Flexible and wearable electrochemical biosensors based on two-dimensional materials: Recent developments

Abstract

The research interest in wearable sensors has tremendously increased in recent years. Amid the different biosensors, electrochemical biosensors are unparalleled and ideal for the design and manufacture of such flexible and wearable sensors because of their various benefits, including convenient operation, quick response, portability, and inherent miniaturization. A number of studies on flexible and wearable electrochemical biosensors have been reported in recent years for invasive/non-invasive and real-time monitoring of biologically relevant molecules such as glucose, lactate, dopamine, cortisol, and antigens. To attain this, novel two-dimensional nanomaterials and their hybrids, various substrates, and detection methods have been explored to fabricate flexible conductive platforms that can be used to develop flexible electrochemical biosensors. In particular, there are many advantages associated with the advent of two-dimensional materials, such as light weight, high stretchability, high performance, and excellent biocompatibility, which offer new opportunities to improve the performance of wearable electrochemical sensors. Therefore, it is urgently required to study wearable/flexible electrochemical biosensors based on two-dimensional nanomaterials for health care monitoring and clinical analysis. In this review, we described recently reported flexible electrochemical biosensors based on two-dimensional nanomaterials. We classified them into specific groups, including enzymatic/non-enzymatic biosensors and affinity biosensors (immunosensors), recent developments in flexible electrochemical immunosensors based on polymer and plastic substrates to monitor biologically relevant molecules. This review will discuss perspectives on flexible electrochemical biosensors based on two-dimensional materials for the clinical analysis and wearable biosensing devices, as well as the limitations and prospects of the these electrochemical flexible/wearable biosensors.Graphical abstract.

Keywords: 2D materials; Biosensor; Electrochemical sensors; Flexible/wearable sensors.

Fig. 1

Classification of wearable biosensors

Fig. 2

Different kinds of glucose sensors based on two-dimensional materials. a Freestanding, flexible PtCo/NPG/GP electrode nonenzymatic invasive glucose biosensor [Source: reprinted from Anshun Zhao, Zhaowei Zhang, Penghui Zhang, Shuang Xiao, Lu Wang, Yue Dong, Hao Yuan, Peiwu Li, Yimin Sun, Xueliang Jiang, Fei Xiao, 3D nanoporous gold scaffold supported on graphene paper: freestanding and flexible electrode with high loading of ultrafine PtCo alloy nanoparticles for electrochemical glucose sensing, Analytica Chimica Acta, 938 (2016) 63–71,, with permission from Elsevier]. b Steps involved in the preparation of PtAu/graphene-CNT-IL/GP invasive glucose sensor developed by He et al. with inset figure amperometric response of PtAu/rGO-CNT-IL/GP compared with other electrodes and SEM image (source: reprinted from Wenshan He, Yimin Sun, Jiangbo Xi, Abduraouf Alamer Mohamed Abdurhman,Jinghua Ren, Hongwei Duan, Printing graphene-carbon nanotube-ionic liquid gel on graphene paper: towards flexible electrodes with efficient loading of PtAu alloy nanoparticles for electrochemical sensing of blood glucose, Analytica Chimica Acta, 903 (2016) 61–68, with permission from Elsevier). c Diagram showing the design of Pt-decorated graphite stretchable sensor developed by Abellan et al. (source: reprinted from A. Abellán-Llobregat,Itthipon Jeerapan,A. Bandodkar,L. Vidal,A. Canals,J. Wang,E. Morallón- A stretchable and screen-printed electrochemical sensor for glucose determination in human perspiration, Biosensors and Bioelectronics, 91 (2017) 7, with permission from Elsevier)

Fig. 3

Different kinds of glucose sensors based on two-dimensional materials. a Fabrication process of Cu NPs-LIG composite with CV curves and the amperometric response of Cu NPs-LIG composite (source: reprinted from Yue Zhang,Na Li, Yangjun Xiang, Debo Wang, Peng Zhang, Yanyan Wang, Shan Lu, Rongqing Xu, Jiang Zhao, A flexible non-enzymatic glucose sensor based on copper nanoparticles anchored on laser-induced graphene, Carbon (2020) 506–513), with permission from Elsevier). b Schematic diagram of the manufacture of GOx/gold/MoS₂/gold nanofilm on the polymer electrode (source: reprinted from Jinho Yoona, Sang Nam Leeb, Min Kyu Shina, Hyun-Woong Kima, Hye Kyu Choia, Taek Leec, Jeong-Woo Choi- Flexible electrochemical glucose biosensor based on GOx/gold/MoS2/gold nanofilm on the polymer electrode, Biosensors and Bioelectronics, 140 (2019) 111343, with permission from Elsevier). c Diagrammatic illustration of Ti₃C₂T_x/PB based glucose/lactate and pH sensor developed by Lei et al. (Source: reprinted from Yongjiu Lei, Wenli Zhao, Yizhou Zhang, Qiu Jiang, Jr-Hau He, Antje J. Baeumner, Otto S. Wolfbeis, Zhong Lin Wang, Khaled N. Salama, and Husam N. Alshareef- A MXene-based wearable biosensor systemfor high-performance in vitro perspiration analysis, Small 2019, 1,901,190, with permission from Elsevier)

Fig. 4

Lactate-sensing mechanism and sensors based on two-dimensional materials. a Ti₃C₂T_x/PB-based glucose/lactate and pH sensor and its chronoamperometric response towards lactate sensing (source: reprinted from Yongjiu Lei, Wenli Zhao, Yizhou Zhang, Qiu Jiang, Jr-Hau He, Antje J. Baeumner,Otto S. Wolfbeis, Zhong Lin Wang, Khaled N. Salama, and Husam N. Alshareef- A MXene-based wearable biosensor system for high-performance in vitro perspiration analysis, Small 2019, 1,901,190, with permission from Elsevier). b Schematic representation of GO nanosheets embedded between the references and working electrode of the polyamide membrane. Lactate calibration dose-response in human sweat (source: reprinted from Kai-Chun Lin, Sriram Muthukumar, Shalini Prasad, Flex-GO (Flexible graphene oxide) sensor for electrochemical monitoring lactate in low-volume passive perspired human sweat, Talanta (2020), with permission from Elsevier). (c) Schematic representation of fabrication of GP-MoS₂-Cu-LOD electrode (source: reprinted from Zhengyun Wang, Shuang Dong, Mengxi Gui, Muhammad Asif, Wei Wang, Feng Wang, Hongfang Liu, Graphene paper supported MoS₂ nanocrystals monolayer with Cu submicron-buds: high-performance flexible platform for sensing in sweat, Analytical Biochemistry (2018) 82–89, with permission from Elsevier)

Fig. 5

Flexible as well as a wearable sensor for detection of small molecules like ascorbic acid, uric acid, and so on. a Fiber-based GF/NiCo₂O₄ sensor for the detection of AA, DA, and UA (source: reprinted from Weihua Cai, Jianwei Lai, Ting Lai, Haoting Xie, Jianshan Ye- Controlled functionalization of flexible graphene fibers for the simultaneous determination of ascorbic acid, dopamine and uric acid, Sensors and Actuators B: Chemical, 224 (2016)225–232, with permission from Elsevier). b Schematic fabrication procedure for preparation of MoS₂ grown on Al foil for detection of UA. (Source: reprinted from Rinky Sha,Nandimalla Vishnu, Sushmee Badhulika-MoS₂ based ultra-low-cost, flexible, non-enzymatic and non-invasive electrochemical sensor for highly selective detection of uric acid in human urine samples, Sensors and Actuators B: Chemical, 279 (2019) 53–60, with permission from Elsevier)

Fig. 6

Flexible as well as wearable sensor for detection of small molecules like ascorbic acid, uric acid, and so on. a Manufacturing of laser scribed paper board (source: reprinted from Thiago R. L. C. Paixão, Lúcio Angnes, José R. Silva, et al, Single-step reagentless laser scribing fabrication of electrochemical paper-based analytical devices, Angewandte Chemie, 129 (2017) 5, with permission from Elsevier). b LSG and Pt/LSG electrode patterns on PI sheet (Source: Reprinted from Pranati Nayak, Narendra Kurra, Chuan Xia, and Husam N. Alshareef.- Highly efficient laser scribed graphene electrodes for on-chip electrochemical sensing application, Advanced Electronic Materials, 2 (2016) 1–11, with permission from Elsevier). c Diagrammatic representation of Pt/rGO sensor fabricated by Zan et al. for detection of DA secreted by live PC 12 cells (source: reprinted from Xiaoli Zan Hongwei Bai, Chenxu Wang, Faqiong Zhao, and Hongwei Dua - Graphene paper decorated with a 2D array of dendritic platinum nanoparticles for ultrasensitive electrochemical detection of dopamine secreted by live cells-, Chemsitry, 22 (2016) 5240–5210,https://creativecommons.org/licenses/by-nc-nd/4.0/, https://chemistryeurope.onlinelibrary.wiley.com/doi/full/10.1002/chem.201504454

Fig. 7

Two-dimensional material-based flexible/wearable sensor for H₂O₂ detection. Diagrammatic representation of metal–metal oxide nanostructures developed on a freestanding graphene paper developed by Duan et al. and the corresponding amperometric response of the sensor (source: reprinted from Fei Xiao, Yuanqing Li, Xiaoli Zan, Kin Liao, Rong Xu, and Hongwei Duan- Growth of metal–metal oxide nanostructures on freestanding graphene paper for flexible biosensor, Advanced Functional Materials 22, (2012)2487–2494,, with permission from Elsevier)

Fig. 8

Two-dimensional material-based flexible/wearable sensor for H₂O₂ detection. Diagrammatic representation of fabrication H₂O₂ sensor based on the hybrid electrode of 2D Au particles on graphene paper and corresponding amperometric response of the fabricated sensor (source: reprinted from Fei Xiao, Jibin Song, Hongcai Gao, Xiaoli Zan, Rong Xu, and Hongwei Duan- Coating graphene paper with 2D-assembly of electrocatalytic nanoparticles: a modular approach towards high-performance flexible electrode, ACS Nano, 6 (2012) 100–110, Copyright (2020) American Chemical Society)

Fig. 9

Two-dimensional material-based flexible/wearable sensor for H₂O₂ detection. a Flexible microelectrode based on graphene developed by Peng et al.(Source: reprinted from Peng, Yu Lin, Deqing Justin Gooding, J. Xue, Yuhua Dai, Liming- Flexible fiber-shaped non-enzymatic sensors with a graphene-metal heterostructure based on graphene fibers decorated with gold nanosheets, Carbon (2018) 329–336, with permission from Elsevier). b Diagrammatic representation of the manufacturing of paper-based Cat-Fe₃O₄/rGO electrode and H₂O₂electrocatalytic reduction. (Source: reprinted from Kader Dağcı Kıranşan, Mine Aksoy, Ezgi Topçu- Flexible and freestanding catalase-Fe₃O₄/reduced graphene oxide paper: enzymatic hydrogen peroxide sensor applications, Materials Research Bulletin, 106(2018) 57–6

Fig. 10

Flexible as well as wearable pH sensors. a Schematic diagram of the sensor structure based on graphene/RuO₂ (Daniel Janczak, Andrzej Peplowski, Grzegorz Wroblewski, Lukasz Gorski, Elzbieta Zwierkowska, and Malgorzata Jakubowska- Investigations of printed flexible pH sensing materials based on graphene platelets and submicron RuO₂ powders, Journal of Sensors (2017)1–7, Copyright © 2017 Daniel Janczak et al. b Flexible PGM based sensor, its pH sensing performance and stability (reproduced with permission from Z. Tehrani1, S.P. Whelan1, A B Mostert, J V Paulin, M Ali1, E. Daghigh Ahmadi1, C F O Graeff, O J Guy and D T Gethin- Printable and flexible graphene pH sensors utilizing thin film melanin for physiological applications, 2D Mater. In (2020),10.1088/2053-1583/ab72d5, https://creativecommons.org/licences/by/3.0

Fig. 11

a Fabrication and functionalization of AJP graphene IDE sensor, which includes aerosol jet printing of graphene in PI substrate, thermal annealing process to generate oxygen-rich species on the graphene IDE sensor, immobilization of desired antibodies on the graphene surface, and covering of unfunctionalized areas of the graphene IDE sensor using a blocking agent to maintain the selectivity. b Non-specific adsorption test of AJP graphene IDE modified with histamine antibody against other interfering protein molecules usually present in food samples, which can be used as blocking agents that can interfere with the antibody activity. c Nyquist plots for different concentrations of histamine in fish broth sample and d calibration plot of change in charge transfer resistance v/s histamine concentrations in fish broth sample. (Source: reprinted from Parate K, Pola CC, Rangnekar S V., Mendivelso-Perez DL, Smith EA, Hersam MC. Aerosol-jet-printed graphene electrochemical histamine sensors for food safety monitoring. 2D Mater. 2020(1–13);7)

Fig. 12

Photographs of the a fabrication of graphene films using the centrifugal vacuum evaporation and b fabrication of a three-electrode system of CV with graphene film as a working electrode. c Schematic image of the fabricated immunosensor based on graphene film for the detection of rotavirus. d CV of the bare graphene electrode, G/Ab, G/Ab/rotavirus (10⁵ pfu/mL) and G/Ab/variola virus used as a negative control. (Source: reprinted from Liu F, Choi K S, Park T J, Lee S Y, Seo T S. Graphene-based electrochemical biosensor for pathogenic virus detection. Biochip J. 2011;5:123–128)

Fig. 13

a Schematic image of the fabrication and functionalization of the AJP graphene in IDE pattern, which includes the formulation of graphene ink for aerosol printing, printing of graphene ink on PI substrate, immobilization of antibodies on the functionalized graphene surface, and the covering of a surface with blocking agent to prevent non-specific adsorption during biosensing. The detection of b IL-10 and c IFN-γ using the AJP graphene IDE sensors, the photograph of the bendable graphene IDE sensor, is shown in the inset of c (source: reprinted from Parate K, Rangnekar S V, Jing D, Mendivelso-P D L, Ding S, Secor EB, et al. Aerosol-jet-printed graphene immunosensor for label-free cytokine monitoring in serum. ACS Appl Mater Interfaces. 2020;12:8592–603, Copyright @2020,ACS)

Fig. 14

a Schematic representation of the fabrication of flexible immunosensor (gp120 Ab/Cys/Au/MoS₂/Au) nanolayer deposited on the PET substrate through spin coating for the detection of gp120 antigen. b SEM image of the Au/MoS₂/Au nanolayer on PET. c Selectivity bar diagram of gp120 (Ab)/Cys/Au/MoS₂/Au nanolayer on flexible PET substrate to different types of antigens and proteins such as Hb, Mb, PSA, and Trx in PBS solution. d Square wave voltammetry (SWV) results from the detection of gp120 antigen in human serum with concentration range between 0.1 and 10 pg/mL. e Flexure plots of Au sputter-coated PET, Au/MoS₂/Au on the flexible PET substrate, conventional electrode (source: reprinted from Shin M, Yoon J, Yi C, Lee T, Choi JW. Flexible HIV-1 biosensor based on the au/MoS₂ nanoparticles/au nanolayer on the PET substrate. Nanomaterials.2019; 9:1–12)

Fig. 15

a Schematic representation for the fabrication of nanobioprobes via the coimmobilization of antibody and HRP on to monodispersed silica NPs and assay procedure utilized to synthesize microfluidic paper-based electrochemical immunodevice (AFP was given as an example) and b electrocatalytic currents detected for the different antigens on the different working electrodes (source: reprinted from Wu Y, Xue P, Kang Y, Hui KM. Paper-based microfluidic electrochemical immunodevice integrated with nanobioprobes onto graphene film for ultrasensitive multiplexed detection of cancer biomarkers. Anal Chem. 2013;85:8661–8, copyright@2013,ACS)

Fig. 16

Schematic representation for the preparation of NH₂-G/Thi/AuNPs nanocomposites and immune assay protocol for a antigen CEA and b CA125; c DPV responses of immunosensor for the detection of CEA in clinical serum sample with different concentrations; d photographs of the WE, REF, and counter electrode after cutting (source: reprinted from Wang Y, Xu H, Luo J, Liu J, Wang L, Fan YA. novel label-free microfluidic paper-based immunosensor for highly sensitive electrochemical detection of carcinoembryonic antigen. Biosens Bioelectron.2016;83:319–26, with permission from Elsevier). e DPV responses of immunosensor for the detection of CA 125 with different concentrations. f Photograph of immunosensor with silver pad for the detection of CA 125 (source: reprinted from Fan Y, Shi S, Ma J, Guo Y. A paper-based electrochemical immunosensor with reduced graphene oxide/thionine/gold nanoparticles nanocomposites modification for the detection of cancer antigen 125. Biosens Bioelectron. 2019;135:1–7, with permission from Elsevier)

Fig. 17

Schematic demonstration for a the design and fabrication of ePAD, b overall preparation of impedimetric immunosensor including immobilization step for the detection of ferritin and DPV response of sensor with and without ferritin. (Source: reprinted from Boonkaew S, Teengam P, Jampasa S, Rengpipat S, Siangproh W, Chailapakul O. Cost-effective paper-based electrochemical immunosensor using a label-free assay for sensitive detection of ferritin. Analyst. 2020;145:5019–5026, with permission from RSC). b The complete fabrication process including rGOP fabrication, AuNP deposition, and modification using biotin–streptavidin, antibody immobilization, and E. coli detection of the rGOP-based impedimetricimmunosensor, d plot for the relative response of E. coli against various bacteria with a photograph of rGOP in the inset, e the impedance response of rGOP-based immunosensor v/s bending numbers for the detection of E. coli O157:H7 (1.5 × 10⁵ cfu mL⁻¹). (Source: reprinted from Wang Y, Ping J, Ye Z, Wu J, Ying Y. Impedimetric immunosensor based on gold nanoparticles modified graphene paper for label-free detection of Escherichia coli O157: H7. Biosens Bioelectron. 2013;49:492–498,with permission from Elsevier). f Impedimetric response of TR-GO modified DEP electrode surface for the detection of IgG (signal as R_{ct anti-IgG}) (source: reprinted from Loo AH, Bonanni A, Ambrosi A, Poh HL, Pumera M (2012) Impedimetric immunoglobulin G immunosensor based on chemically modified graphenes. Nanoscale 4:921–925, with permiion from RSC)

Fig. 18

a Illustration for the presumed cortisol transdermal sweat monitoring prototype device. b SEM images of polyamide substrate before and after MoS₂ coating. c Schematic representation of the prepared MoS₂-based cortisol sensor d EDAX spectra. Source: Kinnamon, David, Ghanta, Ramesh Lin, Kai Chun Muthukumar, Sriram Prasad, Shalini- Portable biosensor for monitoring cortisol in low-volume perspired human sweat, Scientific Reports,7(2017),1–13,10.1038/s41598-017-13684-7, http://creativecommons.org/licenses/by/4.0/