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Recent Advances in Self-Powered Electrochemical

Biosensors for Early Diagnosis of Diseases
Vardan Galstyan,* Ilenia D’Onofrio, Aris Liboà, Giuseppe De Giorgio, Davide Vurro,
Luigi Rovati, Giuseppe Tarabella, and Pasquale D’Angelo

Modern sensing technologies are highly required for health 1. Introduction

monitoring. In this respect, the development of small-size, high-performance, Modern requirements for personal
and self-powered biosensors for detecting and quantifying disease markers healthcare have greatly increased the
in biofluids can bring crucial changes and improvements to the concept of demand for developing sensing tech-
nologies with advanced functionalities.
health monitoring systems. Clinical trials identify a wide range of biomarkers
In contrast to conventional large-scale
in biofluids that provide significant health information. Research into novel and costly diagnostic systems that re-
functional materials with outstanding properties opens up new perspectives quire trained personnel, and laborious
for fabricating new-generation biosensors. Furthermore, energy conversion processes, new-generation sensing de-
and storage units are investigated to integrate them into biosensors and vices should be cost-effective, portable,
develop self-powered systems. Electrochemical methods are very attractive for and easy to use to perform real-time
analysis. In this regard, developing
applications in biosensor technology, both in terms of biomarker detection and biosensors for disease marker detection
energy generation. Here the recent achievements in research into self-powered and quantification in biofluids indicates
electrochemical biosensors to detect sweat and saliva biomarkers their great significance in biomedical
are presented. Potential biomarkers for efficient analysis of these fluids diagnostics.[1] In these devices, the
are discussed in light of their importance in identifying various diseases. The biosignal is registered by the transducer,
which converts it into a detectable output.
influence of electrode materials on the performance of sensors is discussed.
The operating mechanism determines
Progress in developing operating strategies for self-powered electrochemical the output signal of biosensors.[2] Elec-
monitoring systems is also discussed. A summary and outlook are trochemical biosensors (ECBSs) convert
presented, mentioning major achievements and current issues to be explored. bioreactive processes into electrical
signals such as current, resistance, or
potential changes.[1d,3] In addition, the
use of biological recognition elements
can significantly enhance their selectivity.[1b,4] The advantages
V. Galstyan, I. D’Onofrio, A. Liboà, G. De Giorgio, D. Vurro, G. Tarabella, mentioned above as well as the relatively simple architecture and
P. D’Angelo
Institute of Materials for Electronics and Magnetism functionality of electrochemical biosensors make them suitable
National Research Council (IMEM-CNR) structures for the rapid detection of biomarkers in real time.
Parco Area delle Scienze 37/A, Parma 43124, Italy Conventional electrochemical sensors typically consist of three
E-mail: [email protected] electrodes: working, reference, and counter. Heterogeneous reac-
V. Galstyan, L. Rovati tions drive electrochemical sensing, where the working electrode
Department of Engineering "Enzo Ferrari”
University of Modena and Reggio Emilia
and species in biofluids exchange charge carriers. Therefore,
Via Vivarelli 10, Modena 41125, Italy the electrode material plays a crucial role in these processes.[3a]
I. D’Onofrio, A. Liboà Research into exploring novel functional materials with attrac-
Department of Chemical tive physicochemical properties opens up new perspectives for
Life and Environmental Sustainability Sciences fabricating high-performance electrochemical biosensor systems
University of Parma and their application in human health monitoring. Furthermore,
P.co Area delle Scienze 11/a, Parma 43124, Italy
nanotechnology and nanoscale materials offer innovative tools to
address issues associated with sensitivity, power consumption,
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/admt.202400395 and miniaturization of biosensors.[1b,c,2c,5]
© 2024 The Author(s). Advanced Materials Technologies published by
Typically, electrochemical sensors require an external power
Wiley-VCH GmbH. This is an open access article under the terms of the supply to operate, which is a problem in producing small portable
Creative Commons Attribution License, which permits use, distribution or wearable sensors. Miniaturization of electrochemical sensors
and reproduction in any medium, provided the original work is properly can reduce their power consumption. Furthermore, research
cited. shows that redox reactions using chemical species in biofluids
DOI: 10.1002/admt.202400395 generate energy that can be utilized to operate two-electrode

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electrochemical systems.[3a,6] The power generated by electro- test diagnostics can take advantage of this abundance. However,
chemical energy conversion varies depending on the concentra- a major aspect makes it difficult to think of blood tests as a quick
tion of the bioanalyte.[3a,7] Thus, the above sensors can operate and cheap way to perform self-diagnostic tests. The complexity
without an external power source. Various studies have reported of whole blood is a limiting factor in making it the most suit-
the successful application of microbial fuel cells in self-powered able matrix for biosensor testing. In addition, the liquid compo-
biosensing, where one of the electrodes acts as an active sensing nents of blood, i.e., plasma, and serum, are also complex ma-
element.[8] Using an electrochemical galvanic cell for biomarker trices, in which, first, many interfering molecules are similar
detection is an efficient method for producing self-powered mon- to the selected analyte and can be detected. Various blood com-
itoring systems. Hence, an electrochemical sensor can function pounds may affect the activity of recognition elements. For in-
like a battery system, where the biofluids to be analyzed are also stance, protein biofouling on the sensing interface in contact with
used as electrolytes and the redox reactions generate the electric the blood samples can cause a partial exposure of the active recog-
current.[9] Triboelectric nanogenerators can be used as an alter- nition interface to its conjugated analytes,[16] while complex elec-
native strategy for developing self-powered biosensors.[10] Here, trolytic environments in electrochemical biosensors may affect
mechanical energy is converted into electrical energy due to the the biosensor performance.[17]
electrification of the contact between a liquid and a solid.[11] or
the movement of a body.[12]
The fabrication of new electrode structures with tunable ad- 2.1.1. Biomarkers in Blood
sorption and catalytic properties and the further development of
effective strategies for electrochemical sensor architecture make Various types of biomarkers can be measured in blood using a
them promising devices for detecting disease biomarkers in biosensor and can be used to detect and monitor several dis-
blood, sweat, and saliva.[13] Progress in energy harvesting tech- eases. Intermediate or final metabolites play a fundamental role
nologies that provide efficient solutions to increase energy output in human physiological activity. Detectable blood metabolites
in electrochemical sensors is leading to the development of the are typically small molecules with different functions and rep-
next generation of health monitoring devices. Hence, evaluation resent an important class of biomarkers for disease diagnosis
of progress in self-powered ECBS research is necessary. (Figure 1). Main blood biomarkers and their threshold levels for
This paper discusses recent advances and current challenges the monitoring of diseases are reported in Table 1. The canon-
in developing self-powered electrochemical sensors considering ical example is glucose, one of the well-known molecules in
potential biomarkers for efficient analysis of blood, sweat, and the blood associated with health monitoring. From a physiolog-
saliva. ical point of view, the maintenance of glucose concentration is
tightly regulated.[18] Excess glucose levels in the blood caused
by metabolic disorders are harmful. Herein, diabetes mellitus
2. Biofluids and their Monitoring is a major disease associated with excess glucose levels, causing
Clinical studies have shown that biofluids such as blood, sweat, several complications such as blindness, cardiovascular disease,
and saliva contain compounds that can be used as biomark- and kidney failure.[19] Expected normal glucose concentrations in
ers for the early diagnosis of diseases. These findings encour- blood range 70−100 mg dL−1 (3.9−5.6 mmol L−1 ). Glucose con-
age researchers to develop biosensor systems for rapid and centrations of 100−125 mg dL−1 (5.6−6.9 mmol L−1 ) are consid-
real-time health monitoring. Recent advances in electrochemi- ered prediabetic, when the glucose level in the blood is higher
cal biosensors make them very attractive for fabricating high- than 126 mg dL−1 (7 mmol L−1 ), diabetes is diagnosed.[20] Mea-
performance, self-powered monitoring devices to detect various suring glucose levels in this manner is critical for diagnosing and
biomarkers. monitoring diabetes.
Another important metabolite associated with anaerobic glu-
cose metabolism in muscle is lactate. When the level of lactate
2.1. Monitoring of Blood in the blood increases, a state of hyperlactatemia is achieved,
which determines a decrease in pH. This condition results from
Blood is classified as a liquid connective tissue that performs tissue hypoperfusion and hypoxia occurring in shock, severe
many physiological functions due to its complex composition.[14] anemia, respiratory failure, and hypermetabolic states. How-
It consists of corpuscular elements, i.e., red and white blood cells ever, it may also result from exposure to various drugs, tox-
(erythrocytes and leukocytes, respectively) and platelets (throm- ins, mitochondrial defects, or sepsis that impair aerobic en-
bocytes). Cells or cell fragments are suspended in plasma, the ergy production and lactate consumption.[21] A decrease in cel-
liquid component of blood consisting mainly of water (90%). lular pH can lead to cellular acidosis, which impairs mus-
Plasma also contains various compounds, including proteins, cle function.[22] In a physiological scenario, whole lactate pro-
electrolytes, carbohydrates, minerals, and fats.[15] The transport duction levels range from 15 to 30 mmol kg−1 day−1 . Nor-
of oxygen and nutrients to tissues and living cells is the main mally, lactate concentration in the bloodstream is maintained at
function of blood. However, it also serves a purification func- 0.5−1.0 mmol L−1 due to a tightly regulated balance between
tion by loading waste while releasing oxygen. Other important lactate production and consumption. When lactate levels exceed
functions are delivering immune cells to areas where infections 1.0 mmol L−1 hyperlactatemia occurs.[21] For these reasons, mea-
are present, buffering effect, and stabilizing body temperature.[14] suring blood lactate levels can provide important information
The highest levels of bioanalytes, present in other biometric in- for assessing disease severity or monitoring the health status of
dicators of the body, are characteristic of blood, therefore blood patients.

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Figure 1. Schematic representation of some canonical blood biomarkers and their associated diseases. The range of components in human blood and
its physiological functions make it rich in many biological data. Several markers in the blood are associated with the monitoring and diagnosis of many
diseases. The markers presented in the schematic illustrate some recognition elements, the detection of which is important for the development of
sensor systems for rapid health monitoring in real-time. Created with BioRender.com.

Table 1. Main blood biomarkers and their physiological concentration in blood. The onset of related diseases is associated with excessing maximum
concentration.

Biomarker Concentration Disease Refs.

Glucose 70–126 mg dL−1 Diabetes [20]

Lactate 0.5–1.0 mmol L−1 Hyperlactatemia [21]
Cholesterol 200–250 mg dL−1 Cardiovascular diseases – diabetes [23]
Dopamine 0.01–1 μM Parkinson’s disease – attention deficit hyperactivity disorder or other diseases [27b]
CRP 0.02–13.5 mg L−1 Inflammation state or other diseases [28a]
IL-3 > 89.4 pg mL−1 High mortality rate in sepsis or other diseases [29a]
IL-6 >52.60 pg mL−1 Sepsis [32]
IL-6 0–43.5 pg mL−1 COVID-19 or viral infection state [33]
TNF-𝛼 3.9–18.5 ng L−1 Inflammation state or other diseases [35a]
Trysoin >1,4 μg mL−1 Pancreatic diseases [36]

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Cholesterol is an essential lipid, a component of cell mem- Another pleiotropic cytokine is Interleukin 6 (IL-6), which
branes, and a common precursor for the biosynthesis of vitamin plays a key role in host defense mechanisms. IL-6 is readily pro-
D, hormones, and bile acids. Genetic modification or increased duced during inflammation, tissue damage, or infection, con-
intake of dietary lipids may upset the balance of blood cholesterol tributing to physiological acute phase immune responses, as well
levels.[23] In a healthy person, the blood cholesterol concentra- as hematopoiesis. Abnormal IL-6 levels are involved in differ-
tion should be below 200 mg dL−1 , and levels between 200 and ent pathologies such as cancer, rheumatoid arthritis, autoim-
249 mg dL−1 are considered borderline. A cholesterol level above mune and chronic inflammatory diseases.[30] IL-6 is recognized
250 mg dL−1 indicates several conditions (e.g., high blood pres- as an important biomarker for monitoring the acute phase of
sure, heart attack, peripheral artery disease, stroke, and type 2 sepsis and is also considered a biomarker for cancer patients.[31]
diabetes).[23–24] Rapid and easy monitoring of blood cholesterol The threshold level of IL-6 in the blood for diagnosing sepsis
using biosensors is an important tool for assessing the risk of in healthy people is 52.60 pg mL−1 .[32] The detection and mon-
cardiovascular disease or other forms of disease associated with itoring of IL-6 was also evaluated in viral infections, including
high cholesterol. COVID-19, with blood levels in healthy donors ranging from 0
Neurotransmitters are endogenous messengers that transmit to 43.5 pg mL−1 , with higher concentrations associated with the
information between neurons and are represented by chemical infection state.[33]
substances that play an important role in the nervous system Another potent proinflammatory and immunoregulatory cy-
of the human body.[25] Measuring levels of neurotransmitters in tokine present in the blood corresponds to tumor necrosis fac-
the blood can be important for monitoring health and detecting tor (TNF)𝛼, produced by tumor cells, fibroblasts, keratinocytes,
disease. Dopamine is an example of one of the most important macrophages, neutrophils, B, T, and NK cells, T and B cells.[34]
and studied neurotransmitters, occupying a fundamental posi- TNF𝛼 is a major mediator of the inflammatory and immune re-
tion in the central nervous system (CNS), binding to specific re- sponse in many pathologies such as cancer, multiple sclerosis,
ceptors on neuronal membranes, and playing a crucial role in the Parkinson’s disease, inflammatory bowel disease, rheumatoid
control of movement, learning, working memory, cognition, and arthritis, and HIV.[35] Thus, detection and monitoring of TNF-
emotion.[26] Physiological levels of dopamine in the blood range 𝛼 levels in the blood is fundamental for the assessment of vari-
from 0.01 to 1 μM. Dysregulation of dopamine levels under- ous diseases. The level of TNF-𝛼 in the blood in healthy people
lies euphoria, attention deficit hyperactivity disorder, and Parkin- is 3.9–18.5 ng L−1 , higher concentrations are associated with in-
son’s disease. There is also growing evidence of dopamine hy- flammation and/or various pathologies.[35b] Trypsin is a protein
peractivity in schizophrenia.[27] Therefore, accurately determin- produced by the pancreas that is an important biomarker found
ing dopamine levels is important for the early detection of these in blood and serum. It plays a crucial role in diagnosing pancre-
diseases. atic diseases such as pancreatitis. Normal levels of trypsin in the
One of the most important classes of biomarkers for recog- blood are in the microgram range (0.25 mcg mL−1 ). However, an
nizing diverse physiological blood parameters is represented by acute pancreatic attack is indicated by a significant increase in
proteins. These biological macromolecules which provide a wide trypsin concentration exceeding 1.4 μg mL−1 .[36]
range of bodily functions, are useful for detecting and monitor-
ing various blood biomarkers originating from multiple body tis-
sues. The importance of proteins as biomarkers is also reflected 2.1.2. Detection of Biomarkers in Blood
in several diseases that can be detected or monitored. Herein,
we will give examples of some of the most well-known protein Technological advances over the past decade in microfluidics,
biomarkers, in particular cytokines. the fabrication of electrochemical biosensors, and diagnostic sys-
C-reactive protein (CRP) is a common blood biomarker. It is tems for biofluid examination, may offer advantages in diagnos-
a pentameric protein synthesized by the liver and belongs to the tics by allowing direct blood analysis. Biosensors, in particular, ex-
class of opsonins. In the inflammatory state, CRP opsonizes the ploit recognition elements such as physiologically produced en-
surface of microbes and dead or irreparably damaged cells, act- zymes and antibodies, or even synthetic complex molecules such
ing as an attack complex for complement proteins and promoting as aptamers and nanobodies, to accomplish their operation.[37]
macrophage-mediated phagocytosis. Its level in healthy people is This is independent of the transduction mechanisms they rely
0.02–13.5 mg L−1 , which may increase by four orders of magni- on.
tude due to inflammation or other disorders. Significant concen- The scientific literature of the sector demonstrates that it is
tration fluctuations make the detection and monitoring of CRP a quite challenging to find electrical and optical biosensors that are
powerful tool for assessing the effectiveness of therapy and mon- effective in testing whole blood. Indeed, the tendency to saturate
itoring the progression of various diseases.[28] the biosensor response due to analytes abundance in blood and
Interleukin-3 (IL-3) is an important blood biomarker for iden- interfering effects influencing the recognition efficiency mirrors
tifying inflammatory conditions and/or sepsis. It is an inflam- the complexity of blood and related matrices. Preziosi et al. stud-
matory cytokine that biologically promotes the production, pro- ied the response of organic electrochemical transistors (OECTs)
liferation, and survival of white blood cells. On the other hand, in the presence of whole blood and plasma. Inter alia, they
IL-3 enhances immune responses in sepsis, where high concen- showed that, even in the case of OECTs gated by gold (Au) elec-
trations of IL-3 correlate with increased mortality. Infected pa- trodes, which are less effective in promoting a channel current
tients with serum concentrations of >89.4 pg mL−1 are associated change in the presence of electrolytes, an almost undistinguish-
with higher mortality rates.[29] Therefore, blood IL-3 determina- able response may be found by comparing whole blood and
tion and monitoring are critical in some clinical circumstances. plasma responses.[38] Indeed, Olkhov et al. have shown that a

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Table 2. Parameters of ECBSs for the detection of biomarkers in blood and serum.

Anode material Cathode material Biomarker Concentration/detection Output LOD Detection method Refs.
range

Carbon Paper /FeMe2 - Carbon Paper/ Glucose 1–20 mM Power 480 μM Linear polarization [42]
LPEI/GOx AnMWCNTs/Laccase 0.19 μWn M−1
poly-methylene Bilirubin oxidase Glucose 0,03−10 mM Power NA Dependence between [43]
blue/ FAD- 1.4 μW cm−2 analyte concentration and
Glucose power density
dehydrogenase
(FADGDH) from
Aspergillus niger
Silver/carbon ink/ BOx Glucose 5−30 mM NA NA Chronoamperometric [44]
FADGDH∖ measurement
MWCNT/NQ-LPEI/FAD- Silver oxide/carbon paste Glucose 5−18 mM Voltage NA Charge of a capacitor [13a]
GDH 11.3 mV mM−1
PANI/TPU/GOx PANI/TPU/ Glucose 5−10 mM NA NA Dependence between the [45]
output current and
glucose concentration
GOx- polyethyleneimine anthracene-modified Glucose 1−10 mM Current 0.48 mM Dependence of generated [46]
modified TCP MWCNTs laccase 1.24 μA mM−1 energy and glucose
concentration
Platinum-iridium wire carbon/BOD Glucose From 500 μmol L−1 to NA NA Dependence between [47]
/carbon black/vitamin 100 mmol L−1 glucose concentration
K3/ Dp and GHD and LED switch on
enzymes
The sol-gel membrane of Carbon/Prussian Cholesterol 0.15 mmol L−1 to Current Dependence between [48]
phenothiazine /ChOx blue/ChOx 4.1 mmol L−1 26 mAmol Lcm−2 1.4 μmol L−1 output current and
cholesterol concentration
NA NA Thrombin From 3 nmol L−1 to NA Amperometric detection [49]
1.35 μmol L−1 0.9 nmol L−1
Au/Mg/Al/WPI Au Trypsin 0,5 to 100 μg mL−1 NA Dependence between [50]
0.5 μg mL−1 trypsin concentration and
LED switch meantime
NA: Not available

tricky experimental method is needed to reduce the sources of ing an efficient outcome in the case of real blood samples.
interference in optical biosensors, such as light absorption and Very recent work by Sailapu et al. is targeted to self-powered
scattering due to the presence of cells in whole blood.[39] Table 2 glucose tests in serum responding to REASSURED criteria,[13a]
summarizes the parameters of ECBSs for detecting biomarkers which are affordability, sensitivity, specificity, rapidity, deliverabil-
in blood and serum. ity, equipment-free, and user-friendly character, all these features
Very high glucose concentrations in the blood make it de- in combination with a real-time operation capability.[41] Here,
tectable using many devices available not only in laboratory en- it is shown a paper-based biofuel cell in the form of a smart
vironments but also on the market.[40] Blood tests are a staple of strip, made of printed electrodes on a flexible PET substrate
the current medical practice for glucose detection and monitor- equipped with simplified electronics, which can measure glucose
ing. For this reason, most of the studies on self-powered blood in human serum. The anode is composed of multi-walled car-
tests deal with glucose detection exploiting the strong and facile bon nanotubes (MWCNTs) on a silver/carbon electrode covered
electro-catalytic conversion driven by enzymatic reactions. Self- by a naphthoquinone-functionalized redox polyethyleneimine
powering is a niche topic for the research on biosensing for matrix (NQ-LPEI) containing some flavin adenine dinucleotide-
medical purposes and blood tests based on enzymatic biofuel dependent glucose dehydrogenase (FAD-GDH) enzyme. A glass-
cells are poorly explored in this field, although such biosensors fiber-paper has been used as a spacer with the cathode (silver ox-
allow conjugating devices’ architectural simplicity and the abil- ide/carbon paste mixture) and the sample collector. Here, a cer-
ity to use biofluids based on device operation autonomously in tain volume of serum sample (3.5 μL) is required on the glass-
real life. However, the richness of the blood matrix in metabo- fiber-paper collector to ensure a connection between the anode
lites such as glucose could be of great importance in devel- and cathode. In a simple design that uses only passive circuit
oping sensors using biochemical reactions within the fuel cell elements and is therefore compatible with printed manufactur-
concept. ing, the electronic circuit uses an open circuit voltage drop (Voc)
During the last lustrum, glucose detection by self-powered across a load resistor, which depends on the glucose diffusion
biosensors has been the subject of some interesting works show- through the collector. Thus, the decay rate of Voc is proportional to

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the concentration of glucose in the serum (the higher the glucose A significant example of a real-world application of self-
content, the higher the decay current due to diffusion-limited powered biosensors was demonstrated by Huang et al.[47] Here,
effects at the current-limiting electrode), and the electronic cir- a needle-like enzymatic biofuel cell was developed and used to
cuit is meant to be stored on a capacitor a fraction of the electric monitor underwater the health state of a largely farmed and con-
charge flowing into the circuit due to the current decay. The de- sumed fish (the Tilapia). The active part of the device consists of
vice output is then given by the voltage setting up at the capacitor i) a needle-like anode made of a platinum-iridium wire coated by
plates (which is higher for growing concentrations, since the to- carbon black and functionalized by a vitamin K3 layer (acting as
tal decay charge stored by the capacitor in a given time window an electron mediator) containing diaphorase (Dp) and glutamate
increases with the glucose concentration increase). In this way, a dehydrogenase (GDH) enzymes; ii) a gas-diffusion biocathode
linear calibration curve consisting of the stored voltage as a func- made of carbon cloth modified by some bilirubin oxidase (BOD)
tion of concentration may be assessed. It is important to note that and immersed in a 1% agarose hydrogel containing buffer salts
the sensitivity of ECBS can be finely tuned by properly sizing the (Figure 2a–c). The current/power generation is driven by the an-
electronic components on the printed strip. odic conversion of glucose to NADH due to GDH followed by
Guan et al. have shown an interesting proof of concept the oxidation of NADH to NAD+ (mediated by Dp), producing
consisting of an artificial blood vessel operating as a biofuel O2 and 2 electrons. Electrons reach the cathode via the external
cell for the self-powered detection of glucose.[45] In this case, circuit, favoring the O2 reduction to H2 O catalyzed by BOD. To
a fiber-like conducting polyaniline/thermoplastic polyurethane complete the proposed platform, the cell is connected to a charge
(PANI/TPU) membrane is implemented by using the electro- pump circuit whose output biases an LED indicator. The anode
spinning technique. Two separate parts of the PANI/TPU mem- is inserted into the caudal area of the fish and the cathode is pro-
brane have been loaded with glucose oxidase (GOx) and laccase tected in a hermetically sealed bag and left outside the fish’s body.
enzymes to form the anode and the cathode of the enzymatic cell. Within this scheme, the power generated from the system due to
An electron transfer at the anodic interface is sustained by the the two steps reaction at the anode followed by an oxygen reduc-
GOx-mediated electrocatalytic oxidation of glucose next to the an- tion at the cathode (being accordingly the overall reaction, propor-
ode, leading the production of protons to be driven at the laccase- tional to the glucose level near the anode), controls the process
decorated cathode. Electrons reaching it from the external circuit of charging and discharging the capacitor in the charge pump
allow laccase to catalyze the reversible oxygen reduction reaction regulator. In turn, the charge/discharge process is visualized by
realizing H2 O2 production. The net effect of the process is an effi- the LED as a blinking frequency, which is proportional to the glu-
cient chemical-to-electrical energy conversion. The performance cose levels activating the power generation. Then, a smartphone
of the as-prepared artificial blood vessel was tested in simulated is used to record the blinking frequency through a freely available
blood, also under mechanical stress (stretching up to 200%), and mobile app, i.e., the MudWatt Explorer. A maximum Voc of 0.43 V
showed its effectiveness in determining glucose levels in the di- (power density generated: 11 μW cm−2 ) is produced by the cell at
agnostic window of diabetes when generating a voltage of 50 mV. a glucose concentration of about 1 mmol L−1 (or 180 mg dL−1 ),
Thanks to the non-toxic character of PANI and TPU, the pro- while a dynamic linear response to glucose is found in the con-
posed device is verified to be promising as an implantable battery centration window from 500 μmol L−1 to 10 mmol L−1 .
in blood vessels. Another popular high-concentration metabolite, such as lac-
The work by Escalona-Villalpando et al. demonstrates a self- tate was also detected using commercially available blood tests.
powered glucose sensor platform based on a flow-through However, during the last lustrum, lactate was not detected using
PMMA microfluidic system that is aimed to improve the catalytic self-powered biosensors. On the one hand, lactate excess does
properties of the used biocatalysts.[42] The proposed platform not impact health as glucose does, so its monitoring is not a pre-
consists of a sensing unit connected to a wi-fi unit for data trans- rogative for medical diagnostics in terms of the global burden of
mission. The sensing unit exploits an enzymatic biofuel cell con- disorders due to hyperlactatemia.
sisting of a GOx/polyethyleneimine-modified toray carbon paper Cholesterol in platelet-poor plasma prepared from whole blood
(TCP) bioanode and an anthracene-modified MWCNTs laccase- has been detected by a self-powered biosensor consisting of a
based biocathode. Human blood or serum may act as the anolyte fuel cell made of carbon cloth electrodes acting as anode and
and PBS at pH 5.6 is used as the catholyte. Voc calculated from po- cathode (Figure 2d,e).[48] The anode is modified with a sol-gel
larization curves acquired as a function of glucose concentration membrane of phenothiazine (PTZ) containing the cholesterol ox-
is the operational sensing parameter for the proposed device. idase (ChOx) enzyme, while the carbon cloth cathode is coated
The first characterization round made using PBS at pH 7.4 by a Prussian blue (PB) membrane containing ChOx. Two re-
as anolyte, has shown reproducible and promising results in actions are involved in this biofuel cell. An electrocatalytic reac-
the low millimolar range for glucose (linearity of the maximum tion occurs at the anode due to the oxidation of cholesterol me-
current/power from polarization profiles), also in the presence diated by the PTZ matrix. Hydrogen peroxide is formed at the
of typical blood interferers dopamine (DA), uric acid (UA), and cathode due to the reduction of oxygen to H2 O2 as a result of
ascorbic acid (AA).[42] The analysis using real blood as anolyte the oxidation of cholesterol to cholestenone, catalyzed by ChOx.
has shown the ability to measure glucose levels in blood down to H2 O2 , the concentration of which is proportional to the choles-
about 3 mmol L−1 . Comparison with results obtained by a com- terol concentration, is then monitored at the PB-coated cath-
mercial glucometer (ACCU-CHEK) shows that the proposed plat- ode (sensing electrode). Using this cell architecture, a choles-
form underestimates glucose concentrations with a relative error terol quantification both in PBS buffer solution and in plasma
not exceeding 10%−15% of concentration values obtained by the of healthy volunteers was assessed both from variations of the
commercial testing tool. Voc and faster variations of the short circuit current, which were

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Figure 2. a) Schematic structure of the needle-type enzymatic biofuel cell and schemes of glucose oxidation at the anode along with O2 reduction at the
enzymatic gas-diffusion cathode. b, c) Images of the needle-type enzymatic biofuel cell and the needle-type enzymatic biofuel cell inserted into a living
fish (Tilapia) around the caudal area to access biofuels and a gas-diffusion biocathode sealed in an airtight bag filled with air, respectively.[47] d) Scheme
of the single-enzyme-based self-powered membrane-free cholesterol biosensor. e) Comparative free cholesterol quantification in plasma. (°) Cathodic
system on SPE; (●) anodic system on SPE; (⧫) self-powered biosensor on CCEs. Reproduced with permission,[48] Copyright 2014, American Chemical
Society. f) The rotational paper-based device and use for DMM detection. The integration of valves through “ON/OFF” states can help realize the
function of rinsing, incubation, and reaction for the self-powered EBFC sensor. g) The self-powered paper-based microfluidic chips detect the response
curve of the ammeter with different concentrations of thrombin (3, 10, 20, 30, 75, 150, 335, 675, 1350 nM). The inserted illustration is the quantitative
curve of the DMM signals. h) Selectivity of thrombin was investigated on μPADs, and matrix metalloproteinase 2 (MMP2), trypsin, Immunoglobulin
G (IgG), and Human Serum Albumin (HAS) were selected as the interference agents, and these interference agents are all 1000 nM, respectively. The
concentration of thrombin solution was selected as 10 nM. Reproduced with permission,[49] Copyright 2021, Elsevier.

influenced by the cholesterol dose-dependent cathode reaction for iron ions (Fe3+ ), and the other acts as an anode (site of oxida-
upon the addition of cholesterol aliquots in the analyzed matri- tion) for magnesium ions (Mg2+ ). Before introducing the analyte
ces. In the latter case (short circuit analysis), authors demon- (trypsin), a passivation layer of aluminum prevents the two cells
strated an increased dynamic range (linear response of short from discharging. The passivation layer is etched by adding the
circuit current vs cholesterol concentration) in a concentration analyte and sodium hydroxide (NaOH), which exposes the mag-
range from 0.15 mmol L−1 to 4.1 mmol L−1 (a range that is nesium anode to the electrolyte bridge, effectively completing the
compatible with the analysis of undiluted serum samples) a bet- electrical circuit and generating current. This approach offers a
ter sensitivity (26.0 ± 0.5 mA mol L−1 cm−2 ) and a limit of de- simple and specific method for detecting trypsin. Notably, the
tection (LOD) of 1.4 μmol L, calculated following the IUPAC current generated can even power a light-emitting diode (LED).
standard from the linear regression of the calibration curve as Moreover, it correlates with trypsin concentration, with a LOD of
3𝜎 slope /sensitivity. Herein, 𝜎 slope is the standard deviation of the 0.5 μg mL−1 . However, the sensor has limitations. It is intended
slope (or the system sensitivity) of the linear best fit to the cal- for single use only and has a long reaction time (up to 3 h) due
ibration curve. A linear correlation was also found with the re- to the need to incubate the analyte in a gelatin solution.
sponse of the standard kit (BioVision Cholesterol/Cholesteryl Es- Another model molecule for biosensing is the thrombin, a pro-
ter Quantitation Kit II). coagulant enzyme also involved in the homeostasis of blood ves-
Trypsin exhibits activity in an alkaline environment, especially sels. Although blood normal levels are in the nanomolar range
in the presence of calcium (Ca2+ ), magnesium (Mg2+ ), and man- (from 1 to 500 nmol L−1 ),[52] its role in biosensing has been fos-
ganese (Mn2+ ) ions.[51] This feature was used to develop a self- tered by the explosion the aptamers, which are short oligonu-
powered biosensor for real-time detection of trypsin in body flu- cleotides from synthetic DNA, RNA, XRA, or peptides able to
ids. The fabricated device consists of two half-cells connected by bind the related target molecules with an enhanced specificity.
an agarose bridge containing potassium chloride (KCl) as the Aptamers are currently used as outperforming biorecognition el-
electrolyte.[50] One half-cell acts as a cathode (site of reduction) ements in biosensors and, historically, the first anti-thrombin

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aptamer, known as TBA, was developed shortly after introduc- tion in non-invasive diagnostics of several diseases.[13b] From a bi-
ing this new concept for tailoring a high-affinity recognition in ological perspective, sweat is a biofluid produced by sweat glands
biosensors. Recently, Li et al. reported a self-powered paper-based and carried to the epidermis surface via secretory ducts. Sweat
microfluidic chip to detect thrombin.[49] The device consists of glands are found in the dermis layer of the skin all over the body
two parts interfaced with each other and free to rotate around a and, based on location, structure, and function, are divided into
central axis perpendicular to their surfaces (Figure 2f. The upper eccrine, apocrine, and apocrine glands. Each type of sweat gland
part is a reaction disk hosting two circular-shaped hydrophilic secretes different amounts and quality of biomarkers. Therefore,
reaction areas decorated by Au nanoparticles (NPs) coated by a the detection of specific metabolites and drugs depends largely
sandwich-like structure made of i) a thiolated DNA sequence on the sampling site in the body. Apocrine and apocrine sweat
bond to Au NPs using an Au-sulfur interaction; ii) a second glands are limited to areas of the body such as the axilla, while
DNA sequence modified by GOx (GOx-DNA); iii) the thrombin eccrine glands are the most numerous sweat glands, distributed
aptamer HD22 linking the DNA sequences to form the sand- over almost the entire surface of the body and open freely to the
wich. The lower part is a paper-based disk equipped with two surface of the epidermis. The sweat produced by eccrine glands
supercapacitors whose plates, made of Ag/AgCl/polyvynil alco- is readily available and can be collected from children and adults
hol/carbon structures, are deposited by printing routes on both at convenient sites on the body in a non-invasive and on-demand
sides of the paper disk layer. Upon rotating the reaction area, the manner (e.g., through local chemical stimulation). This type of
reaction disk may be positioned in correspondence with the bot- sweat contains water and various electrolytes and can be released
tom plate of the capacitor. In this framework, the analyte detec- directly onto the surface of the skin.[53] The amount of sweat
tion can be implemented as follows. Upon exposure of the re- produced can change based on the individual’s physical condi-
action area with diluted serum samples from the whole blood of tion and can be monitored by electrochemical sensing methods.
healthy volunteers spiked with thrombin aliquots. The thrombin- Sweat monitoring systems can be positioned close to the source
HD22 interaction releases the GOx-DNA, which is transported of sweat production to quickly detect analytes before they are de-
toward the detection area previously dipped with a potassium graded. Quantitative in-situ sweat analysis is important for mon-
ferricyanide-glucose solution in PBS. GOx interaction with glu- itoring physiological health status and diagnosis of diseases.[54]
cose allows its oxidation and consequent reduction of iron ions
in ferricyanide solution (Fe3+ →Fe2+ ) leading to the formation of
ferrocyanide and to a concentration change of ferricyanide that 2.2.1. Biomarkers in Sweat
is proportional to the thrombin content in serum. Electrons gen-
erated from glucose oxidation are collected and measured in an Sweat is produced by sweat glands to regulate body temperature
amperometric scheme for analyte quantification and, at the same and to moisturize and protect the skin. It is 99% water and con-
time, they allow the supercapacitor charging. The fabricated de- tains a wide range of critical biomarkers that can indirectly or
vice allowed to collection of a lin-log calibration curve in a throm- directly reflect human health and thereby help track disease pro-
bin concentration range between 3 nmol L−1 and 1,35 μmol L−1 gression. Table 3 reports the main biologically significant mark-
(Figure 2g−h), with the LOD of 0.9 nmol L−1 estimated by the ers and their concentrations in human sweat. Chemicals present
signal-to-noise ratio criterion (S/N>3). in sweat (Figure 3) can be classified into three types: electrolytes,
Even if power generation is affected by several factors, us- (Na+ , K+ , Cl− , NH4 + , Zn2+ , and Cu2+ ), metabolites (glucose, cor-
ing metabolite-rich biometric data in blood makes ECBSs very tisol, lactate, urea, and ethanol), and macromolecules (cytokines,
promising for fabricating self-powered blood monitoring sys- peptides, and proteins).[54] Na+ and Cl− ions are the predomi-
tems. However, most studies were performed on developing self- nant electrolytes found in human sweat and play a key role in
powered ECBSs for glucose detection (Table 2). Several biomark- determining the amount of water present in sweat, which is es-
ers present in blood (Table 1) have not yet been used to evaluate sential for calculating sweat rate. Simultaneously, the concentra-
self-powered biosensing systems. Unfortunately, detailed infor- tion of Na+ in sweat influences the body’s electrolyte levels and
mation on the stability of these devices is not available, which plays a crucial role in maintaining osmolality, hydration, and pH
could be the subject of future investigations. Preparing new elec- levels.[55] The range of Na+ concentrations under normal physio-
trode structures and their functionalization with appropriate ad- logical conditions is 10–100 mM, but large losses of Na+ in a pa-
ditive materials could provide effective solutions for producing tient’s sweat may indicate hyponatremia, electrolyte imbalance,
electrochemical systems and their application in detecting other or dehydration. These conditions can harm human health and
biomarkers in the blood. Thus, future research efforts are needed reduce physical and mental performance.[56] Sweat chloride anal-
to explore new electrode materials and develop effective func- ysis is considered the most reliable method for identifying cystic
tional strategies for a more accurate evaluation of the feasibility fibrosis, a genetic disease characterized by the production of thick
of self-powered ECBSs in blood monitoring. and sticky mucus due to increased concentrations of chloride in
the extracellular fluid that affects the lungs, pancreas, and other
organs.[57] Sweat-based biomedical technologies are considered
2.2. Monitoring of Sweat effective non-invasive approaches for analyzing fibrosis progres-
sion.
Acids, peptides, proteins, metabolites, and hormones enter the Schematic representation of the anatomical structure of hu-
sweat from the blood and interstitial fluid. Sweat is therefore man sweat glands (eccrine, apocrine, and apocrine) and the se-
composed of biomarkers and has been considered a suitable elec- baceous gland within a cross-section of the skin. Sweat, released
trolyte for developing electrochemical sensors and their applica- from sweat glands, is transferred to the epidermal surface via

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Table 3. Main biologically significant markers and their concentrations in cramps but can also be life-threatening in patients with cardio-
human sweat. vascular disease.[56b,59] The calcium concentration in sweat can
vary greatly, with levels typically ranging from 0.3 to 10 mg dL−1
Biomarker Concentration Disease Refs. and averaging around 5 mg/dL. Increased variability is proba-
Na+ 10–100 mM hyponatremia, electrolyte [56a] bly caused by the location of the sample, surface contamination,
imbalance, dehydration and varying levels of perspiration.[60] Monitoring sweat Ca2+ lev-
Cl− 10–100 mM Dehydration, cystic fibrosis [58a] els is important to control the risk of hypocalcemia and predict
K+ 1–18.5 mM Dehydration, muscle cramps [56b,59] diseases like acid-base imbalance, cirrhosis, myeloma,[61] renal
Ca2+ 0.3 –10 mg dL−1 Acid-base balance disorder, [61–63] failure,[61–62] and normocalciuric hyperparathyroidism.[63] Cop-
myeloma, cirrhosis, per (Cu) is a crucial redox metal for the majority of living or-
normocalciuric ganisms. Indeed, redox catalysis, oxygen transport, and electron
hyperparathyroidism, renal transfer are just a few of the basic biochemical activities that na-
failure ture has adapted to rely on the redox cycle between Cu+ and Cu2+ .
NH4 + 0.5 e 25 mM Muscle fatigue [77] On the other hand, this redox capability can also be risky as the
Cu ≈0.5–1.5 mM Menkes’ and Wilson’s disease [64] Cu redox cycle efficiently triggers the production of reactive oxy-
Glucose 0.06–0.2 mM Diabetes, hypoglycemic shock [59,78] gen species (ROS), leading to oxidative damage to biomolecules.
Lactate 10–25 mM Heart failure, liver failure, renal [67,69] Specific measurement of the metabolic Cu pool in sweat is of in-
failure, cystic fibrosis creasing interest for the study of copper metabolism and also as
(AA 10–50 mM Tumors, cancer, kidney disease, [75] a potential diagnostic tool. The concentration of Cu in sweat is
thrombosis stones ∼0.5–1.5. Changes in Cu concentrations can cause Menkes’ dis-
Ethanol 0–100 mM Inebriation [73a,79] ease (MD) and Wilson’s disease (WD).[64]
Cortisol 8,16–141,7 ng mL−1 Hypoglycemia, elevated blood [70]
Glucose is among the main metabolites in human sweat. The
pressure, hyponatremia, level of glucose in human sweat ranges from 0.06 to 0.2 mM. Fur-
electrolyte disturbance, obesity, thermore, sweat is the most accessible form of glucose because it
fatigue, post-traumatic stress offers a wide range of sampling locations outside the body, easy
disorder placement of devices, and contains electrolytes and metabolites
IL-6 10.0 ± 2.2 pg mL−1 Depression [76] relevant to the body’s functions. Because sweat offers the great-
est number of sample sites outside the body, continual access,
simplicity of device implantation, and the presence of physiolog-
secretory ducts. The magnification of an individual drop of sweat ically relevant electrolytes and metabolites, it is the most readily
illustrates the list of major sweat biomarkers, divided into elec- available source of glucose.[65] Therefore, sweat glucose testing
trolytes, metabolites, and macromolecules. may be an alternative to blood glucose analysis. Unlike blood glu-
For both newborns and adults, a sweat Cl− level of ≥ 60 mM cose measurement, sweat monitoring is a non-invasive approach.
confirms the presence of cystic fibrosis, while a sweat Cl− below Sweating happens rapidly and sweat glands have a good blood
30 mM suggests that cystic fibrosis is improbable.[58] Potassium supply, allowing for the evaluation of glucose levels using sweat
is crucial for the functionality of nerve and muscle cells, as well as samples.[65b] Thus, self-powered sweat-based glucose sensors can
for carbohydrate metabolism and cellular biochemical reactions. be an effective solution for indirectly determining blood glucose
Sweat contains 1–18,5 mM K+ . Excess potassium loss through levels. Nevertheless, there are notable obstacles in acquiring pre-
sweat can indicate dehydration, which not only causes muscle cise sweat glucose data because of fluctuations in environmental

Figure 3. Schematic representation of sweat components. Created with BioRender.com.

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factors like temperature, skin impurities, irregular sampling tent indicates certain human diseases.[74] For example, tumors,
without iontophoretic stimulation, limited capacity, and combin- cancer, kidney diseases, and thrombosis.[75]
ing previous samples with fresh ones. Furthermore, monitoring IL-6 was found in eccrine sweat. The concentration of IL-6 in
sweat glucose levels is very challenging because of its low con- sweat is 10.0 ± 2.2 pg ml−1 . In addition, monitoring IL-6 levels in
centration, making highly sensitive devices necessary.[66] sweat can help manage the risk of depression. Individuals diag-
Acetate is the most important metabolite of anaerobic respi- nosed with depression had a mean of 133.8 pg mL−1 IL-6 found
ration. It is produced during anaerobic activities such as high- in their sweat, a level that was notably elevated compared to indi-
intensity exercises. Determination of lactate in sweat plays an viduals without the disorder.[76]
important role in treating some critically ill patients, as it pro-
vides information for detecting diseases such as renal, heart, and
liver failure. Moreover, studies have been conducted using sweat 2.2.2. Detection of Biomarkers in Sweats
lactate as a marker for cystic fibrosis (as it also results in a reduc-
tion of available oxygen).[67] Regarding physical activities, lactate Research studies indicate a correlation between the levels of
levels can be estimated to determine the human health status af- sweat and blood glucose, which can be a critical factor in manag-
ter exercise.[68] The lactate concentration range for a healthy per- ing diabetes.[78,80] Furthermore, in enzyme-based ECBSs, bioen-
son is 10−25 mM, which can differ based on gender and age. Its ergy is converted into electrical energy, which enables the de-
high levels, leading to increased sweating, can be a sign of tissue velopment of self-powered detection systems. Here, glucose can
damage.[69] be used as a fuel and sweat serves as an electrolyte for self-
Sweat includes not only ions and molecules but also hormone- powered biofuel cells. Table 4 reports the parameters of ECBSs
like molecules and low molecular-weight proteins like cortisol, for detecting biomarkers present in sweat. Recent studies in-
cytokines, and neuropeptides. Non-invasive detection of cortisol dicate that fabricating composite electrode structures based on
in sweat has received much attention in recent years. Biochemi- functional nanomaterials is an efficient strategy to enhance their
cal analysis of this component has become an important basis for performance. Enzyme loading can be improved by using specific
quantifying stress and stress-related diseases. Cortisol is a glu- nanostructures with a large surface area as a support. In addi-
cocorticoid secreted by the adrenal cortex, which is essential for tion, the application of nanomaterials can improve the stability
maintaining the balance and stability of physiological functions and functionality of enzymes in biofuel cells. For example, DNA-
in patients under severe psychological stress. In reaction to envi- templated silver (Ag) nanoclusters with their excellent electronic
ronmental stress or fear, the adrenal glands release it as the end properties, facilitate efficient charge transfer between the GOx
product of the hypothalamic-pituitary-adrenal (HPA) axis activa- enzyme and the electrode during redox reactions.[7] Ag nanos-
tion cascade. Human sweat cortisol concentrations range from tructures readily donate and accept electrons during redox reac-
8.16 to 141.7 ng mL−1 , and abnormal cortisol levels in patients tions, and these processes are reversible. Cyclic voltammetry (CV)
typically result in hypoglycemia, increased blood pressure, hy- tests were carried out. The anodic peak values were used to cal-
ponatremia, electrolyte disturbances, obesity, fatigue, and post- culate the current density, which was increased with glucose con-
traumatic stress disorder.[70] centration. The LOD of the sensor was 29 μM. This value is signif-
Other biomarkers, such as ethanol, drugs (e.g., nicotine or lev- icantly lower than the glucose concentration in the body’s bioflu-
odopa), and vitamin C, are also used for therapeutic, nutritional, ids. Here, the current dentistry increases with the concentration
and abuse purposes. The metabolism of ethanol has been stud- of glucose showing a nonlinear dependence. The obtained results
ied extensively in humans because it is the key molecule that suggest that the enzymatic reactions control the electrochemical
causes intoxication when drinking alcohol in excess. Blood and processes. Enzymes catalyze the oxidation of glucose enhancing
urine are the most prevalent biological samples for analyzing al- the kinetics of biomarker capture. Thus, the functionalization of
cohol consumption. Although this method provides very accu- the working electrodes with glucose enzymes speeds up the sens-
rate measurements of blood alcohol concentration (BAC), it re- ing reactions and enables selective detection of glucose in sweat.
quires invasive data collection methods and cannot be performed Furthermore, the nanomaterials were prepared on electrode sub-
on-site.[71] Breath alcohol concentration measurement was sub- strates by screen printing technique, which is another advantage
sequently developed because it showed a good correlation with for developing modern self-powered sensing technologies.[7]
blood alcohol levels. The advantage of sweat testing as an alter- Advances in research into portable electronic devices are
native to blood and breath tests is that it contains compounds that opening up new solutions for self-powered detection systems.
can function as biomarkers without requiring traditional invasive The coupling of flexible photovoltaic cells with environmentally
testing techniques.[71–72] Experimental findings indicate a corre- friendly and lightweight zinc manganese oxide (Zn-MnO2 ) bat-
lation between the levels of ethanol in blood and sweat, which teries was used to power an enzyme-based ECBS for real-time
could enable the continuous monitoring of blood-alcohol levels sweat glucose detection. However, in the first stage of glucose
through sweat analysis.[73] The concentration of ethanol detected tests, the amount of sweat collected was insufficient and the out-
in sweat may depend on the amount of alcohol consumed. put signal was not stable. The required amount of sweat for accu-
Measuring vitamin C (or AA) in sweat can provide valuable rate determination of glucose was achieved after 10 min of phys-
information about an individual’s antioxidant status. Currently, ical activity.[13b] However, the concentration of ions (e.g., Na+ and
AA is measured using expensive blood tests requiring trained Ka+ ) also increases due to physiological activities. Therefore, the
personnel. Instead, sweat sampling is a cost-effective and non- reaction current can be influenced by inorganic ions. To over-
intrusive method for detecting AA. The relative concentration of come this issue Lu et al. proposed using compensation electrodes
AA in sweat varies from 10 to 50 μmol L−1 , and its abnormal con- by isolating them with membranes.[81] In addition, their findings

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Table 4. Parameters of ECBSs for the detection of biomarkers in sweat.

Anode material /Working Cathode Material Biomarker/Biofluid Concentration/detection range LOD Output Detection method Refs.
electrode /reference

NA a) DNA-templated Glucose <200 μM 29 μM NA Electrochemical reaction [7]

AgNCs/GOx
b) Au/Prussian blue/GOx Au/AgAgCl Glucose 50−200 μM NA Current Electrochemical reaction [13b]
3.18 nAmM−1 of glucose
b) Au/Chitosan/NiCo
2 O4 AgAgCl Glucose 5−25 mM 10 μM Current Oxidative reaction of [81]
nanowires 0.5 mAmM−1 glucose with Ni and
Co nanowires
NA NA Glucose/ artificial 10 nM to 50 μM 1 nM NA Chronoamperometry [65b]
sweat
LDH/RGO-CNT/TMC a) RGO-CNT/TMC Lactate/artificial 0−10 mM 9.49 μM Current Impedance spectroscopy [68]
sweat 18.46 mAmM−2
b) Graphene-modified NA Ascorbic acid (AA) NA 66 μM <current Square wave voltammetry [75]
polyimide film 0.015 (SWV) and
mAmM−2 Chronoamperometry
(CA)
Mg a) Ag/AgCl Artificial sweat NA NA NA Electrochemical reaction [9]
functionalized aptamers ( a) Zinc Cortisol From 10 fg mL−1 to 0.17 fg mL−1 NA Electrochemical sensing [70c]
with V2 CTx MXene, Co, 100 ng mL−1
and Ni
a) b)
(Working electrode); (Reference electrode).

indicate that enzyme-free electrodes can be integrated with su- de/(3-glycidyloxypropyl) trimethoxysilane (PDG) yarn. This
percapacitors for self-powered monitoring of glucose (Figure 4a). structure is both lightweight and stable for bending. The detec-
This is a promising achievement to extend the lifetime of the tion signal was achieved by maintaining a temperature variance
sensing device. of 2.2 K between the human body and the surroundings. In this
Metal cobaltites with their attractive electrical and electro- case, the working electrode was also functionalized with the GOx
chemical properties were used for fabricating electrodes and their enzyme for selective glucose detection, and the sensor showed a
integration into ECBSs. The electrical conductivity and electro- linear dependence on glucose concentration.
chemical activity of nickel cobaltite (NiCo2 O4 ) nanomaterials are A composite material of reduced graphene oxide (RGO) and
significantly higher than pure cobalt and nickel oxides (Co3 O4 carboxylated MWCNTs was fabricated on cellulose fibers.[68] To
and NiO).[82] The experimental results show that electrodes based produce the anode and cathode, the electrodes were function-
on NiCo2 O4 nanowires can be successfully used in the architec- alized with lactate dehydrogenase and laccase, respectively. The
ture of miniaturized micro-supercapacitors and electrochemical performance of the system was studied by impedance spec-
sensors for sweat monitoring. The material retained 96% of its troscopy (EIS). The RGO and MWCNT, which have high conduc-
initial capacitance value after 20 000 cycles (Figure 4b). The pres- tivity, reduced the resistance of the electrodes and enhanced the
ence of Ni and Co in the electrode material of the ECBS signifi- charge transport. However, the enzyme coating for selective de-
cantly affects the oxidation of glucose and the response current tection of lactate partially increased the transfer resistance of the
of the sensing system was varied as a function of glucose concen- electrons. In addition, the electrochemical response of the system
tration (Figure 4c). The detection limit of the sensor was 10 μM. was measured at different lactate concentrations (0−100 mM).
These results show that NiCo2 O4 nanowires are promising struc- The redox reactions improved with the lactate concentration,
tures for the fabrication of self-powered ECBS and the detection which was saturated above 80 nM. The current density of the
and quantification of glucose in sweat. Wherein, enzyme-free sensor retained 95% of the initial value after 300 bends and 83%
electrodes can facilitate the fabrication of ECBSs and extend their after 30 days of operation. The effect of lactate concentration on
lifetime.[81] the power output of the BECS was also investigated. The system
Thermoelectric generators (TEGs), in which the temper- achieved a maximum power of 18.46 μW cm−2 at a lactate concen-
ature difference between the environment and the human tration of 10 mM. Thus, each component in the electrode design
body is converted into electrical energy, were also used plays a critical role in the sensing characteristics and power out-
in self-powered ECBSs for glucose detection. However, put of the self-powered ECBS. Graphene prepared on polyimide
the temperature difference should be sufficient to gener- substrates was used for the electrochemical detection of AA in
ate the energy required by ECBS.[65b] Here, the electro- artificial sweat, where the LOD of the sensors was 66 μM.[75] In
chemical system is activated by thermoelectric fabrics. The this case, the selectivity of the working electrode needed further
ECBS and TEG were fabricated using cotton and poly(3,4- investigation and the system was operated with solar cells. In an-
ethylenedioxythiophene):poly(styrenesulfonate)/dimethylsulfoxi- other work, solar cells and rechargeable batteries were combined

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Figure 4. a) Schematic illustration of transection for glucose sensor, compensation electrode, [Na+ ] and [K+ ] sensors. Mode 1 is amperometric sen-
sor and the Mode 2 is the capacitance-type sensor. b) Variation of capacitance stability of MSCs with 20000 cycles. c) Linear relationship of responsive
current versus glucose concentration. Reproduced with permission,[81] Copyright 2019, Elsevier. d−k) Real-time on-body sweat sensing and data trans-
mission powered by hybrid nanogenerator modules. (d) Output performance of energy harvesting devices during walking, running, and jumping. (e)
Module diagram of the self-powered wearable sweat analysis system (SWSAS). (f) Operation flow of the SWSAS. (g) A photograph of an individual with
the SWSAS strapped to the arm during running. The SWSAS wirelessly senses Na+ and K+ in sweat via Bluetooth and records the data to a mobile
phone. (h) A photograph of SWSAS strapped to the arm. i) Mobile phone interface of sweat sensing and analysis developed based on the WeChat
applet. (j) Real-time potential of the capacitor charged by an HNGM. (k) The real-time concentration of Na+ and K+ in sweat during running by using
SWSAS. Reproduced with permission,[87] Copyright 2022, John Wiley & Sons. (l) Schematic illustration of the preparation process of the Schottky CoNi-
MLDH@V2 CTx heterojunction. (m) OCP-I curves of the constructed self-powered aptasensor for the detection of cortisol with different concentrations
(10 fg mL−1 , 0.1 pg mL−1 , 1 pg mL−1 , 10 pg mL−1 , 100 pg mL−1 , 1 ng mL−1 , 10 ng mL−1 , 100 ng mL−1 ). (n) Relationship between the caused ΔOCP and
the cortisol concentration. Reproduced with permission,[70c] Copyright 2023, Elsevier.

with ECBS to estimate the pH value of sweat.[83] The aforemen- However, ambient temperature and sweat amount can affect the
tioned sensing systems were considered self-powered. However, cell capacitance.
it is worth noting that in these approaches, power is not gener- Another promising approach is the development of hydroelec-
ated in the ECBS device by electrochemical energy conversion or tric generators in self-powered ECBS where the electrical energy
by converting mechanical energy into electrical energy, as in tri- is generated through the interaction of a liquid with a solid sur-
boelectric nanogenerators. face. In this case, electrostatic interactions lead to the migration
Artificial sweat is also used to evaluate the performance of of counter ions to the surface, creating a gradient in their con-
self-powered sensor devices.[9,84] A battery system in which ar- centration. This streaming potential is used to generate electric-
tificial sweat (an aqueous solution of NaCl and lactic acid) per- ity in hydroelectric generators.[85] For example, silicon nanowires
forms the function of a biofluid was studied. Magnesium (Mg) were functionalized with carbon NPs to increase the charge den-
and Ag/AgCl were used as anode and cathode, respectively.[9] In sity at the electrode surface and improve the generated electri-
this case, the separator was a dry cellulose membrane. In the cal energy.[86] The performance of the electrode was investigated
absence of biofluid, the electrochemical cell is in an open cir- in an aqueous NaCl solution using the open-circuit potential
cuit state, and when the membrane absorbs sweat, the circuit is method. The Voc and the short-circuit current (Isc ) decreased with
closed. The operating voltage provided by this design was ≈1.6 V. increasing NaCl concentration and showed a linear dependence.

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In this case, the sensitivity of a hydroelectric device depends on tivity of sensors. Furthermore, appropriate modification of the
the Debye length and the channel width. The Debye length is de- morphology and the structure of semiconductor nanomaterials
termined by the quantity of ions present in the solution. The de- may improve the charge transport and increase the charge den-
sired current values can be achieved by connecting hydroelectric sity at the electrode surface. The use of enzymes, aptamers, and
devices in parallel or in series. Experimental analyses with vol- selective membranes has a significant effect on the sensitivity
unteers showed that the Voc decreases with increasing exercise and selectivity of sensors. However, the influence of each compo-
duration, which was attributed to the body dehydration and elec- nent in the electrode structure needs to be investigated in detail
trolyte concentration. The authors also suggested that the selec- to optimize the performance of ECBS systems and power gener-
tivity of the sensor in such a system can be tuned by modifying ation. Various approaches, such as electrochemical energy con-
the surface of nanowires with ion-selective membranes for the version, hydroelectric and TEGs, and flexible photovoltaic cells
specific binding of certain ions. can be considered to operate ECBS for sweat monitoring. As with
A triboelectric nanogenerator, in which the energy of body blood monitoring, research into the development of ECBS for
movement is converted into electricity, was also successfully used sweat analysis has primarily chosen glucose as the target ana-
to develop self-powered ECBSs.[87] Here, the power device is a lyte. Some studies have also examined lactate, cortisol, and AA
combination of triboelectrification and electrostatic induction. (Table 4). Therefore, further experimental and theoretical studies
The sensor patch was developed on polymeric substrates. So- are needed to explore new electrode materials for the selective de-
lutions of NaCl and KCl were used as electrolytes. The sensor tection of other biomarkers present in sweat. Another important
response was studied to Na+ and K+ ions. The use of artificial issue is the stability of ECBSs for sweat monitoring, which needs
sweat allows for testing the sensitivity of the sensor at the de- to be investigated in detail.
sired analyte concentration at the laboratory level. Moreover, this
study also suggests that integrating selective membranes into
cellular architecture enhances their selectivity. Tests on volun- 2.3. Monitoring of Saliva
teers (Figure 4d−k) showed that a sufficient concentration of
sweat was collected and accurate determination of the analyte Saliva is a sophisticated liquid made by the parotid, submandibu-
was possible after 9 min of running, which confirms previously lar, and sublingual glands, in addition to 600–1000 smaller sali-
reported findings.[13b] Hence, accurate health monitoring by an- vary glands. It consists mainly of water (>99%) and several mi-
alyzing biomarkers present in sweat requires time on the order nor components with important metabolic functions, such as
of several minutes. electrolytes, immunoglobulins, proteins, enzymes, and mucins.
Advances in printing techniques make it possible to prepare Gingival crevicular fluid, microorganisms, desquamated epithe-
electrode materials and control their shape and thickness at lial cells, and food debris are also present in saliva.[89] Thus, this
relatively low operating temperatures. These technologies open biological fluid performs several important functions in the hu-
up new possibilities for manufacturing electrodes based on pa- man body. Thanks to water, it moisturizes and cleanses surfaces
per materials. For example, ZnCl2 and polyvinyl alcohol (PVA) of the oral cavity, making the texture of saliva sticky. Electrolytes
were deposited on filter paper using an inkjet printing process, are important to neutralize acid and protect teeth. Finally, or-
whereby the porosity of the paper improves the adhesion of the ganic matter promotes antimicrobial activity, tissue repair, diges-
material to its surface.[88] Electrochemical characterization of the tion, and salivary sac formation. Therefore, saliva is important for
electrodes showed that the current generation varied depending non-invasive diagnosis and monitoring of diseases. Moreover, re-
on the humidity conditions in the cell, which is a good perfor- cent years have seen an increase in research into changes caused
mance for functioning as a self-powered system. The bending by environmental exposures, such as air pollution and smok-
partially affected the shape of the prepared electrode materials. ing, as well as the diagnosis and evolution of diseases.[90] Several
However, the ECBS showed a quite stable sensor performance biomarkers can be detected in this matrix, and since sampling
when the bending angle was increased to 180°. is fast, simple, and performed using noninvasive methods, it is
More recently, the effect of immobilizing functional aptamers also used for large-scale epidemiological studies. Collected sam-
on composite electrodes based on V2 CTx MXene, Co, and Ni for ples can be divided into stimulated whole saliva, extracted using
selective cortisol detection was investigated (Figure 4m,n).[70c] paraffin chewing gum, and unstimulated whole saliva, collected
EIS measurements showed that the electrochemical sensing re- by passive salivation or oral swab to sample a specific area.[91] Ac-
sponse increased with increasing cortisol concentration, which is cording to the sampling procedure, the presence of biomarkers
important for analyte quantitation. However, the ECBS response in the samples varies greatly due to changes in salivary flow rate
was saturated when cortisol concentrations exceeded 10 ng mL−1 . and protein secretion.
In addition, immobilization of the aptamer affected charge trans-
fer and reduced the output voltage due to the formation of a corti-
sol complex with the aptamer. These results seem to suggest that 2.3.1. Biomarkers in Saliva
the effect of aptamer concentration on ECBS functionality and
energy production should be carefully studied to find the optimal There are several types of DNA biomarkers such as DNA methy-
electrode composition. lation, cell-free DNA, circulating tumor DNA (ctDNA), and
Overall, various organic and inorganic nanomaterials have telomere length.[92] Biomarkers present in saliva for detecting
been studied to detect biomarkers in sweat. The application of diseases are listed in Table 5. DNA methylation occurs when a
nanostructured semiconductor materials in the architecture of methyl group is added to the cytosine dinucleotide, leading to
electrodes may enhance the electrochemical response and selec- an epigenetic modification.[93] It has been studied in saliva in

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Table 5. Biologically significant markers and their concentrations in saliva. effective solution for early warning of disease risk and prediction
of treatment effects (Figure 5).[104]
Biomarker Concentration Disease Refs. Saliva contains more than 3000 different proteins with a wide
Cotinine 1−25 ng mL−1 Smoking [95] range of molecular weights that support health and can also be
Pepsin 4−500 ng mL−1 reflux-related disorders [107a]
used as biomarkers for screening and diagnosis.[105] Salivary en-
zymes include salivary amylase, lingual lipase, lysozyme, car-
Amylase 2−12 U mL−1 Obesity and oral cancer [119]
bonic anhydrase, phosphatase, maltase, carbonic anhydrase, per-
IgA 0.19 mg mL−1 Respiratory infection [108]
oxidases, and kallikrein. They are commonly used for food di-
IgG 0.014 mg mL−1 human cytomegalovirus [108]
gestion, as an antimicrobial agent, and for energy production.
MMP-8 2.5–300 ng mL−1 inflammatory diseases, oral cancer [120] However, their use as a biomarker has also been well-studied
CRP From 500pg to Pneumonia and tuberculosis [121] in cardiovascular cancer, oral cancer, and Alzheimer’s disease
50 μg mL−1 monitoring.[106] Among them, the most studied enzymes are
Cortisol From 1.0 fg mL−1 to Stress and Parkinson’s disease [114b] pepsin and amylase.[107]
10000 pg mL−1 Immunoglobulins, including immunoglobulin A (IgA) and
Oxytocin 1.75−220 pg mL−1 depression and anxiety [122] immunoglobulin G (IgG), are important to protect oral immu-
Glucose 0.03-−10 mM Diabetes mellitus [118a] nity through their antimicrobial activity. IgA and IgG are the most
common antibodies and prevent bacteria from adhering to the
surface of teeth. They can be detected in both plasma and saliva.
cancer, psychiatry, environmental, and lifestyle diseases through However, the concentrations of IgG and IgA in plasma are ap-
metabolomic analysis.[94] One of the most alarming lifestyle risk proximately 12.5 and 2.2 mg mL−1 , and in saliva – 0.014 and
factors is smoking, as it represents a major public health problem 0.19 mg mL−1 , respectively. Therefore, the monitoring of IgG and
and has serious implications for health systems. For these rea- IgA in saliva is limited.[108] However, salivary IgA levels corre-
sons, a rapid and sensitive approach to identifying early smokers late with the risk of upper respiratory tract infections, and low
could be a powerful resource, especially for monitoring younger levels may increase their frequency and duration. Higher levels
generations. can also be used to prevent SARS-COV-2 infection.[109] IgA is
Assessing DNA methylation status using ddPCR analysis in also a biomarker for assessing alcohol dependence, along with
salivary DNA samples and correlating these results with cotinine, other salivary glycoproteins such as 𝛼-amylase, clusterin, and
an important biomarker of nicotine, may be an efficient tool for haptoglobin.[110]
assessing smoking status in adolescents.[95] The methylation of Alterations in protein glycosylation have been found in many
the cytosine phospho guanine (CpG) dinucleotide pair in gene diseases, including cancer, influenza A virus, COVID-19 spike
cg05575921 of the aryl hydrocarbon receptor repressor is a pre- glycoprotein, and cardiovascular and neurodegenerative dis-
cise marker for smoking.[96] eases. Aberrant glycosylation occurs during tumor genesis and
Moreover, saliva cells of smokers with chronic periodontitis evolution, hence tumor-specific glycosylation is commonly used
display a methylated SOCS1 gene promoter, whereas saliva cells as a biomarker.[111]
of nonsmokers do not show this methylation pattern.[97] More- Fifteen different lectins with strong effects on salivary gly-
over, abuse of opioids and cannabinoids can also be detected not copatterns have been proposed as biomarkers for early diag-
only by people monitoring their use but also by directly quanti- nosis of breast cancer by replacing biopsies.[112] C-reactive pro-
fying the impact of medical cannabis treatments. In total, 65 po- tein (CRP) is an inflammatory biomarker for detecting some
tential pharmacodynamic biomarkers sensitive to cannabis were infectious diseases such as pneumonia and tuberculosis, as
identified using mass spectrometry analysis in patients suffering well as non-infectious diseases such as tumors or immune
from autism spectrum disorder. The most significant biomark- diseases.[113]
ers used are N-acetylaspartic acid, spermine, and dehydroisoan- In terms of hormone detection, cortisol concentration is an
drosterone 3-sulfate.[98] DNA methylation analyzed in saliva sam- important indicator.[114] Implementing point-of-care diagnos-
ples is also a valuable resource for screening tests and diagno- tics using non-invasive ECBSs.[114b] to replace traditional proce-
sis of several other diseases, from celiac disease.[99] to monitor- dures such as enzyme-linked immunosorbent assay.[115] or liq-
ing borderline personality disorder.[100] and obesity.[101] Telomere uid chromatography-tandem mass spectroscopy.[116] can be an
length analysis shows important applications in forensic science efficient solution as these immunosensors exhibit excellent dy-
for assessing sex and age in cigarette samples.[102] Nevertheless, namic range and detection limit.[117] Detection of salivary glucose
sampling saliva rather than blood results in lower precision and can also be a reliable source of diagnosis for diabetes. A signifi-
longer telomere lengths.[103] cant correlation exists between blood glucose levels determined
Currently, the main concern regarding this class of biomark- through enzymes and saliva in diabetic patients.[118] However,
ers is the presence of both human and microbial DNA in the salivary glucose concentration may vary depending on the sam-
oral cavity. Therefore, the presence of infection must be carefully pling process and storage conditions. For example, glucose levels
assessed before testing. The presence and concentration of mi- in saliva continued to decrease with increasing stimulation levels
croorganisms show strong correlations with some chronic dis- and fluctuated throughout the day due to the circadian rhythm in-
eases, and their variations may reflect an individual’s health and fluence on the human body. Therefore, taking samples for anal-
disease status. The ability to perform analysis in real-time is an ysis early in the morning is recommended.[118a]

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Figure 5. Conceptual representation of the ECBS system for biomarker detection in saliva. Biomarkers present in saliva samples are used to identify
various pathologies or conditions of an individual. Once sampled, the saliva sample is analyzed using electrochemical measurements to detect the
presence and concentration of target biomarkers. Once processed, this data can be used to identify pathologies, select personalized therapy, monitor
human health status, and provide support to medical professionals. Created with BioRender.com.

2.3.2. Detection of Biomarkers in Saliva density was increased by combining two electrochemical cells in
series (Figure 6a–d) using screen-printed electrodes (SPEs).[43]
The development of self-powered ECBSs for detecting biomark- The bioanodes were initially coated with poly-methylene blue fol-
ers in saliva is a new and emerging field of research that has lowed by immobilization of flavin-dependent glucose dehydroge-
seen a significant increase in scientific results in recent years. nases (FADGDH) from Aspergillus niger on the surface of the
The parameters of ECBSs for saliva monitoring are reported electrodes. Unlike GOx, FADGDH can oxidize glucose to glu-
in Table 6. For example, Bolella et al. developed an innova- conic acid without producing O2 and H2 O2 , thereby providing
tive approach where commercial carbon-based screen-printed an efficient function of the enzymatic fuel cell. The biocathodes
electrodes were functionalized with Au NPs to increase their were functionalized with bilirubin oxidase, which works effec-
active surface area.[13c] In addition, chorinascus thermophilus tively in the normal pH range of saliva (6.2−7.6). The proposed
(CrCDH) and trameters hirsuta laccase (ThLac) were used for double-cell system was tested with saliva samples ranging from
the functionalization of the anode and cathode, respectively. 30 to 100 μM, achieving a power output of 1.4 μW cm−2 . This
Here, glucose detection was performed in a biofuel cell work- value is slightly higher than the power output value obtained
ing by direct electron transfer. In this case, the electron trans- using the single-cell system with SPE, which can be attributed
fer from the enzyme to the electrode does not involve redox to the low glucose concentration in saliva and the presence of
species, which is beneficial.[123] Experiments were carried out in interferometers.[43] Using FADHDG instead of the basic GOx im-
a phosphate-buffered glucose solution with a glucose concentra- proved the stability of the device over time (half-life >24 h) due
tion of 100 μM, which is the maximum physiological glucose to less susceptibility to the harmful effects of molecular oxygen.
concentration in human saliva. The output power density was The energy level mismatch between enzymes and electrodes
1.57 μW cm−2 at a Voc of 0.58 V. When the electrodes were tested affects the output power density of the ECBS.[128] Polymeric ma-
using real saliva, where the glucose concentration was lower com- terials, in particular n-type polymers, can be used to overcome
pared to the synthetic solution (between 30 and 100 μM), the this issue. Unlike p-type polymer materials, n-types possess elec-
power density decreased to about 1.10 μW cm−2 at a Voc of 0.41 V. tron transfer properties owing to the presence of ethylene gly-
Thus, the ECBS system exhibited lower power output density col in polymeric backbones, which increases the electron cou-
when operating with real fluid. In terms of stability, the proposed pling between them and enzymes. This is a significant factor
solution guarantees optimal performance in the first hours of op- that facilitates the reaction of electrodes with an analyte, such
eration with a sharp drop (up to 50%) at 8 h. The output power as glucose, without the contribution of molecular oxygen, which

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promotes the reduction of dioxygen. Naftalene dicarboximide chemical systems to detect other salivary biomarkers and expand
and bithiophene copolymer (NDI-T2) were employed to fabricate the application of ECBSs.
a miniature self-powered glucose ECBS based on an enzymatic
fuel cell power unit that drives an OECT as the sensing com-
ponent. The OECT uses NDI-T2 polymer deposited on the Au 3. Summary and Outlook
gate electrode and channel of the transistor. The GOx enzyme
was immobilized on the polymer gate film. This setup exhib- The sharply growing interest in developing self-powered ECBSs
ited a sensing response over a wide range of glucose concentra- for health monitoring is evident from research conducted over
tions (10 nM−20 mM) in the electrolyte solution with a LOD of the past few years. Blood analysis in the search for bioanalytes
10 nM, which is in line with other gate-functionalized electro- presents a challenge due to its complexity, although such body
chemical transistors.[129] Here, the power unit contains an en- fluid is overloaded with numerous biomarkers for diagnostic pur-
zymatic fuel cell, the anode electrode of which is made based poses. Nevertheless, the abundance of metabolites that react to
on NDI-T2, and the cathode is a p-type copolymer of ethylene- enzymes at very high concentrations makes blood the benchmark
dioxythiophene (EDOT) and hydroxymethyl ethylenedioxythio- for self-powered biofuel cells that use enzymes to generate sig-
phene (EDOTH) capable of reducing molecular oxygen. Glucose nificant power output. Even if power generation is affected by
in saliva was oxidized by GOx, producing electrons at the anode, several factors influencing the durability and stability of the sup-
which then flow to the cathode reducing oxygen and generating plied power, such as diffusion effects at the anode rather than the
power from glucose and oxygen. The generated power density non-ideal reversibility of most available enzymatic reactions, the
was 1.5 μW cm−2 at a glucose level of 100 μM, which is similar to exploitation of biometrics over-rich in metabolites is promising
the values achieved by other approaches reported in Table 6 and for developing biosensors that can simultaneously detect an ana-
equal to the value obtained by the sensing system with double lyte and use it to generate a power source that could allow devices
SPEs.[123] Meanwhile, the generated power was enough to supply to operate autonomously in implantable devices.
small electronic components such as light-emitted diodes (LEDs) Clinical trials show that sweat contains a wide range of
or OECT. In addition, this approach enables stable functional- biomarkers that reflect human health. Their identification and
ities over time. Using a protective polymeric layer (Nafion) on quantification provide important information about diseases and
p-type polymers and membranes to divide the two electrodes en- health conditions, including depression. It has been shown that
hanced the stability of the device for up to 30 days (half-life).[124] there is a correlation between blood and sweat biomarkers.
Enzyme-based electrodes can be used in fabricating ECBS on Therefore, high-performance BECSs for sweat monitoring can
a printed circuit board (PCB) to detect glucose in saliva. For become versatile tools for non-invasive health analysis. Unlike
example, highly porous Au electrodes with large surface areas blood sensors, electrochemical sensor systems for sweat and
were used as both bioanode and biocathode.[125] The bioanode saliva monitoring are non-invasive. The concentration of some
was modified with an osmium redox polymer, which acted as biomarkers in sweat is very low, and therefore particular atten-
a charge transfer mediator, onto which the GOx enzyme was tion should be paid to the fabrication of highly sensitive elec-
immobilized. trode materials. In this regard, the preparation of complex com-
The biocathode was functionalized with bilirubin oxidase, fol- posite nanostructures with large surface areas where the synergy
lowed by the addition of a blocking agent (StartingBlock) to pre- effect is considered is a very promising way to improve the elec-
vent glucose oxidation (Figure 6a). Then, the self-powered de- trical properties and sensitivity of ECBSs. Functionalization of
vice was tested using a buffer solution containing 1 mM glucose electrodes with enzymes and aptamers has a crucial effect on
and artificial saliva. In the first case, an output power density of the selective detection of specific analytes. Furthermore, nanoma-
9.6 μW cm−2 was achieved, and it was varied as a function of glu- terials with different morphologies improve the immobilization
cose concentration in the buffer. It exhibited a good sensitivity of enzymes However, enzymes and aptamers can also influence
(14.13 μA cm−2 mM−1 ) within the physiological range of 50 μM to charge transfer. Thus, the effect of their concentration on sensor
1 mM. As a proof-of-concept, the device was further tested using functionality and energy production in an electrochemical sys-
saliva and showed better sensitivity due to the higher conductiv- tem should be carefully investigated.
ity of saliva (21.5 μA cm−2 mM−1 up to 2 mM). Nevertheless, the The use of ion-selective membranes is another effective strat-
device exhibited stable functionalities for 7 days. egy for binding specific ions. The application of compensation
Although clinical studies have identified a wide range of sali- electrodes by isolating them with membranes has proven an effi-
vary biomarkers (Table 5), research on self-powered ECBSs has cient method for developing enzyme-free ECBSs, which may also
been performed mainly to detect glucose in saliva (Table 6). extend the lifetime of the device. Obtaining the required amount
Meanwhile, the number of studies on self-powered ECBSs for of sweat for accurate determination of analytes is achieved af-
saliva analysis is limited. Research findings indicate that en- ter a few minutes of physical activity. Developing and integrating
zymes are primarily used to provide selective detection of an- small-size heating elements in ECBS systems that can warm lo-
alytes in saliva. Additionally, the output power density of self- calized areas of the body and stimulate sweating can be very use-
powered ECBSs using artificial saliva may be reduced when ful to overcome the above-mentioned issue. Biofuel cells, hydro-
tested in real liquid. Unfortunately, there is no information about electric generators, and TEGs have been used to operate ECBSs.
the LOD of these devices. However, the stability of these sensing The experimental findings indicate that the amount of sweat and
systems has been tested and the results confirm their promise the ambient temperature affect the power output. Integration of
for future applications. Thus, further research is needed to pre- miniature solar cells and rechargeable batteries into monitoring
pare appropriate electrode materials and develop efficient electro- systems has been proposed to ensure their stable functionality.

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 Adv. Mater. Technol. 2024, 9, 2400395
Table 6. Parameters of ECBSs for the detection of biomarkers in saliva.
www.advancedsciencenews.com

Anode material Cathode material Biomarker/Biofluid Concentration/detection range Output Detection method Stability Refs.
[mM]

Graphene/AuNPs Graphite/AuNPS/ Trameters Glucose/ 0.03−0.1 Power Dependence between Half-life [13c]
/cellobiose dehydrogenase from Hirsuta laccase (ThLac) Saliva 1.10 μW cm−2 analyte concentration >8 h
Chorinascus Thermophilus (CrCDH) and power density
poly-methylene blue/ FAD-Glucose Bilirubin oxidase Glucose/ 0.03−0.1 Power Dependence between Half-life [43]
dehydrogenase (FADGDH) from Saliva 1.4 μW cm−2 analyte concentration >24 h

2400395 (17 of 23)

Aspergillus niger and power density
Au/NDI-T2/GOx copolymer of Glucose /Saliva 0.01−10 Power Electrical measurement 30 d [124]
ethylenedioxythiophene 1.5 μW cm−2 using OECT
(EDOT) and
hydroxymethyl
ethylenedioxythiophene
(EDOTH).
hPG/[Os(2,2′- hPG/bilirubin oxidase/ Glucose/ 0.05−2 Current Dependence between 7d [125]
bipyridine)2 (polyvinylimidazole)10 Cl]Cl StartingBlock Artificial Saliva 21.5 uA cm−2 mM−1 analyte concentration
(OsPVI)/GOx and power density
Graphite electrode modified with pyranose Gold electrode/ Glucose/ NA Power Linear sweep voltammetry 12 h [126]
dehydrogenase immobilized with Myrothecium Saliva 6 μW cm−2
[Os(4,4′-dimethyl-2,2′- verrucaria (BOx)
bipyridine)2 (poly(vinylimidazole))10 Cl]+ adsorbed on gold
and carbon nanotube nanoparticles (AuNPs)
Gold electrode/AuNPS/CDH Gold electrode/AuNPS/Box Glucose/ 5 mM Power Dependence between NA [127]
Saliva 2.5 μW cm-2 analyte concentration
and power density
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Figure 6. Schematic representation of the different EFCs assembling procedures: a) 2 normal SPEs in one electrochemical cell, one bioan-
ode (SPE-MWCNTs/pMB25/FADGDH/PVA-SbQ) and one biocathode (SPE-MWCNTs/2-ANT/BOx); b) 2 double-sided SPEs connected in se-
ries, each one comprising both bioanode and biocathode. c) Polarization curves recorded for double-sided EFCs connected in series (SPE-
MWCNTs/pMB25/FADGDH/PVA-SbQ | SPE-MWCNTs/2-ANT/BOx || SPE-MWCNTs/pMB25/FADGDH/PVA-SbQ | SPE-MWCNTs/2-ANT/BOx) in (solid
black and red curves) human saliva and (dashed black and red curves) artificial human serum. The plots were obtained from linear sweep voltamme-
try at 1 mV s−1 from the OCV to 0 V. d) Double-sided EFCs connected in series operating in human saliva to power an LED light. Reproduced with
permission.[43] Copyright 2020, Elsevier. e) A schematic illustrating the operating principle of an enzymatic fuel cell fabricated on a printed circuit board.
The anodic is a highly porous Au film coated with the redox polymer osmium coupled to the GOx enzyme, and the cathode is a highly porous Au film
coated with bilirubin oxidase. Glucose present in saliva reacts with GOx, generating electrons that flow from the anode to the cathode, where molecular
oxygen is reduced in water.[125]

Saliva is a crucial biofluid for the early detection and preven- number of interferometers. The energy level mismatch between
tion of diseases. Its value as a diagnostic tool is still under ex- enzymes and electrodes is another factor that affects the output
ploration and depends on its composition. This biofluid contains power density of the sensing system. Research findings suggest
a rich set of biomarkers, metabolites, and proteins, the concen- that preparing n-type polymers can improve the reaction of elec-
trations of which serve as indicators of various diseases such trodes with an analyte due to their superior charge transfer prop-
as diabetes and ischemia, among others. Therefore, saliva has erties.
been chosen as one of the benchmark biofluids used in biosens- Various approaches have been developed to enhance the ef-
ing. Self-powered ECBSs developed for salivary biomarker detec- ficiency of enzymatic fuel cells in terms of output power and
tion are based on immobilized enzymes. However, the proposed long-term stability. Addressing these issues requires intensive re-
methods did not lead to a significant improvement in energy search, including selecting the optimal redox mediator polymer
performance. Herein, the power output is strongly influenced by to enhance enzyme/electrode interaction. In terms of long-term
factors such as the low concentration of analyte in saliva and the stability, recently proposed approaches have extended the lifetime

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Vardan Galstyan is a researcher at the Institute of Materials for Electronics and Magnetism, National
Research Council (IMEM-CNR) of Italy. He got his Ph.D. degree in 2008 from the Yerevan State Uni-
versity. In 2022, V. Galstyan obtained National Scientific Habilitation as a Full Professor in the Italian
higher education system. His research activities mainly deal with the synthesis of organic/inorganic
nanomaterials and nanocomposites, as well as the investigation of their fundamental and functional
properties for applications in gas and biosensors, energy, and biomedicine.

Ilenia D’Onofrio is currently a Ph.D. student in Material Science and Technology at the Department of
Chemical, Life and Environmental Sustainability Sciences of the University of Parma, in collaboration
with the Institute of Materials for Electronics and Magnetism, National Research Council (IMEM-
CNR) of Italy. She received her master’s degree in Genomic, Molecular, and Industrial Biotechnologies
from the University of Parma. Her current research focuses on biosensing devices and the synthesis
and characterization of polymer-based drug delivery systems and their applications in healthcare.

Aris Liboà graduated in food safety and food risk management at the University of Modena and Reggio
Emilia (Italy). He is a Ph.D. student in Material Science and Technology at the Department of Chemi-
cal, Life, and Environmental Sustainability Sciences of the University of Parma, in collaboration with
the Institute of Materials for Electronics and Magnetism, National Research Council (IMEM-CNR) of
Italy. His research activity deals with the development of electrochemical biosensors and drug delivery
systems for the food and feed industry.

Giuseppe De Giorgio is a Postdoctoral Researcher at the Institute of Materials for Electronics and
Magnetism, National Research Council (IMEM-CNR) of Italy. In 2022, he received his Ph.D. in
Biotechnology and Biosciences at the Department of Chemistry, Life Sciences and Environmental
Sustainability, University of Parma. His main research interests are the synthesis of biomaterials for
biomedical and sensor applications, the development of innovative drug delivery systems, the syn-
thesis and characterization of nanoparticles and nanostructured materials, and the application of
engineered materials for the treatment of human diseases.

Adv. Mater. Technol. 2024, 9, 2400395 2400395 (22 of 23) © 2024 The Author(s). Advanced Materials Technologies published by Wiley-VCH GmbH
 2365709x, 2024, 21, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/admt.202400395 by Readcube (Labtiva Inc.), Wiley Online Library on [29/07/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
www.advancedsciencenews.com www.advmattechnol.de

Davide Vurro received his MSc in Science and Technologies of Materials (STM) from the University
of Bari, Aldo Moro in 2016. Afterward, he received a Ph.D. degree in STM at the University of Parma in
2019. Currently, D. Vurro is a researcher at the Institute of Materials for Electronics and Magnetism,
National Research Council (IMEM-CNR) of Italy. His research covers processes such as additive man-
ufacturing techniques to develop biocompatible and sustainable biopolymer-based materials for
bioelectronics and energy applications.

Luigi Rovati graduated (summa cum laude) in Electronic Engineering from the University of Pavia
in 1989 and earned his Ph.D. in Electronics Engineering from the same university in 1994. Currently,
he is a Full Professor of Measurement Engineering and Instrumentation at the Department of Engi-
neering “Enzo Ferrari” at the University of Modena e Reggio Emilia (Italy). His research focuses on
developing innovative sensors and measurement instruments, particularly in the biomedical field. He
has received numerous awards for his contributions and has coordinated and participated in various
national and international research projects.

Giuseppe Tarabella is a researcher at the CNR (IT). He received his Ph.D. in Materials Science in 2012
at the University of Parma, working in the Organic Electronics area, especially with Organic Transistors
applied as biosensors. His main interests are in 1) Sensor devices for diagnostics and biosensing;
2) 3D printing for wearable and flexible electronics; 3) Electrochemical characterization and surface
bio-functionalization; and 4) Unconventional Computing. Since 2022, he has been the IMEM-CNR
unit coordinator of the European Project EIC, IV-Lab Pathfinder Challenge, the project’s goal being the
development of non-invasive sensors for the continuous monitoring of one’s health state.

Pasquale D’Angelo graduated in Physics and received his Ph.D. in “Innovative Technologies for Ma-
terials, Sensor and Imaging” at the University of Naples Federico II. He devoted his post-doctoral
activities to serving as a Research Fellow at the Institute for the Study of Nanostructured Materials,
Bologna, Institute de Science et d’Ingénierie Supramoléculaires, Strasbourg, and Imperial College,
London. Since 2012, he has worked as a researcher at the Institute of Materials for Electronics and
Magnetism, National Research Council (IMEM-CNR) of Italy, where he conducts research on organic-
based electronic/bioelectronic devices to realize several types of applications including biosensors,
neuromorphic devices, and energy.

Adv. Mater. Technol. 2024, 9, 2400395 2400395 (23 of 23) © 2024 The Author(s). Advanced Materials Technologies published by Wiley-VCH GmbH