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A Stretchable and Photocatalytically Renewable Electrochemical Sensor Based on Sandwich Nanonetworks for Real-time Monitoring of Cells Ya-Wen Wang, Yan-Ling Liu, Jiaquan Xu, Yu Qin, and Wei-Hua Huang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01396 • Publication Date (Web): 25 Apr 2018 Downloaded from http://pubs.acs.org on April 25, 2018

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Analytical Chemistry

A Stretchable and Photocatalytically Renewable Electrochemical Sensor Based on Sandwich Nanonetworks for Real-time Monitoring of Cells Ya-Wen Wang,† Yan-Ling Liu,† Jia-Quan Xu, Yu Qin, Wei-Hua Huang* Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China * Email: [email protected], Tel: +86-27-68752149 ABSTRACT: Stretchable electrochemical (EC) sensors have broad prospects in real-time monitoring of living cells and tissues owing to their excellent elasticity and deformability. However, the redox reaction products and cell secretions are easily adsorbed on the electrode, resulting in sensor fouling and passivation. Herein, we developed a stretchable and photocatalytically renewable EC sensor based on Au nanotubes (NTs) and TiO2 nanowires (NWs) sandwich nanonetworks. The external Au NTs are used for EC sensing, and internal TiO2 NWs provide photocatalytic performance to degrade contaminants, which endows the sensor with excellent EC performance, high photocatalytic activity and favorable mechanical tensile property. This allows highly sensitive recycling monitoring of NO released from endothelial cells and 5-HT released from mast cells under their stretching states in real time, therefore providing a promising tool to unravel elastic and mechanically sensitive cells, tissues and organs. Recently, stretchable sensors have made great advances and shown extensive applications in various fields,1-4 such as wearable electronics, e-skins, and transistors owing to their elasticity and deformability. In particular, flexible and stretchable electrochemical (EC) sensors, as a unique class of stretchable devices capable of providing chemical information, play a significant role in health monitoring and cell measurements.5-12 So far, most of these EC sensors are constructed based on engineered one-dimension (1D) nanomaterials (e.g., carbon nanotubes and metal nanotubes), and have been used as sensing platform for cell culture and mechanotransduction monitoring,7 or perspiration analysis.12 However, these sensors are easily to be fouled and passivated by cell secretion or sweat metabolites during the detection,13, 14 and the high specific surface area of nanomaterials would further accelerate the adsorption speed and capacity on the nano-structures. This causes serious fouling on the sensing interface and sharply decreases stability of EC response, which severely affects measurement accuracy and also restricts sensor reutilization. Nowadays, there are two major emerging methods in promoting stability and renewability of rigid EC sensors, including preventing fouling of the electrode by chemical modification of anti-aggregation or anti-adsorption molecules on the electrode, and removing the pollutant by physical and chemical methods under harsh condition.15-17 But these methods can’t fundamentally eliminate contaminant from the electrode or even seriously damage the micro/nano-structure of the electrode surface, and are not appropriate for nanomaterial-based stretchable EC sensors. Recently, an effective method was reported based on photocatalytic degradation to construct renewable EC sensors, and the core was that photocatalyst could produce active oxygen radicals under ultraviolet irradiation to degrade organic pollutant to CO2 and H2O without altering the surface morphology and structure.18, 19 In this respect, introduc-

ing photocatalyst into stretchable sensors will provide a convenient, efficient, and damage-free approach to construct stretchable EC sensors with photocatalytically cleaning property. Nevertheless, despite the excellent photocatalytic capability of semiconductor nano-photocatalyst, such as TiO2, ZnO and CdS, there is still a big challenge to fabricate stretchable EC sensors with these photocatalytic materials, due to low conductivity of the photocatalyst and detachment of common photocatalyst (usually functions in the form of small nanoparticles) from the electrode during mechanical stretching. This brings poor EC sensing performance and insufficient stability to stretchable sensors, and also explains why no stretchable sensor with photocatalytic cleaning property has been reported so far. Percolation networks of 1D nanomaterials were considered as the best materials of stretchable devices because they will rotate and slide against each other to accommodate the strain.20 Herein, in view of the excellent photocatalysis but poor conductivity of TiO2 nanowires (NWs), 21, 22 and inspired by excellent EC activity and outstanding mechanical tensile property of Au NTs network revealed by our previous work,10 TiO2 NWs were intercalated into Au NTs networks to construct a stretchable and photocatalytically renewable EC sensor. In this Au NTs/TiO2 NWs/Au NTs sandwich structure, the top and bottom layered Au NTs networks are served as electrode sensing interface, and the interlayer TiO2 NWs recover the EC activity by photocatalytically cleaning the contaminants on the sensor. This endows this sensor with excellent photocatalytic cleaning property, meanwhile perfectly maintains the outstanding EC performance and desirable mechanical stability of Au NTs networks. With cells cultured thereon, recycling monitoring of NO release from endothelial cells and 5-HT release from mast cells were successfully achieved by this renewable sensor both in their stretching-free and stretching states.

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Figure 1. a) Scheme of fabrication of stretchable Au NTs/TiO2 NWs/Au NTs/PDMS film. I) TiO2 NWs solution was spin on the Ag NWs/PDMS film. II) Ag NWs solution was again spin on the TiO2 NWs/Ag NWs/PDMS film. III) Ag NWs/TiO2 NWs/Ag NWs/PDMS film was under a mild galvanic displacement of sacrificial Ag NWs. IV) Au NTs/TiO2 NWs/Au NTs/PDMS film was used for cell culture and detection under stretch state. V) The electrode was fouled after the cell was detached. VI) The fouled electrode recovered by photocatalytic cleaning under UV light irradiation. b-e) SEM image (b) and EDX mapping (c-e) of Au NTs/TiO2 NWs/Au NTs nanonetworks. f) Schematic diagram of the sandwich structure.

The preparation of Au NTs/TiO2 NWs/Au NTs electrode is illustrated in Figure 1a. First, Ag NWs (D = 35-45 nm, L = 20 µm), TiO2 NWs (D = 200 nm, L = 10 µm), and Ag NWs were spin on poly-dopamine (PDA) treated PDMS in turn to get Ag NWs/TiO2 NWs/Ag NWs/PDMS film in which PDA was used to increase the adhesion between Ag NWs and PDMS film. Then Au NTs/TiO2 NWs/Au NTs/PDMS film was obtained by in situ galvanic displacement of sacrificial Ag NWs.10 SEM image (Figure 1b) shows that the thicker NWs are in the interlayer and the thinner NTs are on the top and bottom of the composite structure respectively. In addition, EDX mapping (Figure 1c, d, e) of the composite materials displays that the thinner NTs are composited of Au element and the thicker NWs are composited of Ti element. These results reveal that Au NTs and TiO2 NWs were uniformly distributed on PDMS film to successfully form a sandwich Au NTs/TiO2 NWs/Au NTs network structure (Figure 1f). Further optimization of Au NTs/TiO2 NWs mass ratio was performed by controlling the spinning times of TiO2 NWs, and both high photocatalytic activity (percentage of signal recovery ≥ 95%) and excellent EC sensing performance could be simultaneously achieved on the sandwich nanonetworks (Figure S1). For comparison, other two structures based on Au NTs and TiO2 NWs were also constructed, but the low conductivity of top layer TiO2 NWs brought poor electrochemical activity for TiO2 NWs/Au NTs/PDMS film. The Au NTs/TiO2 NWs/PDMS film had good electrochemical activity, but the resistance increased dramatically under tensile stress owing to the weak adhesion between TiO2 NWs and PDA treated PDMS film. Conversely, these results further proved the elegant design and satisfactory overall performance of the sandwich structure. To test the flexibility of the sandwich structure, Au NTs/TiO2 NWs/Au NTs/PDMS film was wrapped on cylindrical objects with different radius of curvature and folded in half (Figure S2a). There was no significant change in the relative resistance (∆R/R0) when the bending radii was as small as 0.5 mm. As for stretchability (Figure S2b), ∆R/R0 increased no more than 70% even though it was under a maximum strain of 50%. This can be account for that the randomly distributed Au

NTs and TiO2 NWs inside the networks can rotate and slide against each other to accommodate the strain. Cyclic voltammograms (CVs) in K3[Fe(CN)6] of the sandwich structure bended different times with radii of curvature 1mm (Figure 2a) and stretched to different tensile strains (Figure 2b) show that the as-prepared electrode possessed relatively high stability against mechanical deformation. 5-hydroxytryptamine (5-HT) was used as a model passivation molecule to test the renewable performance of the electrode, since it can cause a dramatic drop of EC performance by accumulation of electro-inactive oxidation product of 5-HT on the electrode surface.18, 23, 24 Compared to the original electrode, the redox current of K3[Fe(CN)6] on the electrode after 5-HT oxidation was sharply decreased, but the sensitivity can be recovered efficiently after UV light (12 mW cm2 ) irradiation for 1 h (Figure 2c) with a recovery percentage more than 90 %. To investigate the renewable performance of the electrode fouled by bio-macromolecules, PLL, CCM (cell culture medium) and collagen, which are easily absorbed on the electrode surface in cell culture and detection were used as passivation media. Compared to the weak signals on fouled electrodes, the EC response recovered above 90% after UV irradiation for 1 h (Figure S3a-c), and Figure 2d shows that the electrode still retained high photocatalytically renewable activity after recycling for 3 times. Furthermore, fluorescent and SEM imaging also demonstrate that the adsorbed proteins which are difficult to be completely washed out by water or buffer solution can be efficiently eliminated after UV irradiation (Figure S4). These results indicate that the interlayered TiO2 NWs endow this stretchable sensor with excellent renewable performance. To test the EC performance of the sandwich structured electrode, NO was priorly chosen as probe molecule because NO is an important messengers that plays vital roles in physiological process, especially in response to mechanical stimuli of cells and tissues.7, 25 The electrode displayed excellent EC behavior to NO oxidation, and amperometric response to 5 nmol·L−1 NO (Figure 2e) can be obviously observed, and the detection limit was calculated to be about 2.2 nmol·L−1 (S/N =

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Analytical Chemistry Arg (Figure 3b, black line), verifying that the increase in amperometric current was evoked by NO release. After cell culture and detection, amperometric results showed that the electrode had no obvious response to both NO solution (Figure S7) and NO release from HUVECs (inset of Figure 3b), due to the electrode passivation by proteins in culture medium and cell secretions. After the electrode was irradiated by UV light for 1 h, the EC sensing performance could be efficiently recovered, further demonstrating the excellent renewable ability of the sensor. To test the ability of the sandwich structured electrode as a stretchable and renewable EC sensor, HUVECs were cultured on the electrode (Figure S8) which was then stretched to 10% to induce cell stretching. NO released from stretched HUVECs was also distinctly observed when cells were stimulated with L-Arg (Figure 3c, black line). Subsequently, the electrode was released to initial state from stretching state and cells were detached from the electrode. After UV irradiation, HUVECs culture and NO released from stretched HUVECs were again successfully achieved with comparable performance to the original electrode (Figure 3c, red line). These results demonstrate the strong capability of this electrode as a stretchable and renewable EC sensor for recyclable cell culture and detection. As a representative substance released by mast cells, 5-HT plays a key role in alleviating pain.28-30 It had been reported Figure 2. CVs of Au NTs/TiO2 NWs/Au NTs sandwich structured electrode obtained in K3[Fe(CN)6] after recovering from being a) bended for different times (bending radius: 1 mm) and b) stretched to different tensile strains. c) CVs in K3[Fe(CN)6] on the electrode before fouling (black line), after fouling by 5-HT (red line), and after recycling by UV light irradiation (blue line). d) Recovery efficiency of the electrode obtained for the K3[Fe(CN)6] oxidation current using three cycles. Black line, red line, blue line, and purple line represent 5-HT, PLL, CCM, and collagen. Amperometric response of the electrode to increasing concentration of e) NO at a potential of + 0.8 V and f) 5-HT at a potential of +0.35 V (vs. Ag/AgCl). The inset of e) is CVs of the electrode in the presence of 0.1 mM NO in deaerated PBS solution (red line) and in PBS solution (black line), and the inset of f) is CVs in 0.5 mM 5-HT solution (black line) and PBS solution (red line).

3). A calibration curve with the linear range from 5 nmol·L−1 to 500 nmol·L−1 was shown in Figure S5a. In addition, 5-HT was also chosen as a probe molecule to further demonstrate EC performance of the electrode, since 5-HT is usually involved in cell mechanotransduction and its oxidation products are easily absorbed on the electrode. Results showed that there was an obvious oxidation current in the inset of Figure 2f and a response of 20 nmol·L−1 5-HT could be clearly observed on the electrode with a calculated detection limit of 16 nmol·L−1 (S/N = 3). Figure S5b displayed a calibration curve with the linear range from 20 nmol·L−1 to 1000 nmol·L−1. Taken together, these EC results demonstrated excellent EC performance of the electrode. Human umbilical vascular endothelial cells (HUVECs) were then seeded on the sandwich structured electrode to investigate its capability for cell culture and EC sensing. The cells proliferated well and covered almost all over the electrode after being cultured for 72 h (Figure S6a-f). Fluorescence staining showed that the cells were almost all alive (Figure 3a), demonstrating the good biocompatibility of the composite nanomaterials. The release of NO was evoked by stimulating HUVECs with fast injecting of L-Arg26, 27 and there was an obvious amperometric signal (Figure 3b, red line). While, there were no amperometric response when L-Arg was injected into the sensor without cells (Figure 3b, blue line) or cells were stimulated by a mixture of L-NAME (NOS inhibitor) and L-

Figure 3. a) The microscopic images of the Calcein-AM (green) and PI (red) stained HUVECs cultured on Au NTs/TiO2 NWs/Au NTs sandwich structured electrode. b) Amperometric response of the electrode to NO released from unstretched HUVECs. The inset of b) represent amperometric response of fouled (black line) and recovered (red line) electrode to NO released from HUVECs. c) Amperometric response of original (black line) and renewed (red line) electrodes to NO released from stretched HUVECs. d) Amperometric response of the electrode to 5-HT released from unstretched P815 cells. e) Amperometric response of recovered (black line) and fouled electrode to 5-HT release. f) Amperometric response of original (black line) and renewed (red line) electrode to 5-HT released from P815 cells with a stretching magnitude of 10%. In c and f, the yellow dotted lines indicate the beginnings of stretching, and the purple lines indicate the endings of stretching. A potential of + 0.80 V (vs. Ag/AgCl) was applied for detection of released NO and a potential of + 0.35 V (vs. Ag/AgCl) was applied for detection of released 5-HT.

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that the degranulation of the mast cells increases when it is stimulated by mechanical force, making 5-HT levels greatly increased.31-33 Hence, P815 cells (a cell line of mastocytoma) were seeded on sandwich structured electrode, and proliferated well with high viability (Figure S9). Then 80 mM high K+ solution was used to stimulate P815 cells to release 5-HT,34 and there was a significant amperometric response (Figure 3d). Given that release of 5-HT was caused by Ca2+ influx into cells,34, 35 Cd2+ (a Ca2+ channel inhibitor) was used here to down-regulate 5-HT release. The current response decreased tremendously after cells were incubated in 100 µM Cd2+ solution for 20 min. Further considering the fact that there was no response when the sensor was stimulated without cells thereon, these combined results indicate that the increase in current was evoked by 5-HT release. Similarly, photocatalysis-induced regeneration of the sensors was investigated after EC monitoring of 5-HT release from mast cells both in their stretching-free (Figure 3e) and stretching states (Figure 3f). The results show that there were no ampere-responses to 5-HT release from P815 cells on the electrodes after cell culture and detection, owing to the electrode fouling by cell secretions and 5-HT oxidation product. After UV irradiation, the electrochemical performance could be efficiently recovered. This enabled recyclable detection of 5-HT release from both unstretched (black line in Figure 3e) and stretched mast cells (red line in Figure 3f), and also strongly support the great potential of such stretchable and renewable EC sensor in cell and tissue detections. In summary, the stretchable EC sensor was endowed with photocatalytic cleaning property for the first time, by an ingenious combination of Au NTs and TiO2 NWs. In the stretchable sandwich structure, Au NTs rendered excellent and stable EC sensing performance, and TiO2 NWs provided outstanding photocatalytically renewable ability. This allowed successful realtime recycling monitoring of both NO released from HUVECs and 5-HT released by P815 cells under their stretching state, indicating the prospect of this stretchable and renewable sensor for recyclable monitoring of cells and tissues. Importantly, our strategy by introducing 1D nano-photocatalysts into stretchable sensor provides a versatile and efficient way to promote the biomedical applications of stretchable devices in the future, such as in vivo cell and tissue monitoring, body fluid analysis and so on.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental methods and materials, optimization of electrode, flexible and renewable characterization of the electrode, cell culture and image

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. † These authors contributed equally to this work.

Notes

This work was supported by the National Natural Science Foundation of China (Nos. 21725504, 21675121, 21721005, 21575110), the Open Funds of the State Key Laboratory of Electroanalytical Chemistry (SKLEAC201706), and the China Postdoctoral Science Foundation (No. 2017M620329).

REFERENCES (1) Rogers, J. A.; Someya, T.; Huang, Y. Science 2010, 327, 1603-1607. (2) Hammock, M. L.; Chortos, A.; Tee, B. C. K.; Tok, J. B. H.; Bao, Z. A. Adv. Mater. 2013, 25, 5997-6037. (3) Qian, Y.; Zhang, X. W.; Xie, L. H.; Qi, D. P.; Chandran, B. K.; Chen, X. D.; Huang, W. Adv. Mater. 2016, 28, 9243-9265. (4) Root, S. E.; Savagatrup, S.; Printz, A. D.; Rodriquez, D.; Lipomi, D. J. Chem. Rev. 2017, 117, 6467-6499. (5) Yang, Y. L.; Chuang, M. C.; Lou, S. L.; Wang, J. Analyst 2010, 135, 12301234. (6) Windmiller, J. R.; Wang, J. Electroanalysis 2013, 25, 29-46. (7) Liu, Y. L.; Qin, Y.; Jin, Z. H.; Hu, X. B.; Chen, M. M.; Liu, R.; Amatore, C.; Huang, W. H. Angew. Chem. Int. Ed. 2017, 56, 9454-9458. (8) Bandodkar, A. J.; Nuñez-Flores, R.; Jia, W.; Wang, J. Adv. Mater. 2015, 27, 3060-3065. (9) Bandodkar, A. J.; Jeerapan, I.; You, J. M.; Nuñez-Flores, R.; Wang, J. Nano Lett. 2016, 16, 721-727. (10) Liu, Y. L.; Jin, Z. H.; Liu, Y. H.; Hu, X. B.; Qin, Y.; Xu, J. Q.; Fan, C. F.; Huang, W. H. Angew. Chem. Int. Ed. 2016, 55, 4537-4541. (11) Jin, Z. H.; Liu, Y. L.; Chen, J. J.; Cai, S. L.; Xu, J. Q.; Huang, W. H. Anal. Chem. 2017, 89, 2032-2038. (12) Gao, W.; Emaminejad, S.; Nyein, H. Y. Y.; Challa, S.; Chen, K.; Peck, A.; Fahad, H. M.; Ota, H.; Shiraki, H.; Kiriya, D.; Lien, D.-H.; Brooks, G. A.; Davis, R. W.; Javey, A. Nature 2016, 529, 509-513. (13) Geise, R. J.; Adams, J. M.; Barone, N. J.; Yacynych, A. M. Biosens Bioelectron. 1991, 6, 151-160. (14) Yang, X.; Kirsch, J.; Fergus, J.; Simonion, A. Electrochim. Acta. 2013, 94, 259-268. (15) Bhalla, V.; Carrara, S.; Stagni, C.; Samori, B. Thin Solid Films 2010, 518, 3360-3366. (16) Liu, X.; Xiao, T.; Wu, F.; Shen, M.; Zhang, M.; Yu, H.; Mao, L. Angew. Chem. Int. Ed. 2017, 56, 11802-11806. (17) Zhu, X.; Chen, Y.; Feng, C.; Wang, W.; Bo, B.; Ren, R.; Li, G. Anal. Chem. 2017, 89, 4131-4138. (18) Hu, L.; Huo, K.; Chen, R.; Gao, B.; Fu, J.; Chu, P. K. Anal. Chem. 2011, 83, 8138-8144. (19) Xu, J. Q.; Liu, Y. L.; Wang, Q.; Duo, H. H.; Zhang, X. W.; Li, Y. T.; Huang, W. H. Angew. Chem. Int. Ed. 2015, 54, 14402-14406. (20) Yao, S.; Zhu, Y. Adv. Mater. 2015, 27, 1480-1511. (21) Feng, X. J.; Zhu, K.; Frank, A. J.; Grimes, C. A.; Mallouk, T. E. Angew. Chem. Int. Ed. 2012, 51, 2727-2730. (22) Pu, Y. C.; Wang, G.; Chang, K. D.; Ling, Y.; Lin, Y. K.; Fitzmorris, B. C.; Liu, C. M.; Lu, X.; Tong, Y.; Zhang, J. Z.; Hsu, Y. J.; Li, Y. Nano Lett. 2013, 13, 3817-3823. (23) Jackson, B. P.; Dietz, S. M.; Wightman, R. M. Anal. Chem. 1995, 67, 11151120. (24) Pihel, K.; Hsieh, S.; Jorgenson, J. W.; Wightman, R. M. Anal. Chem. 1995, 67, 4514-4521. (25) Hu, Z. Q.; Xiong, Y.; Han, X. F.; Geng, C. Y.; Jiang, B. B.; Huo, Y. Q.; Luo, J. C. Plos One 2013, 8, e71359. (26) Palmer, R. M. J.; Ashton, D. S.; Moncada, S. Nature 1988, 333, 664– 666. (27) Ridnour, L. A.; Isenberg, J. S.; Espey, M. G.; Thomas, D. D.; Roberts, D. D.; Wink, D. A. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 13147-13152. (28) Theoharides, T. C. Perspect. Biol. Med., 1983, 26, 672-675. (29) Minogiannis, P.; El-Mansoury, M.; Betances, J. A.; Sant, G. R.; Theoharides, T. C. Int. J. Immunopharmaco. 1998, 20, 553-563. (30) Oliveira, S. M.; Drewes, C. C.; Silva, C. R.; Trevisan, G.; Boschen, S. L.; Moreira, C. G.; Cabrini, D. A.; Cunha, C. D.; Ferreira, J. Eur. J. Pharmacol. 2011, 672, 88-95. (31) Metcalfe, D. D.; Baram, D.; Mekori, Y. A. Physiol. Rev. 1997, 77, 10331079. (32) Scott, A.; Danielson, P.; Abraham, T.; Fong, G.; Sampaio, A. V.; Underhill, T. M. J. Musculoskelet. Neuronal Interact., 2011, 11, 124-132. (33) Shi, Y.; Qi, L.; Wang, J.; Xu, M. S.; Zhang, D.; Wu, L. Y.; Wu, H. G. World J. Gastroenterol. 2011, 17, 3733-3738. (34) Li, Y. T.; Tang, L. N.; Ning, Y.; Shu, Q.; Liang, F. X.; Wang, H.; Zhang, G. J. Sci. Rep. 2016, 6: 28018. (35) Kim, T. D.; Eddlestone, G. T.; Mahmoud, S. F.; Kuchtey, J.; Fewtrell, C. J. Biol. Chem. 1997, 272, 31225-31229.

The authors declare no competing financial interest.

ACKNOWLEDGMENT

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