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An In Vitro Electric Field Exposure Device with Real-Time Cell Impedance Sensing

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Abstract

Electric fields are known to affect cell growth and viability. Using electric field treatments for cancer therapy and regenerative medicine is actively researched because of the noninvasive, efficient and low-price nature of electric field exposure. To monitor the effects of such treatments on cells, chemical assays are conventionally used after treatment which are usually time-consuming, expensive, offline and destructive to the sample under study. Electric cell impedance sensing has recently been shown to provide comparable monitoring capability for chemical treatments nondestructively. Here, we report a novel device that provides electric field treatment with online cell-substrate impedance sensing, both combined through a single microelectrode array. Design, numerical simulations and dosimetry, microfabrication and in vitro tests are described, and the electronic systems realized to flexibly control electric field exposure amplitude and timings are explained. The fast, nondestructive performance of the resulting stimulus–ECIS system is successfully confirmed in comparison with chemical assays. Also a real experiment is reported showing the prevention of cancerous cell growth by 26% with exposure to a weak EF at 150 kHz frequency. The fast, online response of the device signifies its potential to become a popular standard setup for experimental cell research.

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References

  • Abdolahad M, Taghinejad M, Taghinejad H, Janmaleki M, Mohajerzadeh S (2012) A vertically aligned carbon nanotube-based impedance sensing biosensor for rapid and high sensitive detection of cancer cells. Lab Chip 12:1183–1190

    Google Scholar 

  • Ahadian S, Ramón-Azcón J, Ostrovidov S, Camci-Unal G, Hosseini V, Kaji H, Ino K, Shiku H, Khademhosseini A, Matsue T (2012) Interdigitated array of Pt electrodes for electrical stimulation and engineering of aligned muscle tissue. Lab Chip 12:3491

    Google Scholar 

  • Arndt S, Seebach J, Psathaki K, Galla H, Wegener J (2004) Bioelectrical impedance assay to monitor changes in cell shape during apoptosis. Biosens Bioelectron 19:583–594

    Google Scholar 

  • Bagnaninchi PO, Drummond N (2011) Real-time label-free monitoring of adipose-derived stem cell differentiation with electric cell-substrate impedance sensing. Proc Natl Acad Sci USA 108:6462–6467

    Google Scholar 

  • Banks TA, Luckman PSB, Frith JE, Cooper-White JJ (2015) Effects of electric fields on human mesenchymal stem cell behaviour and morphology using a novel multichannel device. Integr Biol 7:693–712

    Google Scholar 

  • Bieberich E, Guiseppi-Elie A (2004) Neuronal differentiation and synapse formation of PC12 and embryonic stem cells on interdigitated microelectrode arrays: contact structures for neuron-to-electrode signal transmission (NEST). Biosens Bioelectron 19:923–931

    Google Scholar 

  • Binh T, Cho S, Min J (2013) Hydrogel-based diffusion chip with Electric Cell-substrate Impedance Sensing (ECIS) integration for cell viability assay and drug toxicity screening. Biosens Bioelectron 50:453–459

    Google Scholar 

  • Cai S, Bodle JC, Mathieu PS, Amos A, Hamouda M, Bernacki S, McCarty G, Loboa EG (2017) Primary cilia are sensors of electrical field stimulation to induce osteogenesis of human adipose-derived stem cells. FASEB J 31:346–355

    Google Scholar 

  • Cucullo L, Dini G, Hallene KL, Fazio V, Ilkanich EV, Igboechi C, Kight KM, Agarwal MK, Garrity-Moses M, Janigro D (2005) Very low intensity alternating current decreases cell proliferation. Glia 51:65–72

    Google Scholar 

  • Dan Z, Zu-Hui W, Ji-Yao C, Lu-Wei Z (2013) The effects of electrical stimuli on calcium change and histamine release in rat basophilic leukemia mast cells. Chin Phys Lett 30(6):068702

    Google Scholar 

  • Gamal W, Borooah S, Smith S, Underwood I, Srsen V, Chandran S, Bagnaninchi PO, Dhillon B (2015) Real-time quantitative monitoring of hiPSC-based model of macular degeneration on Electric Cell-substrate Impedance Sensing microelectrodes. Biosens Bioelectron 71:445–455

    Google Scholar 

  • Hondroulis E, Melnick SJ, Zhang X (2013) Electrical field manipulation of cancer cell behavior monitored by whole cell biosensing device. Biomed Microdevices 15(4):657–663

    Google Scholar 

  • Janigro D, Perju C, Fazio V, Hallene K, Dini G, Agarwal MK, Cucullo L (2006) Alternating current electrical stimulation enhanced chemotherapy: a novel strategy to bypass multidrug resistance in tumor cells. BMC Cancer 6:1–12

    Google Scholar 

  • Jinchuang Z, Hao Z, Wenli F, Xingxing Z (2016) Design and implementation of multi-parameter portable biological information measurement system. 2016 Chinese Control and Decision Conference (CCDC), Yinchuan, pp 3762–3765

  • Keese CR, Bhawe K, Wegener J, Giaever I (2002) Real-time impedance assay to follow the invasive activities of metastatic cells in culture. Biotechniques 33:842–850

    Google Scholar 

  • Keese CR, Wegener J, Walker SR, Giaever I (2004) Electrical wound-healing assay for cells in vitro. Proc Natl Acad Sci USA 101:1554–1559

    Google Scholar 

  • Kirson ED, Dbalý V, Tovaryš F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y (2007) Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci 104:10152–10157

    Google Scholar 

  • Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y (2009) Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis 26:633–640

    Google Scholar 

  • Koreckij TD, Hill C, Azure L, Nguyen H, Kunz LL, Azure A, Corey E, Lange P, Vessella RL (2010) Low dose, alternating electric current inhibits growth of prostate cancer. Prostate 70:529–539

    Google Scholar 

  • Lee GH, Pyun J-C, Cho S (2014) Electrical impedance characterization of cell growth on interdigitated microelectrode array. J Nanosci Nanotechnol 14:8342–8346

    Google Scholar 

  • Lim J-H, McCullen SD, Piedrahita JA, Loboa EG, Olby NJ (2013) Alternating current electric fields of varying frequencies: effects on proliferation and differentiation of porcine neural progenitor cells. Cell Reprogram 15:405–412

    Google Scholar 

  • Mamouni J, Liju Y (2011) Interdigitated microelectrode-based microchip for electrical impedance spectroscopic study of oral cancer cells. Biomed Microdevices 13(6):1075–1088

    Google Scholar 

  • McCullen SD, McQuilling JP, Grossfeld RM, Lubischer JL, Clarke LI, Loboa EG (2010) Application of low-frequency alternating current electric fields via interdigitated electrodes: effects on cellular viability, cytoplasmic calcium, and osteogenic differentiation of human adipose-derived stem cells. Tissue Eng Part C Methods 16:1377–1386

    Google Scholar 

  • Mohamadou Y, Oh TI, Wi H, Sohal H, Farooq A, Woo EJ, McEwan AL (2012) Performance evaluation of wideband bio-impedance spectroscopy using constant voltage source and constant current source. Meas Sci Technol 23:105703

    Google Scholar 

  • Pajkossy T, Kolb DM (2001) Double layer capacitance of Pt (111) single crystal electrodes. Electrochim Acta 46:3063–3071

    Google Scholar 

  • Piasecki T, Chabowski K, Nitsch K (2016) Design, calibration and tests of versatile low frequency impedance analyser based on ARM microcontroller. Meas J Int Meas Confed 91:155–161

    Google Scholar 

  • Robinson KR (1985) The responses of cells to electrical fields: a review. J Cell Biol 101:2023–2027

    Google Scholar 

  • Sarro E, Lecina M, Fontova A, Sola C, Godia F, Cairo JJ, Bragos R (2012) Electrical impedance spectroscopy measurements using a four-electrode configuration improve on-line monitoring of cell concentration in adherent animal cell cultures. Biosens Bioelectron 31:257–263

    Google Scholar 

  • Stolwijk JA, Hartmann C, Balani P, Albermann S, Keese CR, Giaever I, Wegener J (2011) Impedance analysis of adherent cells after in situ electroporation: non-invasive monitoring during intracellular manipulations. Biosens Bioelectron 26:4720–4727

    Google Scholar 

  • Tran TB, Baek C, Min J (2016) Electric cell-substrate impedance sensing (ECIS) with microelectrode arrays for investigation of cancer cell–fibroblasts interaction. PLoS ONE 11:1–12

    Google Scholar 

  • Trebbels D, Woelki D, Zengerle R (2010) High precision phase measurement technique for cell impedance spectroscopy. J Phys: Conf Ser 224(1):012159 (IOP Publishing)

    Google Scholar 

  • Wang L, Wang H, Wang L, Mitchelson K, Yu Z, Cheng J (2008) Analysis of the sensitivity and frequency characteristics of coplanar electrical cell-substrate impedance sensors. Biosens Bioelectron 24:14–21

    Google Scholar 

  • Wang L, Wang L, Yin H, Xing W, Yu Z, Guo M, Cheng J (2010) Real-time, label-free monitoring of the cell cycle with a cellular impedance sensing chip. Biosens Bioelectron 25:990–995

    Google Scholar 

  • Wegener J, Keese CR, Giaever I (2000) Electric cell-substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp Cell Res 259:158–166

    Google Scholar 

  • Xiao C, Luong JHT (2003) On-line monitoring of cell growth and cytotoxicity using electric cell-substrate impedance sensing (ECIS). Biotechnol Prog 19:1000–1005

    Google Scholar 

  • Xie F, Xu Y, Wang L, Mitchelson K, Xing W, Cheng J (2012) Use of cellular electrical impedance sensing to assess in vitro cytotoxicity of anticancer drugs in a human kidney cell nephrotoxicity model. Analyst 137:1343

    Google Scholar 

  • Xu Y, Su S, Zhou C, Lu Y, Xing W (2015) Cell electroporation with a three-dimensional microelectrode array on a printed circuit board. Bioelectrochemistry 102:35–41

    Google Scholar 

  • Xu Y, Xie X, Duan Y, Wang L, Cheng Z, Cheng J (2016) A review of impedance measurements of whole cells. Biosens Bioelectron 77:824–836

    Google Scholar 

  • Yang Y, Kang M, Lu Y, Wang J, Yue J, Gao Z (2010) Design of a wideband excitation source for fast bioimpedance spectroscopy. Meas Sci Technol 22(1):013001

    Google Scholar 

  • Yang Y, Zhang F, Tao K, Wang L, Wen H, Teng Z (2015) Multi-frequency simultaneous measurement of bioimpedance spectroscopy based on a low crest factor multisine excitation. Physiol Meas 36(3):489–501. https://doi.org/10.1088/0967-3334/36/3/489

    Google Scholar 

  • Zhang B-T, Yeung SS, Liu Y, Wang H-H, Wan Y-M, Ling S-K, Zhang H-Y, Li Y-H, Yeung EW (2010) The effects of low frequency electrical stimulation on satellite cell activity in rat skeletal muscle during hindlimb suspension. BMC Cell Biol 11:87

    Google Scholar 

  • Zhang J, Li M, Kang E-T, Neoh KG (2016) Electrical stimulation of adipose-derived mesenchymal stem cells in conductive scaffolds and the roles of voltage-gated ion channels. Acta Biomater 32:46–56

    Google Scholar 

Download references

Acknowledgements

The authors wish to express gratitude to Dr. Reza Faraji-dana from the center of excellence on numerical electromagnetics and bioelectromagnetics at the University of Tehran for kind support with instrumentation during the tests. The authors have no competing interests to disclose.

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Correspondence to Mehrdad Saviz.

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Shamaee, AM., Saviz, M., Solouk, A. et al. An In Vitro Electric Field Exposure Device with Real-Time Cell Impedance Sensing. Iran J Sci Technol Trans Sci 44, 575–585 (2020). https://doi.org/10.1007/s40995-020-00861-z

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  • DOI: https://doi.org/10.1007/s40995-020-00861-z

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