

g
e
c

f
Table 8
List of selective binding-based electrochemical non-enzymatic glucose sensors

Ref Gulucose Binding Substrate/ Method of Chemical Environmentc Real Sample Testd Linear Range LOD Sensitivity Selectivitye Long-term Repeatabilityg Reproducibility
Moietya Electrodeb Detectionc (mM) (mM) Stabilityf

[67] BA f-PEI-Au NP/GCE PT BB (0.1 M, pH 9) HBS (diluted) 0.5e50 25 N/A AA, DA, UA 10 d (N/A. 7.68% (n ¼ 3) 7.25% (n ¼ N/A)
96.6%)
[337] BA PABA NT array/Au PT PBS (0.1 M, pH 7.4) e 2e14 500 1.5 mV mM1 N/A N/A 4.4% (n ¼ 5) N/A
 
[338] BA Polymeric liquid PT PB (0.05 M, pH 8.0) e 1e100 200 N/A Fru, Gal, NO3 , SCN , N/A Stable (n ¼ 5) N/A
membrane Cl
[339] BA f-PTh film/GCE PT BB (0.1 M, pH 9) HBS (diluted) 5e50 500 N/A AA, DA, UA, NaCl N/A 5.3% (n ¼ 5) N/A
[340] BA f-Au NP/PANI/Pt PT BRB (0.008 M, pH 12) e 0.31e33 200 þ47 mV decade1 DA, UA 6 d (N/A, 94.2 N/A 5.8e6.9%
e97.8%) (n ¼ 3)
[341] BA f-SAM layer/Au PT PBS (0.1 M, pH 7.4) e 0e55.5 7700 N/A N/A 1 d (60  C, N/A N/A
Stable)
[68] BA f-rGO/GCE DPV PBS (N/A) e 0.002e0.06 0.8 N/A N/A N/A N/A N/A

D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

[69] BA f-Au NP/PAz A/GCE CV PBS (0.1 M, pH 7.4) HBS (diluted) 0.00001 0.004 N/A AA, DA, UA, NaCl 30 d (r.t., 94%) N/A 3% (n ¼ 3)
e0.01
[342] BA f-Polymer film/ DPV PBS (0.1 M, pH 7.4) e 0.02e0.5 7.8 N/A N/A N/A 4.3% (n ¼ 5) N/A
GCE
[343] BA f-SAM/Au EIS PB (0.2 M, pH 8.0) e 0e0.01 N/A N/A N/A N/A N/A N/A
[344] BA PABA/ SWCNT CR PBS (0.1 M, pH 7.4) e N/A 3460 0.031 mg L1 AA, UA, CA N/A 18.6% (n ¼ 3) Good (n ¼ 8)
[345] BA f-SWCNT/ Si/SiO2 CR PB (0.01 M, pH 8.4) e 10e20 5 5 nA mM1 @ AP, Fru 2 w (N/A) N/A N/A
wafer 80 kU
[72] BA f-PTh/GCE DPV PB (0.1 M, pH 7.4) HS (diluted) 0.0009 0.45 N/A N/A 1 m (4  C, 92%) 3.8% (N/A) N/A
e0.0091
[346] BA f-polymer NF/ITO CA PB (unspecified, pH 7.5) HBS (unspecified) 1e15 N/A N/A AA, AP, UA, Fru, 50 d (PB, 90%) N/A N/A
Gal,Mal, Man
[76] BA MIP/GCE PT PB (0.1 M, pH 7.4) Fruit juice (unspecified) 0.75e18 230 0.686 mV mM1 Fru, Gal, Suc, Xyl 1 w (PBS, r.t., 1.8% (n ¼ 3) 5.3% (n ¼ 3)
90%)
[77] BA, Amide MIP/AuNP/PTh/ PT PBS (0.1 M, pH 7.4) FPB (unspecified), HS 0.00032e1 0.19 N/A AA, AP, DA, UA, 30 d (PBS, N/A 3.25% (n ¼ 5)
SPCE (unspecified) saccharides 96.75%)
[78] BA MIP/ITO glass CV KNO3 (0.1 M, pH N/A; e 0e50 N/A N/A N/A N/A 3% (N/A) N/A
redox marker)
[79] BA MIP/Au electrode CA HEPES (0.05 M, pH 7.2; e N/A N/A N/A Man, Gal N/A N/A N/A
redox marker)
[80] Amide, -COOH, MIP/Ni foam EIS NaOH (0.1 M, pH 13 ca.) e 10e55 N/A N/A AA, AP, DA, Fru N/A 16% (n ¼ 6) N/A
Pyd N
[81] Amide, -NR2, MIP/Au disk DPSV NaOH (0.1 M) þ KNO3 e 0.2e8 50 N/A AA, UA 1 m (NaOH, N/A 1.5% (n ¼ 5)
-OH, -Ph, -R (0.5 M) 1.5%)
a
BA ¼ boronic acid, -COOH ¼ carboxylic acid, Pyd N ¼ pyridinic N, -OH ¼ hydroxyl, -Ph ¼ phenyl, -R ¼ alkyl,
b
f- ¼ functionalized (with Glucose Binding Moietiesa), PEI ¼ polyethyleneimine, NP ¼ nanoparticle, GCE ¼ glassy carbon electrode, PABA ¼ poly(4-aminophenylboronic acid), NT ¼ nanotube, PTh ¼ polythiophene,
PANI ¼ poly(aniline), SAM ¼ self-assembled layer, rGO ¼ reduced graphene oxide, PAz A ¼ poly(azure A), SWCNT ¼ single-walled carbon nanotube, MIP ¼ molecularly-imprinted polymer film, SPCE ¼ screen-printed carbon
electrode, ITO ¼ indium tin oxide
c
PT ¼ potentiometry, DPV ¼ differential pulse voltammetry, CV ¼ cyclic voltammetry, EIS ¼ electrochemical impedance spectroscopy, CR ¼ chemiresistive sensing, CA ¼ chronoamperometry, DPSV ¼ differential pulse
stripping voltammetry
d
BB ¼ borate buffer, BRB ¼ Britton-Robinson buffer, PBS ¼ phosphate buffered saline, PB ¼ phosphate buffer, HEPES ¼ 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
e
HBS ¼ human blood serum, HS ¼ human saliva, FPB ¼ finger-prick blood
f
AA ¼ ascorbic acid, AP ¼ 4-acetamidophenol, DA ¼ dopamine, UA ¼ uric acid, Fru ¼ fructose, Gal ¼ galactose, Xyl ¼ xylose, Mal ¼ maltose, Man ¼ mannose, Suc ¼ sucrose, Sorb ¼ sorbitol, Arb ¼ arabinose, Lac ¼ lactose, CA ¼
Citric acid, 5-HT ¼ glutathione, NC ¼ sodium citrate, Leu ¼ L-leucine, Pro ¼ L-proline, Cys ¼ L-cysteine, Lys ¼ L-lysine, Gly ¼ L-glycine
g
d ¼ day, w ¼ week, m ¼ month

25
26 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34

Fig. 10. (a) Schematic illustration of the fabrication process of glucose-MIP (molecularly imprinted polymer) sensor. (b) Potentiometric measurements of various glucose con-
centrations and logarithmic calibration plot of the result (inset) using the glucose-MIP sensor. (c) Calibration plots of glucose solution (0.1 M PBS, pH 7.4) in presence of saccharides
and organic interferents. The concentration of each interferents was 0.1 mM. Reprinted with permission from Ref. [77]. Copyright 2017, Elsevier.

low conductivity and sensitivity, but showed excellent selectivity
for glucose in a mixture of interferents. A mixture of glucose with
various oxidizable species (ascorbic acid, uric acid, dopamine and
4-acetamidophenol), and a mixture of glucose with saccharides
(fructose, maltose, mannose, galactose, sucrose and xylose) were
tested against pure glucose solution in 0.1 M PBS (pH 7.4) where all
reagents were in the same concentration. The composite electrode
also performed reasonably well (linear range ¼ 0.32 mMe1.0 mM,
detection limit ¼ 1.9 mM, stable for 30 days), and accurately func-
tioned in diluted saliva and diluted finger-pricked blood.
Developing a selective binding layer onto conventional elec-
trode materials could prove to be a viable strategy in achieving
better selectivity in non-enzymatic glucose sensors. In order to
address the selectivity problem, many nanostructure-based works
introduce a variety of tactics such as ion selective membranes
(Nafion etc.), or use alkaline conditions where all metal/metal ox-
ide-based electrodes should perform well owing to a few reasons
previously mentioned, or test the anti-interference ability with
dilute interferent solutions (more than 10 times dilute than
glucose), which obviously give signals 10 times weaker or less. All
the strategies mentioned above work to provide chemical envi-
ronments that indirectly increase glucose selectivity, not modify
the properties of the electrode itself. The principles of selective
binding might provide a potential way to solve this problem,
especially when sophisticated conditions are required, for example,
in-vivo or continuous glucose monitoring.
Selective binding-based materials, however, have serious chal-
lenges that hinder its practical use. For instance, boronic acid alone
is not selective to glucose but react to all saccharides. Thus, it ne-
cessitates further molecular engineering to enhance its selectivity,
as previously attempted, e.g. diboronic acid or crown ether addi-
tion. MIP, on the other hand, is inappropriate at least for faradaic
techniques because of its poor conductivity. Although potentiom-
etry or impedometry could be considered as a signal conversion
strategy, those can hardly provide linear responses directly pro-
portional to the glucose concentration in principle, resulting in
much lower sensitivity than methods based on faradaic current.
Furthermore, the binding process in MIP is vulnerable to environ-
mental conditions such as pH and temperature, requiring more
research in order to achieve reliable performance comparable to
conventional amperometric and voltammetric analysis.
4. Summary
In this review, the advancement of electrochemical non-enzy-
matic glucose sensors in the last decade was discussed. We briefly
summarized the general performances of the sensors in its scope in
Table 9. The noble metal and alloy-based sensors are advantageous
in that they can operate in neutral pH conditions reasonably well.
However, they show inferior sensitivity, anti-interference and sta-
bility compared to transition metal counterparts. Use of ion-se-
lective protective membranes, nanoengineering and alloying could
 D.-W. Hwang et al. / Analytica Chimica Acta 1033 (2018) 1e34
Table 9
Summary of various electrochemical non-enzymatic glucose sensors.
Materials pHa Anti- Linear Range
Interferenceb (mM)
Acidic Neutral Alkaline Ox Salts Sacc
Pt B M G M M G 1e20
Au B M G M M G 0.1e15
Alloy & Adatoms B M G G G G 0.1e15
Transition Metal- B B G G G G 0.001e5
based
Binding Moieties B M G G G M 1e10
B ¼ bad, M ¼ moderate, G ¼ good.
a
Sensor performance in given pH condition.
b
Sensor's tolerance of given interferents. Ox ¼ easily oxidizable species (ex. ascorbic acid, dopamine), Salts ¼ interfering ions (ex. Cl, SO2-
(ex. fructose, xylose).
alleviate this problem, but we should note that it is not completely
free of stability issues. While the transition metal-based sensors
show superior sensitivity and anti-interference than any other
sensor types, they have linear range that is inappropriate for blood
glucose diagnosis (blood glucose level: 2e8 mM) and perform
poorly in neutral pH, with exception of few iron-based materials
described in Section 3.4. Moreover, some of exceptionally high
sensitivity values often come from the large surface area of sub-
strate materials such as metal foam or foil, which are hundreds of
micrometers thick. Hence, interpreting this result requires caution.
The selective association based sensors are not widely studied
because they are highly dependent on the equilibrium between
glucose and functional groups, operative only under limited con-
ditions. This type of sensors suffer from lack of narrow linear range
and sensitivity and involves stability issue, in which protective layer
and morphology matter mostly. Nonetheless, it seems worthy to
pay attention to its exceptional anti-interference without the help
of intricate nanostructure or protective layers. Nanostructured
materials for sensing exhibit greater sensitivity of glucose than of
interferents, while protective layers are essential to secure selec-
tivity in most practical applications. Reproducibility and durability
issues remain in the sense of mass production. All types of glucose
sensors have pros and cons, demanding intensive research that
tackle the key problems in terms of sensing performance rather
than adhering to the characteristics of new materials.
5. Outlook for non-enzymatic glucose sensor
Non-enzymatic sensors have been drawing huge interest as a
fascinating alternative to overcome the innate limitations of
enzyme sensors, and are expected to present a solution for the
stability issue as well as the complicated and irreproducible process
for mass production of enzyme sensors. As a consequence, an
increasing number of publications are coming out every year. Rapid
advance in nanotechnology and nanomaterial has been fueling
sophistication and diversification of this research topic over the
past 10 years.
The most noteworthy outcome is the substantial progress in
clinical applications of enzyme-free systems based on nanoporous
electrodes [130]. It was proved that sophisticatedly tuning the pore
size, thickness of the nanoporous film, protective sheath etc. can
produce non-enzymatic glucose probes capable of operating in
human serum, plasma, and whole blood, all of which are undiluted.
It was also shown that interferences coming from various electro-
inactive as well as electroactive molecules can be regulated.
Furthermore, the protocol for fabrication of non-enzymatic glucose
probes was established to operate for longer than 30 days in un-
diluted whole blood after a complete sterilization process using an
27
LOD Sensitivity(mA cm2 Repeatability Reproduciblity Long-term
(mM) mM1) Stability
10e100 1e100 M G Days ~ Months
1e50 10e200 M G Days ~ Months
1e50 10e200 M G Days ~ Months
0.1e1 100e2000 G G Days ~ Months
1e500 N/A M M Days ~ Months
4 ), Sacc ¼ interfering saccharides
autoclave that is fatal for enzyme-based electrodes. Besides the
possibility of implantable probes for continuous glucose moni-
toring, the chemical process of nanoporous film fabrication may
enable mass production of disposable non-enzymatic glucose
strips.
Nonetheless, it is yet to surpass enzyme sensors. In terms of
commercialization, non-enzymatic sensors have yet a long way to
go. Most studies have been strongly biased towards materialistic
approaches based on various combination of substances and
structural engineering. The conditions used for tests are far from
practical, clearly revealing the functional limitations of the pro-
posed systems or materials in the standpoint of practical glucose
sensor.
Research in this field needs various novel materials that can
offer new chances to make breakthrough for better electrode and
protective film. For practical use and mass production, however, it
requires more effort to look into sensing mechanism and figure out
the problems hampering reliable operation in clinical samples. The
next step to laboratory-scale studies based on new materials should
endeavor professionally to yield mature technology based on
effective solutions for commercialized non-enzymatic sensors.
Acknowledgement
This research was supported by Nano Material Technology
Development Program through the National Research Foundation
of Korea(NRF) funded by the Ministry of Science, ICT and Future
Planning (2011-0030268). This research was supported by a grant
to CABMC (Control of Animal Brain using MEMS Chip) funded by
Defense Acquisition Program Administration (UD140069ID). This
work was supported by the National Research Foundation of Korea
(NRF) grant funded by the Korean government (MSIT) (No.
2017R1E1A1A01074236).
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