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Available online at www.sciencedirect.com

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Review Article

Recent developments in blood glucose sensors

Hui-Chen Wang a, An-Rong Lee b,*

a
Institute of Pharmaceutics, Development Center for Biotechnology, New Taipei City, Taiwan
b
School of Pharmacy, National Defense Medical Center, Taipei, Taiwan

article info abstract

Article history: Diabetes has recently become a leading cause of death worldwide. To date, although there
Received 30 August 2014 is no means to cure or prevent diabetes, appropriate medication and blood sugar moni-
Received in revised form toring can enhance treatment efficiency, alleviate the symptoms, and diminish the com-
25 November 2014 plications of the condition. This review article deals with current growth areas in the
Accepted 24 December 2014 market for blood glucose sensors and possible future alternatives, which are generally
Available online 14 February 2015 considered to be the point sample test and the continuous glucose monitor (CGM). Most
glucose sensors are enzyme-based, whereas others are enzyme-free. The former class is
Keywords: sensitive and some products are extensively employed for daily self-sensing and in hos-
blood glucose monitoring pital environments as reliable diagnostic tools. The latter class, particularly the boronic
boronic acid acid fluorescent sensor, is facile and extremely promising. Practicality demands that all
molecular recognition types of sensors offer accuracy, specificity, and real-time detection.
saccharides Copyright © 2015, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan
LLC. Open access under CC BY-NC-ND license.

biochemists and medicinal chemists not only because sac-

1. Introduction charides are involved in cellecell interactions within biolog-
ical organisms but also because saccharide sensing offers
Since Emil Fischer established the monumental theory of su- promise for clinical diagnostic applications such as blood
pramolecular chemistry on interactions between substrate sugar level, pathogens, and cancer [11e18].
molecules and specific enzymes, molecule recognition is of
particular interest to numerous scientists [1]. Molecular
recognition based on the lock-and-key principal occurs in
biological systems such as enzymeesubstrate interactions, 2. Saccharides and their importance
antigen evoking antibody [2e5], and sugar binding to lectin
[6e9]. Following development of the first two-dimensional Carbohydrates, the most abundant organic form of material
structure of crown ether for a specific metal ion by Pedersen, on the earth, which form biological building blocks and di-
Cram, and Lehn [10], the possibility of synthetic receptors that etary components, are classified as single sugars (mono-
mimic important biological activities was demonstrated. saccharides) and their polymers, namely oligosaccharides and
Particularly, saccharide recognition attracts the attention of polysaccharides [19e21].

* Corresponding author. School of Pharmacy, National Defense Medical Center, 9F, Number 161, Section 6, Minchun East Road, Taipei
11490, Taiwan.
E-mail address: [email protected] (A.-R. Lee).
http://dx.doi.org/10.1016/j.jfda.2014.12.001
1021-9498/Copyright © 2015, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. Open access under CC BY-NC-ND license.
192 j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 1 9 1 e2 0 0

Monosaccharides are generally the simplest and most applied in pharmaceuticals. For example, the first oligosac-
basic of carbohydrates, serving both as energy fuels and charide analog used as a chemotherapeutic agent was strep-
fundamental constituents of living organisms. For example, tomycin, a bactericidal aminoglycoside antibiotic isolated in
five-carbon sugars exist in information carriers, such as 1943, and also the first cure for tuberculosis. Acarbose, an
deoxyribose in DNA and ribose in RNA; moreover, the best- antidiabetic drug used to treat type II diabetic mellitus by
known six-carbon sugars include D-glucose, also known as inhibiting a-glucosidase, localized in the brush border of in-
either grape sugar or blood sugar; D-fructose, fruit sugar; and testinal epithelium, is also an oligosaccharide derivative
D-galactose, which forms milk sugar when combined with comprising two glucose moieties with a rare sugar unit. Cyclic
glucose. The D series of sugars are thus designated based on oligosaccharides such as cyclodextrins, obtainable by partial
the observation that most natural monosaccharides have the hydrolysis of starch, which bear a hydrophilic exterior and
same configuration at C-5 as D-glyceraldehyde. In aqueous hydrophobic interior, can form hosteguest complexes and be
solution, the isomeric structures of glucose molecules display applied in drug delivery systems (Fig. 2) [21]. Cyclodextrins
equilibrium. In neutral solution, glucose exhibits the linear also have numerous applications in foods, pharmaceuticals,
open-chained form in <0.1% of molecules. Most of these chemicals, and agriculture.
molecules exist as a more stable cyclic hemiacetal with a six- Polysaccharides, macromolecules comprising numerous
membered pyran ring and thus are termed the pyranose monosaccharide moieties, are ubiquitous in nature. They are
(Fig. 1). frequently classified into three classes according to function:
In humans, D-glucose is vital for its role in metabolic ho- structural polysaccharides, water-binding polysaccharides,
meostasis; it acts as an energy source in living systems and and reserve polysaccharides. Polysaccharides are important
maintains human bodily functioning when consumed or biological polymers and possess great structural diversity.
through the formation of other essential saccharides via
biosynthesis. When taken up by human cells, glucose can be
either broken down (glycolysis) to yield energy, converted into 3. Glucose-related disease: diabetes
other metabolites in the form of metabolic intermediates, or
polymerized to form cellulose and starch through biosyn- Various saccharides-related diseases are common in clinical
thesis to function properly. In the human body, besides practice, including disorders of carbohydrate metabolism,
existing in free form, glucose can covalently link to lipids such as lactose intolerance, Andersen's disease, Pompe dis-
(glycolipids) and proteins (glycoproteins) and other biological ease (acid maltase deficiency) [23,24], obesity, hypoglycemia,
molecules as glycoconjugates, which are crucial building hyperactivity (mostly in children), and most important of all,
components of cell membranes and are mainly involved in diabetes [25e27].
the mechanism of intercellular recognition [22]. Diabetes is a chronic disease that has devastating human,
Monosaccharides can also join other sugars via glycosidic social, and economic consequences. According to the World
bonds through the sequential reaction of their anomeric hy- Health Organization (WHO) and the International Diabetes
droxyl groups with the hydroxyl groups of other sugars, Federation, its worldwide prevalence is projected to double
together with the elimination of water, resulting in a yield of over the next couple of decades, from 347 million people in
oligosaccharides or polysaccharides. The simplest and most 2005 to 700 million people in 2030. Notably, >80% of diabetic
biologically important oligosaccharides are disaccharides. patients live in low- and middle-income countries [25,28].
Three naturally abundant disaccharides are maltose, lactose, Diabetes can be divided into three main types. Type I dia-
and sucrose. The glycosidic linkages of these three di- betes is insulin-dependent; it was previously called insulin-
saccharides are formed stereospecifically by enzymes; there- dependent diabetes mellitus or juvenile diabetes. It is caused
fore, only one of the possible configurations (a or b) occurs by deficient insulin production within the body and typically
and, like all glycosides, its mutarotation is not permitted. manifests among the youth. Daily replacement of insulin be-
Maltose, which occurs mainly in malt, comprises two D- comes indispensable for those with the condition. Type II
glucose units joined with an a(1/4) bond via a condensation diabetes is noninsulin-dependent and is caused by insulin
reaction. Lactose, the most important sugar in mammalian resistance, a condition in which the target organs develop a
milk, is the combination of D-galactose and D-glucose. Su- failure to properly respond to insulin. Type II diabetes is
crose, also named table sugar, consists of D-glucose and D- termed adult-onset diabetes and makes up >95% of all cases.
fructose. Oligosaccharides also form glycoconjugates with Gestational diabetes occurs when pregnant women, usually
proteins and lipids, some of which are important in cell without a previous history of diabetes, develop a high blood
biology. Additionally, taking advantage of their biological ef- glucose level. Women with gestational diabetes typically have
fects, complex oligosaccharides and their analogs are widely a high risk of eventually developing type II diabetes.
Although diabetes is not actually caused by saccharides, it
HO is one of the most notorious saccharide-related diseases. This
is because body cells cannot digest glucose from blood
OH OH O OH themselves. To maintain blood sugar concentration following
O ingesting carbohydrate, the body requires insulin, produced
HO OH
OH and released from the B- (or b-) cells of the pancreas, to
OH OH
OH transport glucose into cells for subsequent metabolism. The
result of inefficient insulin production or secretion is an
Fig. 1 e Linear and cyclic form of D-glucose. excessive rise in blood glucose, even spilling into the urine.
 j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 1 9 1 e2 0 0 193

Fig. 2 e Common oligosaccharides and their analogs.

Seven million people develop diabetes annually. The WHO 4.1. Point sample test
has also warned that the number of deaths from diabetes is
expected to increase by >50% over the next decade. Nowa- The earliest method for glucose detection was based on the
days, one person dies from diabetes every 10 seconds. Dia- formation of a Schiff base (imine) between aldehydes and
betes has become an urgent global problem that requires aromatic amines. The reaction of the aldehyde group on
serious action. glucose with 2-methylaniline (o-toluidine) forms a stable blue/
green color imine (an anil). The resulting imine displays a
maximum absorption (lmax) in the visible region of the spec-
4. Glucose sensors trum at 625 nm (Scheme 1). The glucose concentration is
proportional to the absorption intensity. The glucose con-
Despite the lack of any known cure for diabetes, we have centration in the test sample can be obtained based on the
managed to improve treatment efficiency to alleviate its plot of a standard curve. The main weakness of this method is
symptoms and diminish its complications through appro- its lack of selectivity owing to aldehyde being the common
priate medication and blood sugar monitoring, to improve functional group in numerous sugars and consequent preva-
treatment decisions and glucose control. Glucose sensor sys- lence of false-positive results. Fortunately, glucose is the
tems are classified into two groups based on duration of principal saccharide in the blood; other monosaccharides and
measurement method and time: the point sample test and the disaccharides are present only in very low concentrations.
continuous glucose monitor (CGM) (Table 1) [29]. Most glucose By exploiting glucose oxidase as an enzyme specific to b-D-
sensors are enzyme-based, whereas others are enzyme-free. glucose, an enzyme-based assay was introduced to assess
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Table 1 e Technologies under development for glucose sensors [29].

Glucose sensor Point sample Urine dipstick
Finger prick glucometer
Continuous Invasive Subcutaneous amperometric electrodes, microdialysis, intravenous
implantable devices, and micropores/microneedles
Noninvasive Transdermal: reverse iontophoresis, sonophoresis, etc
Optical: fluorescence, infrared spectroscopy, Raman spectroscopy, etc

Scheme 1 e Reaction of D-glucose and o-toluidine.

glucose levels. Molecular oxygen, O2, when catalyzed by 4.2.1. Invasive continuous glucose sensors
glucose oxidase, readily oxidizes b-D-glucose to D-gluconic In 1954, the first oxygen electrode, known as the “Clark elec-
acid, while it is reduced to hydrogen peroxide (H2O2). The trode”, was invented by the American biochemist Leland C.
generated H2O2 can then further oxidize o-toluidine to form a Clark, also considered the “Father of Biosensors” [30]. To
colored product with a concentration proportional to that of monitor oxygen signals and calibrate the oxygen electrode,
H2O2 and hence to that of glucose. Based on this concept, Clark used glucose and a glucose-specific enzyme, glucose
several commercial test kits have been employed as routine oxidase, to remove oxygen by reducing it to H2O2. This process
diagnostic tools, including those utilizing chemical strips, and found the decrease of oxygen to be proportional to the con-
those used to test blood and urine glucose levels by sampling centration of glucose in the solution. Eventually, Clark real-
specimens directly into the strip followed by visual reading of ized that this simple device could be used to measure oxygen/
the color charts (Scheme 2). glucose in water, blood, and other solutions. Most modern
In 1971, Clemens developed the Ames Reflectance Meter glucose sensors used daily by millions of diabetics are based
(ARM), a device to detect reflected light and automatically on Clark's concept.
assess strip color change, using a standard strip for calibra- Invasive continuous glucose sensor research involves four
tion. The ARM was also the first blood glucose monitor patent technologies: subcutaneous amperometric electrodes, micro-
filed in the USA for point-of-care test devices for diabetes dialysis, intravenous implantable devices, and micropores/
patients [29]. microneedles. To date, only subcutaneous and microdialysis
Existing point sample tests require patients to draw blood studies have yielded commercial products. Subcutaneous
with a lancet several times daily. Such discrete tests are un- needle-type sensors adapt protected technologies, and
suited for use while sleeping or driving, and moreover hyper- immobilize enzyme and mediator onto a polymer membrane
or hypoglycemia events are unlikely during sampling. and electrode surface. Glucose oxidase serves as the catalyst
to convert glucose to gluconolactone. Reductioneoxidation
4.2. CGM reactions can generate a concentration-dependent current or
voltage to be measured by electrochemistry (Fig. 3) [29,31].
Investigations have demonstrated that intensive glycemic In 1990, the Medtronic MiniMed (Northridge, CA, USA)
control to maintain blood sugar levels as near normal (eugly- introduced the Continuous Glucose Monitor System (CGMS),
cemia) as possible can diminish complications of diabetes and the first CGM approved by the US Food and Drug Administra-
improve quality of life, stimulating the launch of numerous tion (FDA). The CGMS allows 3-day continuous glucose moni-
investigations on CGMs. CGM systems employ a tiny sensor toring and data recording, where blood glucose measurement
inserted beneath the skin and remain in place for a period of records can be processed and analyzed retrospectively. Cur-
time to assess glucose levels in tissue fluid. CGM systems rent Medtronic products are the Guardian REAL-Time and
should provide data on glucose levels, particularly the ten- MiniMed Paradigm Real-Time (glucose monitor combined with
dency, magnitude, frequency, period, and changes of fluctu- insulin pump). In 2006, the first real-time continuous glucose
ations in real-time to alarm patients should rapid changes in monitoring system, DexCom-7, was approved by the FDA and
glucose levels occur in the blood, particularly while sleeping or in 2007 its lifetime was extended from 3 days to 7 days. The
exercising. Numerous technologies are involved in CGM in- latest CGMS model to follow this FreeStyle Navigator achieved
vestigations, and they can be classified as invasive and 5 days of continuous glucose monitoring and was approved by
noninvasive (Table 1). the FDA in 2008 (Table 2) [32e34].
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Scheme 2 e Oxidation of D-glucose catalyzed by glucose oxidase.

Fig. 3 e Enzyme-based electrode with glucose oxidase and mediators [29,31].

Microdialysis probes, which are valuable adjunctive tools 4.2.2. Noninvasive continuous glucose sensors
for glucose trend analyses, use a subcutaneous inserted The availability of home-use glucometers has significantly
hollow fiber combined with a semipermeable membrane improved quality of life for diabetes sufferers; however, such
filter. The membrane is permeable to glucose and other monitors require a new strip for each test, as well as a blood
small molecules. Meanwhile, the fiber is perfused with draw from the finger pricks, with the latter causing pain and
isotonic fluid, glucose in the interstitial fluid diffuses into inconvenience. To overcome the short lifetime and calibration
the fiber, and the fluid is then pumped to an enzyme-based needs of the invasive continuous glucose system, and to in-
electrode. The glucose concentration depends on the equi- crease patient compliance, noninvasive continuous glucose
librium of the interstitial fluid. A common weakness of this sensors represent an obvious solution. Numerous technolo-
technology is membrane blockage owing to biofouling. gies pursued as noninvasive sensor systems can be classified
GlucoDay (Menarini Diagnostics, Firenze, Italy), marketed in as transdermal and optical sensors [33,34].
2002, is the only commercial product approved in Europe
[32]. 4.2.2.1. Transdermal sensors. GlucoWatch (Cygnus Inc., Red-
Consequently, the first generation of invasive CGMs are all wood City, CA, USA), a transdermal noninvasive continuous
enzyme-based sensors and require calibration using the glucose sensor approved by the FDA in 2001, is worn on the
finger-prick blood sensor. Future improvement in invasive wrist like a watch and does not require drawing blood. Glu-
CGMs will undoubtedly focus on accuracy, reliability, cost, coWatch employs reverse iontophoresis. A patented hydrogel
and lifetime. pad is located between the skin and an electrode. A small

Table 2 e Comparison of current market CGMS devices [33,34].

Brand Guardian Real-Time MiniMed 530G with Enlite Dexcon G4 Platinum FreeStyle
Company Medtronic Medtronic Dexcom Abbott
FDA approved date 2006 2007 2007 2008
Sensor life (d) 3 6 7 5
Sensor style Insertion under skin Insertion under skin Insertion under skin Insertion under skin
Startup initialization 2 2 2 10
time (h)
Calibration (Y/N) Y, 2 h after insertion, Y, 2 h after insertion, and Y, every 12 h Y, approximately 1, 2, 10, 24,
with finger-stick test and the first 6 h, then the first 6 h, then every 12 h and 72 h after insertion
every 12 h

CGMS ¼ continuous glucose monitor system; FDA ¼ Food and Drug Administration.
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Fig. 4 e Principle of fluorescence resonance energy transfer (FRET) from Concanavalin A (Con A) to dextran by adding
glucose [36].

current from the electrode passes through the hydrogel and molecule with a rigid structure absorbs light energy from the
draws out interstitial fluid from the skin to the iontophoretic ground state to an excited state, it returns to the ground state
electrode. The glucose concentration in the sampling fluid is by emission of light, at a lower energy level than that at which
1000 times lower than that of interstitial fluid below the skin it absorbed light, from different singlet states and is known as
(the concentration of glucose in the interstitial fluid can fluorescence. Fluorescence-based technology possesses
sometimes be 100 times greater than the oxygen concentra- numerous advantages over the conventional ultraviolet-
tion) and is detected using the glucose oxidase catalytic sys- visible spectrophotometry used in sensing. Fluorescence
tem. Low glucose concentration means oxygen supply ceases spectrophotometry is extremely sensitive and causes only
to be a limitation for glucose oxidase. Additionally, the skin trivial damage to the host. Fluorescence can be measured not
filters off large molecules, reducing biofouling and electro- only by its intensity but also its lifetime (generally <105 s).
chemically active fouling. However, the extended warm-up Fluorescence spectrophotometry also offers information on
time, difficult operation, need for calibration, and most biomolecule structure and environment and how bio-
importantly, skin irritation, are all disadvantages of this molecules respond and change in healthy versus diseased
technology. Consequently, GlucoWatch was withdrawn from states [35].
the market after 2008. The Concanavalin A (Con A) sensor developed in 1984 was
Compared to transdermal technology, alternative optical the first fluorescence-based glucose sensor. Con A is a plant
technology offers more investigative options, including lectin (carbohydrate-binding protein) and a homotetramer,
polarimetry, Raman spectroscopy, scattering/occlusion spec- with each possessing a specific glucose binding site. Con A can
troscopy, (near) infrared spectroscopy, fluorescence, photo- be labeled using a fluorophore (fluorescein isothiocyanate or
acoustic spectroscopy, optical coherence tomography, etc. allophycocyanin, as the fluorescent donor) and immobilized
To date, the medical market lacks a product for optical to fine, hollow fibers. Dextran, another polysaccharide, is also
continuous glucose monitoring. However, owing to the prev- labeled with a fluorophore (rodamine or malachite green, as
alence of diabetes, optical technology has attracted increasing the fluorescent receptor) in the fiber. Glucose and dextran are
scientific attention. Among all types of glucose sensors, fluo- competing ligands of Con A in the fiber system. The combi-
rescence is considered the most promising technology for nation of dextran with Con A causes fluorescence resonance
creating the ideal glucose sensor. energy transfer (FRET) from the fluorescence donor to the
fluorescent receptor. Addition of further glucose replaces
4.2.2.2. Optical sensors: fluorescence-based glucose sensors. more dextran, and consequently a corresponding decrease in
Fluorescence is a specific type of photoluminescence. When a FRET (Fig. 4) [29,36].

Scheme 3 e Reaction of glucose oxidation with flavin adenine dinucleotideeglucose oxidase (FAD-GOx) and reversible
oxidation of FAD [22].
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Scheme 4 e D-Glucose catalyzed by hexokinase forms D-glucose-6-phosphate.

Glucose oxidase can also bind to fluorophores such as cause sensor instability and false alarms, as well as missed
fluorescein, enabling energy transfer from intrinsic flavin blood glucose readings [37]. Numerous efforts have been made
adenine dinucleotide fluorescence of glucose oxidase to the on the development of enzyme-less or enzyme-free glucose
extrinsic fluorophore. In this system, glucose concentration is sensors involving nanostructured electrodes to oxidize
not proportional to the fluorescence intensity, but rather to glucose directly on the surface. However, chloride fouling
the time between the addition and the fluorescence change following a long detection period remains problematic
(Scheme 3) [22]. [38e44]. Another alternative method for enzyme-free glucose
D-Glucose can be subjected to phosphorylation, catalyzed by sensors is synthetic boronic acid-based receptors [31,45].
a hexokinase (glucokinase), to D-glucose-6-phosphate coupling A boronic acid is a substituted boric acid containing a
with the hydrolysis of adenosine-50 -triphosphate (ATP). Hexo- carbon (C)eboron (B) bond that belongs to the larger class of
kinase from yeast usually exists as a dimer and has intrinsic organoboranes and serves as a Lewis acid capable of reacting
fluorescence that is quenched following adding glucose. How- with Lewis bases, such as cis-1,2-diol and cis-1,3-diols or
ever, hexokinase is temperature-unstable, which limits its amino acids, to form reversible covalent complexes of five-
application (Scheme 4) [22]. and six-membered cyclic boronate esters. During the last
decade, numerous boronic acid-based fluorescent sensors
4.3. Newcomers: enzyme-free boronic acid-based glucose have developed as saccharide sensors and some specific bis-
sensors boronic acid sensors even reveal high selectivity for D-glucose
(Scheme 5) [35,46,47].
The above mentioned glucose sensors on the current medical Boronic acidesugar recognition can be explained by the
diagnosis market are mostly enzyme-based sensors, such as nitrogen (N)eB interaction and the photoinduced energy
glucose oxidase or glucose dehydrogenase, and rely on elec- transfer (PET) mechanism [31]. The NeB interaction is some-
trochemical analytical measurement. However, the good times considered a hydrogen bond-like interaction. However,
sensitivity of enzyme-based glucose sensors is counteracted in protic solvent systems, solvent insertion can occur in NeB
by instabilities due to numerous other factors such as envi- interaction to generate a zwitterionic species. Moreover, in
ronmental temperature and pH. The biological foil can also protic media, the NeB interaction can better be described by

Scheme 5 e Interaction of phenylboronic with 1,2- and 1,3-diols to form cyclic boronate esters [46].
198 j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 1 9 1 e2 0 0

R
HO H HO O H
HO B- N+ HO B-
N+
H

N B OH N B OH
R = H (water) HO HO

R = CH3 (methanol), etc.

1 2 HO HO
N B OH N B OH
Fig. 5 e The nitrogeneboron interaction in boronate esters
(1) (not solvent-inserted) and (2) (solvent-inserted).

HN HN
N OH HO
O O
HO B N N B OH

HO
B
OH

3 4
S S S S
Fig. 6 e Structures of N-methyl-o-(aminomethyl)
phenylboronic acid (3) and bis-boronic acid (4). Au
5

Fig. 8 e Gold electrode surfaced functionalized with a

solvent-inserted (2) instead of (1) (Fig. 5). Although the NeB pyrene-based bis-boronic acid [37,51].
interaction in protic solvent systems is indirect, it remains an
important effect in sensory system design and application [48].
Regarding the NeB interaction, the PET mechanism was selectivity for D-glucose can be improved by introducing a
introduced to the design of boronic acid fluorescent sensors. second boronic acid, for example, (4), to the system (Fig. 6) [50].
Initially, it was proposed that a reduction of boronic acid pKa via A fluorophore-spacer-receptor model can clearly describe the
the NeB interaction facilitates binding of the saccharides and fluorescence off-on mechanism of the PET sensor (Fig. 7) [50]. In
boronic acid at physiological pH 7.4. Later, when a 1,2- or 1,3- this model, in the neutral boronic acid state (sugar-free), the
diol binds with a boronic acid, it rapidly but reversibly forms a electrons (in most cases from the nitrogen) can be internally
cyclic boronate ester, increasing the Lewis acidity of boron, as transferred to the fluorophore and cause fluorescence quench-
well as the NeB interaction. Given these advantages, the NeB ing to create the sensor off spate. Once the boronic acid binds
interaction can help modulate the neighboring fluorophore and with a sugar, the increased Lewis acidity of the boronate attracts
create a fluorescence offeon response in the sensory system. the electron from nitrogen, then binds with the boron atom and
The first fluorescence PET sensor was described by James creates a sensor on state, which enhances fluorescent intensity.
et al [49] in 1994 and has recently experienced strong growth. Besides fluorescence analysis, electrochemical impedance
Notably, the anthracene-based N-methyl-o-(aminomethyl) spectroscopy and surface plasmon resonance were also
phenylboronic acid (3) was selective for increase of D-fructose administered in boronic acid-based glucose sensors (Fig. 8)
and fluorescent intensity on addition of saccharides. The [37,51].

Fig. 7 e Schematic representation of the Fluorophore-Spacer-Receptor design assembly for fluorescence photoinduced
energy transfer (PET) sensory system [50].
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