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Figure 7. Affibody-sensor for the detection of human epidermal growth factor receptor 2 (HER2) biomarker. (a) Preparation of AuNP-graphite strip through electrodeposition. (b) Anti-HER2 immobilization over the AuNP-graphite strip. (c) Formation of MCH self-assembled monolayer with the anti- HER2 AuNP-graphite strip. (d) Addition of blocking agent to the electrode strip. (e) Interaction with HER2 and (f) the corresponding impedance signal [100]. Reprinted with permission from [100], Copyright © 2020 Published by Elsevier B.V. GSPEs: Graphite screen-printed electrodes, EIS: Electrochemical impedance spectroscopy. that was linearly proportional to the logarithm OF the MepG- cell concentration. [70]. Affibody-based sensors are a result of using antibody mimicking bioengineered small protein (6 to 7 kDa) molecules to overcome the limitations of immunosensors [97]. These affibodies are engineered according to the need and have high binding affinity, selectivity, and survivability in high temperature conditions [98]. Antibodies typically contain disulfide bonds that lead to poor heat 1 portion of the multidomain protein structure of antibodies is used in antigen detection [1,98]. This is where affibody technology comes into use. The parts of antibodies that are responsible for their affinity and selectivity towards antigens are engineered in vitro h various metal nanoparticles to further enhance their efficacy [99] stability [1]. However, only a sma These affibodies are often paired wit An impedimetric strip ECB for human epidermal growth factor receptor 2 utilized affibody as the biorecogni immobilizing the anti- HER2 affibodies. This resulted in selective interaction wi tion element is shown in Figure 7 [100]. HER2) biomarker that AuNPs were used for th the HER2. Because of that, the impedimetric charge transfer resistance increased linearly with increasing HER2 concentration Analysis of the experimental results provided an LOD of 6 ug/L for the proposed sensor. Compared to conventional immunosensors, the affibody sensor was more sensitive, provided a more rapid response, and higher specificity [100].

Figure 7 Affibody-sensor for the detection of human epidermal growth factor receptor 2 (HER2) biomarker. (a) Preparation of AuNP-graphite strip through electrodeposition. (b) Anti-HER2 immobilization over the AuNP-graphite strip. (c) Formation of MCH self-assembled monolayer with the anti- HER2 AuNP-graphite strip. (d) Addition of blocking agent to the electrode strip. (e) Interaction with HER2 and (f) the corresponding impedance signal [100]. Reprinted with permission from [100], Copyright © 2020 Published by Elsevier B.V. GSPEs: Graphite screen-printed electrodes, EIS: Electrochemical impedance spectroscopy. that was linearly proportional to the logarithm OF the MepG- cell concentration. [70]. Affibody-based sensors are a result of using antibody mimicking bioengineered small protein (6 to 7 kDa) molecules to overcome the limitations of immunosensors [97]. These affibodies are engineered according to the need and have high binding affinity, selectivity, and survivability in high temperature conditions [98]. Antibodies typically contain disulfide bonds that lead to poor heat 1 portion of the multidomain protein structure of antibodies is used in antigen detection [1,98]. This is where affibody technology comes into use. The parts of antibodies that are responsible for their affinity and selectivity towards antigens are engineered in vitro h various metal nanoparticles to further enhance their efficacy [99] stability [1]. However, only a sma These affibodies are often paired wit An impedimetric strip ECB for human epidermal growth factor receptor 2 utilized affibody as the biorecogni immobilizing the anti- HER2 affibodies. This resulted in selective interaction wi tion element is shown in Figure 7 [100]. HER2) biomarker that AuNPs were used for th the HER2. Because of that, the impedimetric charge transfer resistance increased linearly with increasing HER2 concentration Analysis of the experimental results provided an LOD of 6 ug/L for the proposed sensor. Compared to conventional immunosensors, the affibody sensor was more sensitive, provided a more rapid response, and higher specificity [100].

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ECBs often take advantage of the unique chemical properties possessed by nanomaterials [14-16]. Particularly, metal nanoparticles (MNPs) are mostly used due to their biocompatibility, low toxicity, excellent conductivity, and high surface area [17-21]. Among many, gold (AuNPs), silver (AgNPs), and platinum NPs (PtNPs) are some of the most commonly utilized in ECBs [21-28]. In fabricating biosensors, these MNPs often provide the anchoring site for biorecognition components such as antibodies, enzymes, single stranded RNA (ssRNA) and DNA (ssDNA), aptamers, and affibodies [21—24,27,29-31]. The effectiveness and stability of these biochemical interactions are largely dependent on the physicochemical properties of the MNPs [1,20,32]. This is why material researchers have devised unique strategies for controlling size, shape, and other structural features of these MNPs [32,33]. However, MNPs are often combined with a scaffold for increasing stability and catalytic activity that is usually made of nanostructured material [34-37]. Of these, the carbon nanostructures are the most popular candidate due to their availability, good conductivity, and stability [9,35,38—40]. The various carbon nanostructures used are 0D fullerenes, 1D carbon nanotubes (CNTs), 2D graphene (GR), and 3D graphite materials [41-44]. In ECBs, the composites of MNPs and these carbon nanostructures are used to anchor the biorecognition components to the transducer that converts the chemical signal to electronic signal. Figure 1 depicts the various MNPs and their composites that are often utilized in ECBs.
ECBs often take advantage of the unique chemical properties possessed by nanomaterials [14-16]. Particularly, metal nanoparticles (MNPs) are mostly used due to their biocompatibility, low toxicity, excellent conductivity, and high surface area [17-21]. Among many, gold (AuNPs), silver (AgNPs), and platinum NPs (PtNPs) are some of the most commonly utilized in ECBs [21-28]. In fabricating biosensors, these MNPs often provide the anchoring site for biorecognition components such as antibodies, enzymes, single stranded RNA (ssRNA) and DNA (ssDNA), aptamers, and affibodies [21—24,27,29-31]. The effectiveness and stability of these biochemical interactions are largely dependent on the physicochemical properties of the MNPs [1,20,32]. This is why material researchers have devised unique strategies for controlling size, shape, and other structural features of these MNPs [32,33]. However, MNPs are often combined with a scaffold for increasing stability and catalytic activity that is usually made of nanostructured material [34-37]. Of these, the carbon nanostructures are the most popular candidate due to their availability, good conductivity, and stability [9,35,38—40]. The various carbon nanostructures used are 0D fullerenes, 1D carbon nanotubes (CNTs), 2D graphene (GR), and 3D graphite materials [41-44]. In ECBs, the composites of MNPs and these carbon nanostructures are used to anchor the biorecognition components to the transducer that converts the chemical signal to electronic signal. Figure 1 depicts the various MNPs and their composites that are often utilized in ECBs.
Figure 2. Classification ECBs. Left-hand side shows the classification with respect to electroanalytical techniques (EATs) and the right-hand side shows classification with respect to biorecognition components (BRCs).
Figure 2. Classification ECBs. Left-hand side shows the classification with respect to electroanalytical techniques (EATs) and the right-hand side shows classification with respect to biorecognition components (BRCs).
Figure 4. Simplified illustration of different biorecognition components designed based on sandwich, label-free immunosensing assay, aptasensing assay and affisensing assay (a) and the process of signal generation and different electroanalytical techniques used for ECBs (b). itavirus antibody detection for 0.4 to 300 ug/mL. Sensor fabrication and hantavirus detection is wn in Figure 5a. The reported sensor also showed good stability over 21 days [73]. In another work state specific antigen (PSA) detection was carried out with direct label-free method by Camilo et /2]. The report showed that AuNPs and layer by layer (LBL)-assembled nanostructures can be used signal amplification in a direct immunosensor detection system while simultaneously lowering number of biomolecules (antibody) needed. Their proposed sensor required approximately 10 times ver antibodies compared to traditional PSA immunosensors [72]. Label-free immunosensors are » employed for detecting proteins, hormones, bacteria, etc. [74]. Figure 4. Simplified illustration of different biorecognition components designed based on sandwich,
Figure 4. Simplified illustration of different biorecognition components designed based on sandwich, label-free immunosensing assay, aptasensing assay and affisensing assay (a) and the process of signal generation and different electroanalytical techniques used for ECBs (b). itavirus antibody detection for 0.4 to 300 ug/mL. Sensor fabrication and hantavirus detection is wn in Figure 5a. The reported sensor also showed good stability over 21 days [73]. In another work state specific antigen (PSA) detection was carried out with direct label-free method by Camilo et /2]. The report showed that AuNPs and layer by layer (LBL)-assembled nanostructures can be used signal amplification in a direct immunosensor detection system while simultaneously lowering number of biomolecules (antibody) needed. Their proposed sensor required approximately 10 times ver antibodies compared to traditional PSA immunosensors [72]. Label-free immunosensors are » employed for detecting proteins, hormones, bacteria, etc. [74]. Figure 4. Simplified illustration of different biorecognition components designed based on sandwich,
Figure 5. Label-free and sandwich type immunosensor fabrication process. (a) Label-free immunosensor preparation through antibody immobilization for the detection of hantavirus [73]. (b) Schematic representation of the sandwich type electrochemical immunosensor fabrication process for the sensitive detection of LipL32 which is responsible for leptospirosis [80]. Reprinted with permission from [73,80], Copyright © 2020 Published by Elsevier B.V. MPA: 3-mercaptopropionic acid, EDC: N-(3, Dimethylaminopropyl)-N-ethyl-carbodiimidehydrochloride, NHS: N-hydroxysuccinimide ester, Ab: Antibody, GO: Graphene oxide. A See ee Although label-free immunosensors are very selective, they are not adequately sensitive [78] Hence, sandwich the label-free sys interact with the that interacts on type immunosensors were conceived to overcome this limitation [1,78]. Similar tc em, the antibody (Anb1) is first immobilized on the ECB surface and allowed tc antigen (Ang). However, a second antibody (Anb2) is introduced to the systerr y with the Anbl—Ang sites on the electrode surface to produce the sandwict (Anb1—Ang—Anb2) [68,79]. As a result, the change in electronic signal is amplified and the sensitivity is improved. Jam pasa et al. developed an ECB for the sensitive detection of LipL32 protein througt a “signal on” process [80]. The sensor utilized a graphene oxide (GO) layer for immobilizing the Anb1 The modified electrode was allowed to interact with the antigen. Finally, Au conjugated Anb2 was introduced to the electrode system. The electrode fabrication process is shown in detail in Figure 5b This interaction process ensured selectivity and high sensitivity. The DPV technique was utilized for the detection 14 davs [80]. process. The sensor showed a stable current response towards LipL32 for ove:
Figure 5. Label-free and sandwich type immunosensor fabrication process. (a) Label-free immunosensor preparation through antibody immobilization for the detection of hantavirus [73]. (b) Schematic representation of the sandwich type electrochemical immunosensor fabrication process for the sensitive detection of LipL32 which is responsible for leptospirosis [80]. Reprinted with permission from [73,80], Copyright © 2020 Published by Elsevier B.V. MPA: 3-mercaptopropionic acid, EDC: N-(3, Dimethylaminopropyl)-N-ethyl-carbodiimidehydrochloride, NHS: N-hydroxysuccinimide ester, Ab: Antibody, GO: Graphene oxide. A See ee Although label-free immunosensors are very selective, they are not adequately sensitive [78] Hence, sandwich the label-free sys interact with the that interacts on type immunosensors were conceived to overcome this limitation [1,78]. Similar tc em, the antibody (Anb1) is first immobilized on the ECB surface and allowed tc antigen (Ang). However, a second antibody (Anb2) is introduced to the systerr y with the Anbl—Ang sites on the electrode surface to produce the sandwict (Anb1—Ang—Anb2) [68,79]. As a result, the change in electronic signal is amplified and the sensitivity is improved. Jam pasa et al. developed an ECB for the sensitive detection of LipL32 protein througt a “signal on” process [80]. The sensor utilized a graphene oxide (GO) layer for immobilizing the Anb1 The modified electrode was allowed to interact with the antigen. Finally, Au conjugated Anb2 was introduced to the electrode system. The electrode fabrication process is shown in detail in Figure 5b This interaction process ensured selectivity and high sensitivity. The DPV technique was utilized for the detection 14 davs [80]. process. The sensor showed a stable current response towards LipL32 for ove:
Figure 6. Electrochemical aptasensors for the detection of biomolecules. (a) Aptamer anchored on gold electrode surface for Ochratoxin A (OHA) detection through structure switching of the aptamer [88]. (b) ECB for the sensitive detection of carcinoembryonic antigen (CEA) through label-free sandwich method [89]. (c) Aptamer displacement strategy-based sensor for the detection of PTK-7 [93]. (d) Schematics of a label-free competitive aptamer cytosensor design and detection process of hepatocellular carcinoma (HepG2) cells [96]. Reprinted with permission from [88], Copyright © 2020 Published by J-STAGE, [89], Copyright © 2020 Published by Elsevier B.V., [93], Copyright © 2020 Published by Springer Nature, [96], Copyright © 2020 Published by ECS. MCH: 6-mercapto-1-hexanol, PTK-7: protein tyrosine kinase-7, HP: hairpin probe. In the case of type-a biosensors, the immobilized aptamers change their configuration with respect to interactions with the target biomolecules [87]. Mazaafrianto and co-workers developed an aptasensor for detecting ochratoxin A (OHA) based on structure switching [88]. The proposed sensor was able to obtain an LOD of 113 pm through the “signal on” method. Figure 6a shows the OHA sensor setup and its interaction process for electrochemical signaling. OHA interaction induced the structure change in the aptamer that then allowed interaction with methylene blue (MB) that resulted in the increased signal [88].
Figure 6. Electrochemical aptasensors for the detection of biomolecules. (a) Aptamer anchored on gold electrode surface for Ochratoxin A (OHA) detection through structure switching of the aptamer [88]. (b) ECB for the sensitive detection of carcinoembryonic antigen (CEA) through label-free sandwich method [89]. (c) Aptamer displacement strategy-based sensor for the detection of PTK-7 [93]. (d) Schematics of a label-free competitive aptamer cytosensor design and detection process of hepatocellular carcinoma (HepG2) cells [96]. Reprinted with permission from [88], Copyright © 2020 Published by J-STAGE, [89], Copyright © 2020 Published by Elsevier B.V., [93], Copyright © 2020 Published by Springer Nature, [96], Copyright © 2020 Published by ECS. MCH: 6-mercapto-1-hexanol, PTK-7: protein tyrosine kinase-7, HP: hairpin probe. In the case of type-a biosensors, the immobilized aptamers change their configuration with respect to interactions with the target biomolecules [87]. Mazaafrianto and co-workers developed an aptasensor for detecting ochratoxin A (OHA) based on structure switching [88]. The proposed sensor was able to obtain an LOD of 113 pm through the “signal on” method. Figure 6a shows the OHA sensor setup and its interaction process for electrochemical signaling. OHA interaction induced the structure change in the aptamer that then allowed interaction with methylene blue (MB) that resulted in the increased signal [88].
Figure 8. Fabrication of ECB strip for histamine (HA) detection. Portable immunosensor developed for the (point-of-care testing) POCT of HA with PB-CS-AuNPs [105]. Reprinted with permission from [105], Copyright © 2020 Elsevier Ltd. B.V.
Figure 8. Fabrication of ECB strip for histamine (HA) detection. Portable immunosensor developed for the (point-of-care testing) POCT of HA with PB-CS-AuNPs [105]. Reprinted with permission from [105], Copyright © 2020 Elsevier Ltd. B.V.
Figure 9. A “signal off’ ECB for the voltammetric detection of Tau-441 protein. Assembly of multi-walled carbon nanotubes-reduced graphene oxide-chitosan-antibody (MWCNT-rGO-CS) over the gold electrode for the voltammetric detection of AuNP-Tau-441 conjugate [112]. Reprinted with permission from [112], Copyright © 2020, Springer Nature.
Figure 9. A “signal off’ ECB for the voltammetric detection of Tau-441 protein. Assembly of multi-walled carbon nanotubes-reduced graphene oxide-chitosan-antibody (MWCNT-rGO-CS) over the gold electrode for the voltammetric detection of AuNP-Tau-441 conjugate [112]. Reprinted with permission from [112], Copyright © 2020, Springer Nature.
For the potentiometric technique, the change of potential in the electrochemical cell is measured, while the current change is minimal [113]. The potentiometric sensors are also known as ion selective electrodes (ISEs) because they are often designed to generate responses with respect to the change in concentration of a specific ion [113,114]. Their setups are different from the traditional amperometric and voltammetric cells, because they often utilize two reference electrodes that measure the potential change with respect to the target analyte concentration in the cell [113,115]. These ISEs can be converted to ECBs by modifying the electrode with biocatalysts that interact with biomolecules to produce ions that the ISEs can detect [1,113]. Like other ECBs, they can also operate independent of sample volume, have a low LOD, small size, and produce a rapid response. On top of these, potentiometric ISEs are able to provide information regarding the concentration of free ions or ion activity in the cell [114,116] Manjakkal et al. reported the fabrication of a potentiometric pH sensor that can be used as a wearable device [117]. The sensor showed excellent stability to washing and a good sensitivity of 4 mV/pH in the pH range of 6-9 [117], making it an excellent candidate for POCT for various bioanalytes through the incorporation of proper biorecognition component. The fabricated wearable device is shown in Figure 10. Figure 10. Schematic representation and photograph of the wearable ion selective electrodes (ISE) pH sensor. (a) Schematic of the pH sensor where Ag was deposited on the cloth. The sensing electrode (SE) and reference electrodes (RE) are screen printed over the Ag substrate. (b) Picture of the flexible cloth sensor. Inset shows the SE and RE electrodes [117]. Reprinted with permission from [117], Copyright © 2020, MDPI. Figure 10. Schematic representation and photograph of the wearable ion selective electrodes (ISE) pH sensor. (a) Schematic of the pH sensor where Ag was deposited on the cloth. The sensing electrode (SE)
For the potentiometric technique, the change of potential in the electrochemical cell is measured, while the current change is minimal [113]. The potentiometric sensors are also known as ion selective electrodes (ISEs) because they are often designed to generate responses with respect to the change in concentration of a specific ion [113,114]. Their setups are different from the traditional amperometric and voltammetric cells, because they often utilize two reference electrodes that measure the potential change with respect to the target analyte concentration in the cell [113,115]. These ISEs can be converted to ECBs by modifying the electrode with biocatalysts that interact with biomolecules to produce ions that the ISEs can detect [1,113]. Like other ECBs, they can also operate independent of sample volume, have a low LOD, small size, and produce a rapid response. On top of these, potentiometric ISEs are able to provide information regarding the concentration of free ions or ion activity in the cell [114,116] Manjakkal et al. reported the fabrication of a potentiometric pH sensor that can be used as a wearable device [117]. The sensor showed excellent stability to washing and a good sensitivity of 4 mV/pH in the pH range of 6-9 [117], making it an excellent candidate for POCT for various bioanalytes through the incorporation of proper biorecognition component. The fabricated wearable device is shown in Figure 10. Figure 10. Schematic representation and photograph of the wearable ion selective electrodes (ISE) pH sensor. (a) Schematic of the pH sensor where Ag was deposited on the cloth. The sensing electrode (SE) and reference electrodes (RE) are screen printed over the Ag substrate. (b) Picture of the flexible cloth sensor. Inset shows the SE and RE electrodes [117]. Reprinted with permission from [117], Copyright © 2020, MDPI. Figure 10. Schematic representation and photograph of the wearable ion selective electrodes (ISE) pH sensor. (a) Schematic of the pH sensor where Ag was deposited on the cloth. The sensing electrode (SE)
the detection of biomolecules from human serum and urine samples, and pathogens from foods biosecurity purposes [118,122,123]. Figure 11. Conductometric ECB for the detection of phenol. (a) The strip gold electrode with 20 nm thick intermediate titanium (IDT) for phenol detection. (b) SEM image of bacteria over the glassy carbon electrode (GCE) (grey) and gold (dark) conductometric sensor. (c) The change in conductance with respect to the addition of phenol [121]. Reprinted with permission from [121], Copyright © 2020 Elsevier Ltd.
the detection of biomolecules from human serum and urine samples, and pathogens from foods biosecurity purposes [118,122,123]. Figure 11. Conductometric ECB for the detection of phenol. (a) The strip gold electrode with 20 nm thick intermediate titanium (IDT) for phenol detection. (b) SEM image of bacteria over the glassy carbon electrode (GCE) (grey) and gold (dark) conductometric sensor. (c) The change in conductance with respect to the addition of phenol [121]. Reprinted with permission from [121], Copyright © 2020 Elsevier Ltd.
Figure 13. The trend in ECB research over the last decade. The statistical data were obtained from Google Scholar search engine using the following keywords in advance search mode: metal nanoparticle + “glucose”/”dopamine”/"hydrogen peroxide”/”cancer biomarker” + “electrochemical biosensor” for the respective years.
Figure 13. The trend in ECB research over the last decade. The statistical data were obtained from Google Scholar search engine using the following keywords in advance search mode: metal nanoparticle + “glucose”/”dopamine”/"hydrogen peroxide”/”cancer biomarker” + “electrochemical biosensor” for the respective years.
Figure 14. ECB for the detection of prostate specific antigen (PSA). PSA antibody was immobilized on the AuNP-functionalized MWCNT/GCE system that selectively interacted with the PSA—antigen [141] Reprinted with permission from [141], Copyright © 2020 Published by Frontiers.
Figure 14. ECB for the detection of prostate specific antigen (PSA). PSA antibody was immobilized on the AuNP-functionalized MWCNT/GCE system that selectively interacted with the PSA—antigen [141] Reprinted with permission from [141], Copyright © 2020 Published by Frontiers.
Figure 15. Fabrication of an ECB for the simultaneous detection of glucose and H2O2. The sensor utilized an Ag nanoflower and PtNPs (AgNFs-Pt) along with enzymes to be able to detect two analytes simultaneously [153]. Reprinted with permission from [153], Copyright © 2020 Published by ECS AA: L-ascorbic acid. Figure 15. Fabrication of an ECB for the simultaneous detection of glucose and H2O2. The sensor veer noe i. ea PtNPs with cubic, polygonal, or rod shapes offer better anchoring sites for biorecognition ymponents compared to spherical NPs [151]. Huang et al. reported the development of a highly fective glucose and H,O, ECB [153]. For this, flower-like AgNPs were decorated with dewdrop-like tNPs for enhancing the electrocatalytic surface area, selectivity, and stability. Figure 15 shows .e synthesis and morphological structures of the ECB. The sensor showed linear range from 1 uM to mM for H2O, and 1 to 14 mM glucose [152].
Figure 15. Fabrication of an ECB for the simultaneous detection of glucose and H2O2. The sensor utilized an Ag nanoflower and PtNPs (AgNFs-Pt) along with enzymes to be able to detect two analytes simultaneously [153]. Reprinted with permission from [153], Copyright © 2020 Published by ECS AA: L-ascorbic acid. Figure 15. Fabrication of an ECB for the simultaneous detection of glucose and H2O2. The sensor veer noe i. ea PtNPs with cubic, polygonal, or rod shapes offer better anchoring sites for biorecognition ymponents compared to spherical NPs [151]. Huang et al. reported the development of a highly fective glucose and H,O, ECB [153]. For this, flower-like AgNPs were decorated with dewdrop-like tNPs for enhancing the electrocatalytic surface area, selectivity, and stability. Figure 15 shows .e synthesis and morphological structures of the ECB. The sensor showed linear range from 1 uM to mM for H2O, and 1 to 14 mM glucose [152].
Table 1. The table describes ECBs that utilized MNPs with various sizes and shapes along with various conducting nanomaterials (CNMs) for biomolecule sensing. The biorecognition components, biointeraction process, and EATs used in these ECBs are also mentioned.
Table 1. The table describes ECBs that utilized MNPs with various sizes and shapes along with various conducting nanomaterials (CNMs) for biomolecule sensing. The biorecognition components, biointeraction process, and EATs used in these ECBs are also mentioned.
Figure 16. Schematic presentation of the relationship between different allotropes of carbon [9]. Redrawn from [9].
Figure 16. Schematic presentation of the relationship between different allotropes of carbon [9]. Redrawn from [9].
HEV: Hepatitis E virus; GQD: graphene quantum dot; PANI: polyaniline; PDA: poly dopamine; PEDOT: Poly(3,4-ethylenedioxythiophene); SPCE: screen-printed carbon electrode; CS: chitosan; DMF: dimethylformamide; PB: prussian blue; BSA: bovine serum; MPA: 3-mercaptopropionic acid; ATPA: ATP aptamer; XO: Xanthine oxidase. Table 1. Cont.
HEV: Hepatitis E virus; GQD: graphene quantum dot; PANI: polyaniline; PDA: poly dopamine; PEDOT: Poly(3,4-ethylenedioxythiophene); SPCE: screen-printed carbon electrode; CS: chitosan; DMF: dimethylformamide; PB: prussian blue; BSA: bovine serum; MPA: 3-mercaptopropionic acid; ATPA: ATP aptamer; XO: Xanthine oxidase. Table 1. Cont.
artificial mediators for glucose sensing; (iii) third generation ECBs that induce direct electron transfer between glucose and the immobilized enzymes [9]. The mechanisms of these three types of glucose sensors are shown in Figure 17. MNPs can significantly enhance the performance of enzymatic glucose sensors through providing a high surface area, alternative low energy catalytic pathway, and stability for immobilized enzymes [9]. A PtNP-coated SnS2 enzymatic (GOx) glucose sensor was reported with linear range from 0.1-12 mM [168]. Authors concluded from morphological analysis of the prepared electrochemical glucose biosensor that the use of hydrophilic PtNPs significantly enhanced GOx immobilization. This in turn resulted in the sensitive detection of glucose over the wide linear range [168,178]. Magnetic NiNPs have been used for directly immobilizing GOx [179]. The glucose sensor showed linearity up to 12 mM with an LOD of 0.42 mM. The proposed sensing mechanism for the sensor is shown in Figure 18a. The magnetic NiNP sensor did not need to incorporate any other binding material for GOx immobilization [179]. Figure 17. Mechanism of glucose oxidation at ECBs that utilize biocatalytic system. The mechanisms for 1st, 2nd, and 3rd generation glucose sensors are shown [9]. Redrawn from [9]. Although HRP is most commonly employed for H 20, detection, other redox-inducing biorecognition components such as ferredoxin, cytochrome C, and hemoglobin are also utilized [180]. A myoglobin-based HO sensor was reported which used MoS, NPs and GO [176]. The myoglobin/MoS, NP/GO system showed the best current response along with better stability compared to only myoglobin/MoSz NPs or myoglobin/GO systems [181]. In another study, cytochrome C enzyme was used for fabricating the H2O2 sensor—Au nanocubes were utilized for immobilization
artificial mediators for glucose sensing; (iii) third generation ECBs that induce direct electron transfer between glucose and the immobilized enzymes [9]. The mechanisms of these three types of glucose sensors are shown in Figure 17. MNPs can significantly enhance the performance of enzymatic glucose sensors through providing a high surface area, alternative low energy catalytic pathway, and stability for immobilized enzymes [9]. A PtNP-coated SnS2 enzymatic (GOx) glucose sensor was reported with linear range from 0.1-12 mM [168]. Authors concluded from morphological analysis of the prepared electrochemical glucose biosensor that the use of hydrophilic PtNPs significantly enhanced GOx immobilization. This in turn resulted in the sensitive detection of glucose over the wide linear range [168,178]. Magnetic NiNPs have been used for directly immobilizing GOx [179]. The glucose sensor showed linearity up to 12 mM with an LOD of 0.42 mM. The proposed sensing mechanism for the sensor is shown in Figure 18a. The magnetic NiNP sensor did not need to incorporate any other binding material for GOx immobilization [179]. Figure 17. Mechanism of glucose oxidation at ECBs that utilize biocatalytic system. The mechanisms for 1st, 2nd, and 3rd generation glucose sensors are shown [9]. Redrawn from [9]. Although HRP is most commonly employed for H 20, detection, other redox-inducing biorecognition components such as ferredoxin, cytochrome C, and hemoglobin are also utilized [180]. A myoglobin-based HO sensor was reported which used MoS, NPs and GO [176]. The myoglobin/MoS, NP/GO system showed the best current response along with better stability compared to only myoglobin/MoSz NPs or myoglobin/GO systems [181]. In another study, cytochrome C enzyme was used for fabricating the H2O2 sensor—Au nanocubes were utilized for immobilization
of cytochrome C [182]. Figure 18b shows the fabrication process of the reported H2O2 ECB. The sensor showed a linear range from 100-1000 uM for HzO, detection [182]. The use of cubic NPs enhanced the electroactive surface and incorporated a better electron transfer mechanism for biocatalytic HO, reduction. This work shows the importance of shape- and size-controlled MNP fabrication for use in the ECBs. Figure 18. Electrode fabrication process and detection of glucose and H2O>%. (a) the possible mechanism for the simultaneous oxidation of HzO, and glucose molecules by NiNP/Ni substrate-based enzymatic ECB [179]. (b) The synthesis process for cyt c conjugated AuNCs imbedded hydrogel ECB for the sensitive detection of HzO [182]. Reprinted with permission from [179], Copyright © 2020 Published by the American Chemical Society [182], Copyright © 2020 Published by Elsevier B.V.
of cytochrome C [182]. Figure 18b shows the fabrication process of the reported H2O2 ECB. The sensor showed a linear range from 100-1000 uM for HzO, detection [182]. The use of cubic NPs enhanced the electroactive surface and incorporated a better electron transfer mechanism for biocatalytic HO, reduction. This work shows the importance of shape- and size-controlled MNP fabrication for use in the ECBs. Figure 18. Electrode fabrication process and detection of glucose and H2O>%. (a) the possible mechanism for the simultaneous oxidation of HzO, and glucose molecules by NiNP/Ni substrate-based enzymatic ECB [179]. (b) The synthesis process for cyt c conjugated AuNCs imbedded hydrogel ECB for the sensitive detection of HzO [182]. Reprinted with permission from [179], Copyright © 2020 Published by the American Chemical Society [182], Copyright © 2020 Published by Elsevier B.V.
PGA: poly(glutamic acid); NF: nanoflower; GOx: glucose oxidase; UOx: uricase; HUA: humic acid; HNT: Halloysite nanotube; FAD: flavin adenosine dinucleotide; LIG: laser-induced graphene; ITO: indium tin oxide. Table 2. A brief description of various ECBs that have been reported from detection of glucose, dopamine (DA). HoQO>. and uric acid (UA).
PGA: poly(glutamic acid); NF: nanoflower; GOx: glucose oxidase; UOx: uricase; HUA: humic acid; HNT: Halloysite nanotube; FAD: flavin adenosine dinucleotide; LIG: laser-induced graphene; ITO: indium tin oxide. Table 2. A brief description of various ECBs that have been reported from detection of glucose, dopamine (DA). HoQO>. and uric acid (UA).
Fe: ferrocene; LPA-NHS: Lipoic acid N-hydroxysuccinimide ester; rGO: reduced GO; HNF: honey nanofibers; BSA: bovine serum; PAMAM: poly(amidoamine); Strp: streptavidin; Table 3. Cont.
Fe: ferrocene; LPA-NHS: Lipoic acid N-hydroxysuccinimide ester; rGO: reduced GO; HNF: honey nanofibers; BSA: bovine serum; PAMAM: poly(amidoamine); Strp: streptavidin; Table 3. Cont.
CAS: casein; MCH: 6-mercapto-1-hexanol; QD: quantum dot; MPA: 3-mercaptopropionic acid; 16-MUA: 16-[Mercaptoundecanoic acid; EDC: N-(3, Dimethylaminopropyl)-N-ethyl-carbodiimidehydrochloride; NHS: Lipoic acid N-hydroxysuccinimide ester; CASPE-MFD: commercially available screen-printed electrode-based microfluidic devices; AE: gold electrode; Table 3. Cont.
CAS: casein; MCH: 6-mercapto-1-hexanol; QD: quantum dot; MPA: 3-mercaptopropionic acid; 16-MUA: 16-[Mercaptoundecanoic acid; EDC: N-(3, Dimethylaminopropyl)-N-ethyl-carbodiimidehydrochloride; NHS: Lipoic acid N-hydroxysuccinimide ester; CASPE-MFD: commercially available screen-printed electrode-based microfluidic devices; AE: gold electrode; Table 3. Cont.
Table 3. Cont.
Table 3. Cont.
PGNR: porous graphene nanoribbon; MPTES: 3-mercaptopropyltriethoxysilane; AE: gold electrode; BSA: bovine serum; MO: methyl orange; DNR: dendritic nanorods; 4.2.1. MNPs in Carcinoma Embryonic Antigen Sensing Carcinoma embryonic antigen (CEA) is a cell adhesive acidic glycoprotein with properties similar to the human embryonic cell. Normally, the level of CEA is around 5 pg/mL in serum but in the blood the level is very low (<5 ng/mL) [195-198]. Meanwhile, serum CEA has been found to elevate up to 20 ug/mL in people with lung cancer [197]. Blood CEA levels above 10 ng/mL are indicative of cancer in the patient [201]. In several other types of carcinomas such as breast cancer, ovarian cancer, pancreatic cancer, and gastrointestinal cancer, CEA often shows elevation in serum level, which indicates its potentiality as being a tumor marker for clinical cancer diagnosis [195-197]. Therefore, quantitative measurements of CEA in biological fluids such as blood and serum are critical for locating, and understanding the prognosis, staging, and recurrence of multiple cancers [197-201]. For electrochemical immunosensor/aptasensor assays, MNP-based probes which have strong biocompatibility and electrical conductivity are of great interest [201-205] MNPs have superior efficiency as tags or labels for amplifying biomolecular interactions and as the enhancers of electrochemical signals [198-203]. Depending upon the complexity and necessities mono/bi/tri-metallic composites are utilized for constructing different types of ECBs with label-free or abeled, sandwich or non-sandwich strategies for CEA immunosensor/aptasensor [195,196,199,207,210] n mono-metallic-based ECBs, the primary concern is to enhance electrocatalytic surface area for anchoring biomolecules such as the antibody, and labeling enzymes or conductive dyes or biomolecules for developing labeled immunosensors [197,201]. Normally, direct immobilization of electrical signaling molecules such as HRP, MB, Fc to MNPs is not beneficial because it causes the loss of signaling molecules during electrochemical experiments and hence poor stability and reproducibility of the sensor [197] To overcome this problem, Gu et al. constructed an Fc-labeled AuNP-based sandwich immunosensot assay for the highly sensitive electrochemical detection of CEA [197]. In this work, they introduced a thiol group (-SH) into an Fc molecule which assisted the stable chemisorption of Fc over AuNPs via initiating an S-Au covalent bond. After immobilization of Fc-SH, the colloidal Au nanoprobes were stabilized with PEG800. Figure 19a shows the transmission electron microscope (TEM) image of the nanostructured Fc-SH/AuNP-Ab» composite along with the schematics of the fabrication process. Through this Fc-labeled immunosensing assay, they achieved a detection limit for CEA as low as 0.01 ng/mL [197]. Apart from AuNPs as the effective sensing platform and capture antibody, AgNPs also showed great promise in enhancing conductivity for electrocatalytic sensing and
PGNR: porous graphene nanoribbon; MPTES: 3-mercaptopropyltriethoxysilane; AE: gold electrode; BSA: bovine serum; MO: methyl orange; DNR: dendritic nanorods; 4.2.1. MNPs in Carcinoma Embryonic Antigen Sensing Carcinoma embryonic antigen (CEA) is a cell adhesive acidic glycoprotein with properties similar to the human embryonic cell. Normally, the level of CEA is around 5 pg/mL in serum but in the blood the level is very low (<5 ng/mL) [195-198]. Meanwhile, serum CEA has been found to elevate up to 20 ug/mL in people with lung cancer [197]. Blood CEA levels above 10 ng/mL are indicative of cancer in the patient [201]. In several other types of carcinomas such as breast cancer, ovarian cancer, pancreatic cancer, and gastrointestinal cancer, CEA often shows elevation in serum level, which indicates its potentiality as being a tumor marker for clinical cancer diagnosis [195-197]. Therefore, quantitative measurements of CEA in biological fluids such as blood and serum are critical for locating, and understanding the prognosis, staging, and recurrence of multiple cancers [197-201]. For electrochemical immunosensor/aptasensor assays, MNP-based probes which have strong biocompatibility and electrical conductivity are of great interest [201-205] MNPs have superior efficiency as tags or labels for amplifying biomolecular interactions and as the enhancers of electrochemical signals [198-203]. Depending upon the complexity and necessities mono/bi/tri-metallic composites are utilized for constructing different types of ECBs with label-free or abeled, sandwich or non-sandwich strategies for CEA immunosensor/aptasensor [195,196,199,207,210] n mono-metallic-based ECBs, the primary concern is to enhance electrocatalytic surface area for anchoring biomolecules such as the antibody, and labeling enzymes or conductive dyes or biomolecules for developing labeled immunosensors [197,201]. Normally, direct immobilization of electrical signaling molecules such as HRP, MB, Fc to MNPs is not beneficial because it causes the loss of signaling molecules during electrochemical experiments and hence poor stability and reproducibility of the sensor [197] To overcome this problem, Gu et al. constructed an Fc-labeled AuNP-based sandwich immunosensot assay for the highly sensitive electrochemical detection of CEA [197]. In this work, they introduced a thiol group (-SH) into an Fc molecule which assisted the stable chemisorption of Fc over AuNPs via initiating an S-Au covalent bond. After immobilization of Fc-SH, the colloidal Au nanoprobes were stabilized with PEG800. Figure 19a shows the transmission electron microscope (TEM) image of the nanostructured Fc-SH/AuNP-Ab» composite along with the schematics of the fabrication process. Through this Fc-labeled immunosensing assay, they achieved a detection limit for CEA as low as 0.01 ng/mL [197]. Apart from AuNPs as the effective sensing platform and capture antibody, AgNPs also showed great promise in enhancing conductivity for electrocatalytic sensing and
on AgNPs and MnO; for constructing a sandwich immunosensing assay for CEA [201]. AgNPs and MnO), together displayed catalytic activity for the reducing of H,O2 into H2O and molecular O. At the same time, they utilized PANI, which acted as the sacrificial reducing agent for AgNP and as the base material for providing active sites for Ag NP and MnO, immobilization. Figure 19b shows the SEM images of the composites at different fabrication stages. This ultrasensitive dual amplifying sandwich immunosensor showed an LOD for CEA of about 0.17 pg/mL with a broad sensing range of 0.0005-80 ng/mL [201]. Figure 19. ECBs for the detection of CEA. (a) Schematic illustration of two step synthesis process involved in the fabrication of sandwich immunosensor. The TEM image shows Anb»- and Fc-labeled AuNPs [197]. (b) The synthesis step for Ag-PANI@MnO). The SEM images show PANI, Ag—PANI, and Ag-PANI@MnO, [201]. (c) Fabrication of MoS2/g—C3N4—PtCu bimetallic sandwich immunosensor system for light-enhanced CEA detection [199]. (d) Development of a trimetallic (Pd@Au@Pt) ECB and picture of the final strip sensor with a coin for comparison of the size [195]. Reprinted with permission from [195,197], Copyright © 2020 published by Elsevier B.V. [199], Copyright © 2020 published by Springer Nature [201], Copyright © 2020 Hydrogen Energy Publications LLC. Published by Elsevier.
on AgNPs and MnO; for constructing a sandwich immunosensing assay for CEA [201]. AgNPs and MnO), together displayed catalytic activity for the reducing of H,O2 into H2O and molecular O. At the same time, they utilized PANI, which acted as the sacrificial reducing agent for AgNP and as the base material for providing active sites for Ag NP and MnO, immobilization. Figure 19b shows the SEM images of the composites at different fabrication stages. This ultrasensitive dual amplifying sandwich immunosensor showed an LOD for CEA of about 0.17 pg/mL with a broad sensing range of 0.0005-80 ng/mL [201]. Figure 19. ECBs for the detection of CEA. (a) Schematic illustration of two step synthesis process involved in the fabrication of sandwich immunosensor. The TEM image shows Anb»- and Fc-labeled AuNPs [197]. (b) The synthesis step for Ag-PANI@MnO). The SEM images show PANI, Ag—PANI, and Ag-PANI@MnO, [201]. (c) Fabrication of MoS2/g—C3N4—PtCu bimetallic sandwich immunosensor system for light-enhanced CEA detection [199]. (d) Development of a trimetallic (Pd@Au@Pt) ECB and picture of the final strip sensor with a coin for comparison of the size [195]. Reprinted with permission from [195,197], Copyright © 2020 published by Elsevier B.V. [199], Copyright © 2020 published by Springer Nature [201], Copyright © 2020 Hydrogen Energy Publications LLC. Published by Elsevier.
he DPV technique. Despite the simple preparation process, the sensor showed a wide linear rang rom 0.75-100 ng/mL [225]. This indicated the feasibility of the screen-printed label-free sensor in POC’ , number of works have reported that bimetallic, MOF, QD, and core@shell structure further enhanc: he sensitivity and stability of ECBs [220—222,224,227,235]. However, as discussed in the previou: ections, it is important to be able to prepare ECBs on strips so that they can be used for the on-the-spo esting of biomolecules. To this end, Chen and coworkers reported the fabrication of a PSA biosenso ased on the microfluidic principles through screen printing [237]. The ultra-sensitive PSA sensor wa repared through screen printing, making it readily scalable and cost-effective. The sensor fabricatiot rocess is shown in Figure 20a. The proposed sensor used printed gold electrodes as the WE and CE vhile an Ag electrode was used as the control. MagBs were utilized for anchoring the PSA antibody nthe printed gold electrode. The sensor utilized an amperometric technique for the PSA detectior rom 0.001-10 ng/mL, with a low LOD of 0.00084 ng/mL. Authors claimed that the reported sensor wa heap, easy to fabricate and operate, highly reproducible, and extremely sensitive [237]. Such sensor: ould be the key to solving the problems associated with utilization of ECBs for the POCT.
he DPV technique. Despite the simple preparation process, the sensor showed a wide linear rang rom 0.75-100 ng/mL [225]. This indicated the feasibility of the screen-printed label-free sensor in POC’ , number of works have reported that bimetallic, MOF, QD, and core@shell structure further enhanc: he sensitivity and stability of ECBs [220—222,224,227,235]. However, as discussed in the previou: ections, it is important to be able to prepare ECBs on strips so that they can be used for the on-the-spo esting of biomolecules. To this end, Chen and coworkers reported the fabrication of a PSA biosenso ased on the microfluidic principles through screen printing [237]. The ultra-sensitive PSA sensor wa repared through screen printing, making it readily scalable and cost-effective. The sensor fabricatiot rocess is shown in Figure 20a. The proposed sensor used printed gold electrodes as the WE and CE vhile an Ag electrode was used as the control. MagBs were utilized for anchoring the PSA antibody nthe printed gold electrode. The sensor utilized an amperometric technique for the PSA detectior rom 0.001-10 ng/mL, with a low LOD of 0.00084 ng/mL. Authors claimed that the reported sensor wa heap, easy to fabricate and operate, highly reproducible, and extremely sensitive [237]. Such sensor: ould be the key to solving the problems associated with utilization of ECBs for the POCT.
etoprotein in cancer patients [272]. To address the challenge of wide linear range, Li et al. developed in ECB utilizing AuNPs that had a wide linear range from 0.1 to 100 pg/mL [273]. However, the LOD vas 92 ng/mL, which indicates hat this sensor could not be used for the low-level detection of alpha etoprotein. A label-free immunosensor was developed using AgNPs and an rGO composite along with 7nFe,O, for the sensitive detec nabled the CV technique to be tion of alpha fetoprotein [278]. The signal amplification of the sensor used for detecting the pg/mL analyte. The alpha fetoprotein sensor levelopment process and consequent detection mechanism is shown in Figure 21b. The sensor showed 1 very low LOD of 0.98 pg/mL, with a linear range in the region of 0.001-200 ng/mL [278]. A possible vay to improve alpha fetoprotein sensors can be considering the size- and shape-dependent properties xf MNPs. At the same time, uti izing different CNMs for preparing MNPCs is a promising way for urther improving the biosensing capability.
etoprotein in cancer patients [272]. To address the challenge of wide linear range, Li et al. developed in ECB utilizing AuNPs that had a wide linear range from 0.1 to 100 pg/mL [273]. However, the LOD vas 92 ng/mL, which indicates hat this sensor could not be used for the low-level detection of alpha etoprotein. A label-free immunosensor was developed using AgNPs and an rGO composite along with 7nFe,O, for the sensitive detec nabled the CV technique to be tion of alpha fetoprotein [278]. The signal amplification of the sensor used for detecting the pg/mL analyte. The alpha fetoprotein sensor levelopment process and consequent detection mechanism is shown in Figure 21b. The sensor showed 1 very low LOD of 0.98 pg/mL, with a linear range in the region of 0.001-200 ng/mL [278]. A possible vay to improve alpha fetoprotein sensors can be considering the size- and shape-dependent properties xf MNPs. At the same time, uti izing different CNMs for preparing MNPCs is a promising way for urther improving the biosensing capability.
Figure 22. Schematics for the fabrication of a plug-and-play super-sandwich electrochemical immunosensor for 2019-nCoV. (a) shows the synthesis of Premix A and B. (b) combining Premix A with 2019-nCoV RNA and preparation of the super-sandwich for the detection 2019-nCoV through a smartphone [296]. Reprinted with permission from [296], Copyright © 2020 published by Elsevier B.V.
Figure 22. Schematics for the fabrication of a plug-and-play super-sandwich electrochemical immunosensor for 2019-nCoV. (a) shows the synthesis of Premix A and B. (b) combining Premix A with 2019-nCoV RNA and preparation of the super-sandwich for the detection 2019-nCoV through a smartphone [296]. Reprinted with permission from [296], Copyright © 2020 published by Elsevier B.V.
Figure 23. Schematics of hand-held ECBs with potential for POCT. (a) a smartphone-based ECB for the sensitive detection of glucose from blood samples. The figure shows the circuit setup that was used for connecting the ECB with the smartphone and detecting glucose through the CV technique [298]. (b) fabrication of a label-free immunosensor on a screen-printed carbon electrode (SPCE) strip for the detection of CA125 biomarkers from serum samples through the DPV technique [71]. (c) mechanism proposed for a clinically tested ECB for the simultaneous detection of multiplex pathogens for the diagnosis of urinary tract infection; (i) lysis of different bacteria through identification of 16S rRNA; (ii) hybridization with detector probes; (iii) combining with the capture probe immobilized on the electrode surface; (iv) binding of anti-fluorescein HRP tag to form sandwich system; and (v) generation of i-t current signal for a fixed potential that corresponded to the concentration of different bacteria present in the system [300]. Reprinted with permission from [71,298], Copyright © 2020 and 2020 published by Elsevier B.V. [300], Copyright © 2020 and 2020 published by the American Urological Association. DAC: Digital-to-analog converter. Figure 23. Schematics of hand-held ECBs with potential for POCT. (a) a smartphone-based ECB for
Figure 23. Schematics of hand-held ECBs with potential for POCT. (a) a smartphone-based ECB for the sensitive detection of glucose from blood samples. The figure shows the circuit setup that was used for connecting the ECB with the smartphone and detecting glucose through the CV technique [298]. (b) fabrication of a label-free immunosensor on a screen-printed carbon electrode (SPCE) strip for the detection of CA125 biomarkers from serum samples through the DPV technique [71]. (c) mechanism proposed for a clinically tested ECB for the simultaneous detection of multiplex pathogens for the diagnosis of urinary tract infection; (i) lysis of different bacteria through identification of 16S rRNA; (ii) hybridization with detector probes; (iii) combining with the capture probe immobilized on the electrode surface; (iv) binding of anti-fluorescein HRP tag to form sandwich system; and (v) generation of i-t current signal for a fixed potential that corresponded to the concentration of different bacteria present in the system [300]. Reprinted with permission from [71,298], Copyright © 2020 and 2020 published by Elsevier B.V. [300], Copyright © 2020 and 2020 published by the American Urological Association. DAC: Digital-to-analog converter. Figure 23. Schematics of hand-held ECBs with potential for POCT. (a) a smartphone-based ECB for
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