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Finite element modeling to analyze TEER values across silicon nanomembranes

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Abstract

Silicon nanomembranes are ultrathin, highly permeable, optically transparent and biocompatible substrates for the construction of barrier tissue models. Trans-epithelial/endothelial electrical resistance (TEER) is often used as a non-invasive, sensitive and quantitative technique to assess barrier function. The current study characterizes the electrical behavior of devices featuring silicon nanomembranes to facilitate their application in TEER studies. In conventional practice with commercial systems, raw resistance values are multiplied by the area of the membrane supporting cell growth to normalize TEER measurements. We demonstrate that under most circumstances, this multiplication does not ‘normalize’ TEER values as is assumed, and that the assumption is worse if applied to nanomembrane chips with a limited active area. To compare the TEER values from nanomembrane devices to those obtained from conventional polymer track-etched (TE) membranes, we develop finite element models (FEM) of the electrical behavior of the two membrane systems. Using FEM and parallel cell-culture experiments on both types of membranes, we successfully model the evolution of resistance values during the growth of endothelial monolayers. Further, by exploring the relationship between the models we develop a ‘correction’ function, which when applied to nanomembrane TEER, maps to experiments on conventional TE membranes. In summary, our work advances the the utility of silicon nanomembranes as substrates for barrier tissue models by developing an interpretation of TEER values compatible with conventional systems.

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References

  • A. Acheampong, J.-L. Vincent, A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit. Care. 19(1), 251 (2015)

    Article  Google Scholar 

  • A.A. Agrawal, B. Nehilla, K. Reisig, T. Gaborski, D. Fang, C. Striemer, P. Fauchet, J. McGrath, Porous nanocrystalline silicon membranes as highly permeable and molecularly thin substrates for cell culture. Biomaterials. 31(20), 5408–17 (2010)

    Article  Google Scholar 

  • A.D. ávan der Meer, H. JungáKim, M.W. ávan der Helm, A. den Berg, Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems. Lab Chip. 15(3), 745–52 (2015)

    Article  Google Scholar 

  • K. Benson, S. Cramer, H.-J. Galla, Impedance-based cell monitoring: Barrier properties and beyond. Fluids Barriers CNS. 10(1), 5 (2013)

    Article  Google Scholar 

  • S.N. Bhatia, D.E. Ingber, Microfluidic organs-on-chips. Nat. Biotechnol. 32(8), 760–72 (2014)

    Article  Google Scholar 

  • M. Bindschadler, J.L. McGrath, Sheet migration by wounded monolayers as an emergent property of single-cell dynamics. J. Cell Sci. 120(5), 876–84 (2007)

    Article  Google Scholar 

  • M.I. Bogorad, J. DeStefano, J. Karlsson, A.D. Wong, S. Gerecht, P.C. Searson, in vitro microvessel models. Lab Chip. 15(22), 4242–55 (2015)

    Article  Google Scholar 

  • R. Booth, H. Kim, Characterization of a microfluidic in vitro model of the blood-brain barrier (μ bbb). Lab Chip. 12(10), 1784–92 (2012)

    Article  Google Scholar 

  • R. Booth, S. Noh, H. Kim, A multiple-channel, multiple-assay platform for characterization of full-range shear stress effects on vascular endothelial cells. Lab Chip. 14(11), 1880–90 (2014)

    Article  Google Scholar 

  • R.N. Carter, S.M. Casillo, A.R. Mazzocchi, J.-P.S. DesOrmeaux, J.A. Roussie, T.R. Gaborski, Ultrathin transparent membranes for cellular barrier and co-culture models. Biofabrication. 9(1), 015,019 (2017)

    Article  Google Scholar 

  • S.M. Casillo, A.P. Peredo, S.J. Perry, H.H. Chung, Gaborski T.R, Membrane pore spacing can modulate endothelial cell–substrate and cell–cell interactions. ACS Biomaterials Sci. Eng. (2017)

  • H.H. Chung, C.K. Chan, T.S. Khire, G.A. Marsh, A. Clark, R.E. Waugh, J.L. McGrath, Highly permeable silicon membranes for shear free chemotaxis and rapid cell labeling. Lab Chip. 14(14), 2456–68 (2014)

    Article  Google Scholar 

  • C. Crone, O. Christensen, Electrical resistance of a capillary endothelium. J. Gen. Physiol. 77(4), 349–71 (1981)

    Article  Google Scholar 

  • C. Crone, S. Olesen, Electrical resistance of brain microvascular endothelium. Brain Res. 241(1), 49–55 (1982)

    Article  Google Scholar 

  • L. Cucullo, M. Hossain, W. Tierney, D. Janigro, A new dynamic in vitro modular capillaries-venules modular system: cerebrovascular physiology in a box. BMC Neurosci. 14(1), 18 (2013)

    Article  Google Scholar 

  • J. DesOrmeaux, J. Winans, S. Wayson, T. Gaborski, T. Khire, C. Striemer, J. McGrath, Nanoporous silicon nitride membranes fabricated from porous nanocrystalline silicon templates. Nanoscale. 6(18), 10,798–805 (2014)

    Article  Google Scholar 

  • N.J. Douville, Y.-C. Tung, R. Li, J.D. Wang, M.E. El-Sayed, S. Takayama, Fabrication of two-layered channel system with embedded electrodes to measure resistance across epithelial and endothelial barriers. Anal. Chem. 82(6), 2505 (2010)

    Article  Google Scholar 

  • R.S. Eisenberg, E.A. Johnson, Three-dimensional electrical field problems in physiology. Prog. Biophys. Molecul. Biol. 20, 1–65 (1970)

    Article  Google Scholar 

  • N. Ferrell, R.R. Desai, A.J. Fleischman, S. Roy, H.D. Humes, W.H. Fissell, A microfluidic bioreactor with integrated transepithelial electrical resistance (teer) measurement electrodes for evaluation of renal epithelial cells. Biotechnol. Bioeng. 107(4), 707–16 (2010)

    Article  Google Scholar 

  • O. Henry, R. Villenave, M. Cronce, W. Leineweber, M. Benz, D Ingber, Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (teer) measurements of human epithelial barrier function. Lab Chip (2017)

  • D. Huh, D.C. Leslie, B.D. Matthews, J.P. Fraser, S. Jurek, G.A. Hamilton, K.S. Thorneloe, M.A. McAlexander, D.E. Ingber, A human disease model of drug toxicity–induced pulmonary edema in a lung-on-a-chip microdevice. Sci. Translat. Med. 4(159), 159ra147–159ra147 (2012)

    Article  Google Scholar 

  • R. Ishimatsu, J. Kim, P. Jing, C.C. Striemer, D.Z. Fang, P.M. Fauchet, J.L. McGrath, S. Amemiya, Ion-selective permeability of an ultrathin nanoporous silicon membrane as probed by scanning electrochemical microscopy using micropipet-supported ities tips. Anal. Chem. 82(17), 7127–34 (2010)

    Article  Google Scholar 

  • E.A. Jaffe, Cell biology of endothelial cells. Human Pathol. 18(3), 234–9 (1987)

    Article  Google Scholar 

  • D.G. Johnson, T.S. Khire, Y.L. Lyubarskaya, K.J. Smith, J.-P.S. DesOrmeaux, J.G. Taylor, T.R. Gaborski, A.A. Shestopalov, C.C. Striemer, J.L. McGrath, Ultrathin silicon membranes for wearable dialysis. Adv. Chronic Kidney Dis. 20(6), 508–15 (2013)

    Article  Google Scholar 

  • L.C. Kelley, L.L. Lohmer, E.J. Hagedorn, D.R. Sherwood, Traversing the basement membrane in vivo: A diversity of strategies. J. Cell. Biol. 204(3), 291–302 (2014)

    Article  Google Scholar 

  • H.J. Kim, D. Huh, G. Hamilton, D.E. Ingber, Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip. 12(12), 2165–74 (2012)

    Article  Google Scholar 

  • W.L. Lee, A.S. Slutsky, Sepsis and endothelial permeability. England J. Med. 363(7), 689 (2010)

    Article  Google Scholar 

  • A.R. Mazzocchi, A.J. Man, J.-P.S. DesOrmeaux, T.R. Gaborski, Porous membranes promote endothelial differentiation of adipose-derived stem cells and perivascular interactions. Cell. Mol. Bioeng. 7(3), 369–78 (2014)

    Article  Google Scholar 

  • B.J. Nehilla, N. Nataraj, T.R. Gaborski, J.L. McGrath, Endothelial vacuolization induced by highly permeable silicon membranes. Acta Biomaterialia. 10(11), 4670–7 (2014)

    Article  Google Scholar 

  • M.A.L. Pinheiro, G. Kooij, M.R. Mizee, A. Kamermans, G. Enzmann, R. Lyck, M. Schwaninger, B. Engelhardt, H.E. de Vries, Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochimica et Biophysica Acta (BBA)-Molecular Basis Disease. 1862(3), 461–71 (2016)

    Article  Google Scholar 

  • S. Ryu, J. Yoo, Y. Jang, J. Han, S.J. Yu, J. Park, S.Y. Jung, K.H. Ahn, S.G. Im, K. Char, Nanothin coculture membranes with tunable pore architecture and thermoresponsive functionality for transfer-printable stem cell-derived cardiac sheets. ACS Nano. 9(10), 10,186–202 (2015)

    Article  Google Scholar 

  • C.M. Sakolish, M.B. Esch, J.J. Hickman, M.L. Shuler, G.J. Mahler, Modeling barrier tissues in vitro: Methods, achievements, and challenges. EBioMedicine. 5, 30–9 (2016)

    Article  Google Scholar 

  • J. Seok, H.S. Warren, A.G. Cuenca, M.N. Mindrinos, H.V. Baker, W. Xu, D.R. Richards, G.P. McDonald-Smith, H. Gao, L. Hennessy, Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl. Acad. Sci. 110(9), 3507–12 (2013)

    Article  Google Scholar 

  • J. Snyder, A. Clark, D. Fang, T. Gaborski, C. Striemer, P. Fauchet, J. McGrath, An experimental and theoretical analysis of molecular separations by diffusion through ultrathin nanoporous membranes. J. Membrane Sci. 369(1), 119–29 (2011)

    Article  Google Scholar 

  • J.L. Snyder, J. Getpreecharsawas, D.Z. Fang, T.R. Gaborski, C.C. Striemer, P.M. Fauchet, D.A. Borkholder, J.L. McGrath, High-performance, low-voltage electroosmotic pumps with molecularly thin silicon nanomembranes. Proc. Nat. Acad. Sci. 110(46), 18,425–30 (2013)

    Article  Google Scholar 

  • B. Srinivasan, A.R. Kolli, M.B. Esch, H.E. Abaci, M.L. Shuler, J.J. Hickman, Teer measurement techniques for in vitro barrier model systems. J. Laborat. Autom. 20(2), 107–26 (2015)

    Article  Google Scholar 

  • C.C. Striemer, T.R. Gaborski, J.L. McGrath, P.M. Fauchet, Charge-and size-based separation of macromolecules using ultrathin silicon membranes. Nature. 445(7129), 749–53 (2007)

    Article  Google Scholar 

  • T. Sun, E.J. Swindle, J.E. Collins, J.A. Holloway, D.E. Davies, H. Morgan, On-chip epithelial barrier function assays using electrical impedance spectroscopy. Lab Chip. 10(12), 1611–7 (2010)

    Article  Google Scholar 

  • M.L. Sutherland, K.M. Fabre, D.A. Tagle, The national institutes of health microphysiological systems program focuses on a critical challenge in the drug discovery pipeline. Stem Cell Res. Therapy. 4(1), I1 (2013). https://doi.org/10.1186/scrt361

    Article  Google Scholar 

  • N. Tandon, A. Marsano, R. Maidhof, K. Numata, C. Montouri-Sorrentino, C. Cannizzaro, J. Voldman, G. Vunjak-Novakovic, Surface-patterned electrode bioreactor for electrical stimulation. Lab Chip. 10 (6), 692–700 (2010)

    Article  Google Scholar 

  • K. Tanner, Regulation of the basement membrane by epithelia generated forces. Phys. Biol. 9(6), 065,003 (2012)

    Article  MathSciNet  Google Scholar 

  • P.A. Vogel, S.T. Halpin, R.S. Martin, D.M. Spence, Microfluidic transendothelial electrical resistance measurement device that enables blood flow and postgrowth experiments. Anal. Chem. 83(11), 4296–301 (2011)

    Article  Google Scholar 

  • F.R. Walter, S. Valkai, A. Kincses, A. Petneházi, T. Czeller, S. Veszelka, P. Ormos, M.A. Deli, A. Dér, A versatile lab-on-a-chip tool for modeling biological barriers. Sens. Actuators B. 222, 1209–19 (2016)

    Article  Google Scholar 

  • Y.I. Wang, H.E. Abaci, M.L. Shuler, Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol. Bioeng. 114(1), 184–94 (2017)

    Article  Google Scholar 

  • I. Woolhouse, D. Bayley, P. Lalor, D. Adams, R. Stockley, Endothelial interactions of neutrophils under flow in chronic obstructive pulmonary disease. Europ. Respir. J. 25(4), 612–7 (2005)

    Article  Google Scholar 

  • J. Yeste, X. Illa, A. Guimerà, R. Villa, A novel strategy to monitor microfluidic in-vitro blood-brain barrier models using impedance spectroscopy. In: SPIE Microtechnologies, International Society for Optics and Photonics, pp. 95,180N–95,180N (2015)

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Acknowledgements

Authors would like to thank Dr. Henry Chung, Zachery Hulings and Tucker Bergin for their help in COMSOL modeling, and Thomas Andolsek in obtaining the TEER data for validation experiments. They also acknowledge the support of Dr. Allison Elder (Department of Environmental Medicine, University of Rochester) during the early days of this project. This work was supported by funding from the National Institutes of Health under program project grant number: 5 R01 HL125265.

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    Authors and Affiliations

    1. Biomedical Engineering, University of Rochester, Goergen Hall, Rochester, NY, 14627, USA

      Tejas S. Khire, Barrett J. Nehilla, Jirachai Getpreecharsawas, Richard E. Waugh & James L. McGrath

    2. Nexgenia Inc., 454 North 34th St., Seattle, WA, 98103, USA

      Barrett J. Nehilla

    3. Department of Physics, Clarkson University, 277 Science Center, Potsdam, NY, 13699, USA

      Maria E. Gracheva

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    1. Tejas S. Khire
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    6. James L. McGrath
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    Correspondence to James L. McGrath.

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    Funds supporting this research were provided by the US Public Health Service under NIH grant number 5R01 HL125265

    Tejas S. Khire and Barrett J. Nehilla contributed equally to this paper

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    Khire, T.S., Nehilla, B.J., Getpreecharsawas, J. et al. Finite element modeling to analyze TEER values across silicon nanomembranes. Biomed Microdevices 20, 11 (2018). https://doi.org/10.1007/s10544-017-0251-7

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