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Electrical Stimulation Increases Random Migration of Human Dermal Fibroblasts

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Abstract

Exogenous electrical stimulation (ES) has been investigated as a therapy for chronic wounds, as the skin produces currents and electrical fields (EFs) during wound healing. ES therapies operate by applying small EFs to the skin to mimic the transepithelial potentials that occur during the granulation phase of wound healing. Here, we investigated the effect of short duration (10 min) ES on the migration of HDFs using various magnitudes of physiologically relevant EFs. We modeled cutaneous injury by culturing HDFs in custom chambers that allowed the application of ES and then performed timelapse microscopy on a standard wound model. Using MATLAB to process cell coordinate data, we determined that the cells were migrating randomly and fit mean squared displacement data to the persistent random walk equation using nonlinear least squares regression analysis. Results indicated that application of 25–100 mV/mm DC EFs to HDFs on either uncoated or FN-coated surfaces demonstrated no significant changes in viability or proliferation. Of significance is that the HDFs increased random migration behavior under some ES conditions even after 10 min, providing a mechanism to enhance wound healing.

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References

  1. Anglen, J. The clinical use of bone stimulators. J. South. Orthop. Assoc. 12(2):46–54, 2003.

    PubMed  Google Scholar 

  2. Ascione, F., A. Vasaturo, S. Caserta, V. D’Esposito, P. Formisano, and S. Guido. Comparison between fibroblast wound healing and cell random migration assays in vitro. Exp. Cell. Res. 347:123–132, 2016.

    Article  CAS  PubMed  Google Scholar 

  3. Ashby, W. J., and A. Zijlstra. Established and novel methods of interrogating two-dimensional cell migration. Integr. Biol. 11:1338–1350, 2012.

    Article  Google Scholar 

  4. Avrahami, R., J. Rosenblum, M. Gazes, and L. Litman. The effect of combined ultrasound and electric field stimulation on wound healing in chronic ulcerations. Wounds 27:199–208, 2014.

    Google Scholar 

  5. Barker, A., L. Jaffe, and J. Vanable. The glabrous epidermis of cavies contains a powerful battery. Am. J. Physiol. 242(3):R358–R366, 1982.

    CAS  PubMed  Google Scholar 

  6. Bourguignon, G. Y., and L. Y. Bourguignon. Electric stimulation of protien and DNA synthesis in human fibroblasts. FASEB J. 1(5):398–402, 1987.

    CAS  PubMed  Google Scholar 

  7. Bourguignon, G. Y., W. Jy, and L. Y. Bourguignon. Electric stimulation of human fibroblasts causes an increase in Ca2+ influx and the exposure of additional insulin receptors. J. Cell Physiol. 140(2):379–385, 1989.

    Article  CAS  PubMed  Google Scholar 

  8. Brown, M. J., and L. M. Loew. Electric field-directed fibroblast locomotion involves cell surface molecular reorganization and is calcium independent. J. Cell Biol. 127:117–128, 1994.

    Article  CAS  PubMed  Google Scholar 

  9. Calvey, C., W. Zhou, K. S. Stakleff, P. Sendelbach-Sloan, A. B. Harkins, W. Lanzinger, and R. K. Willits. Short-term electrical stimulation to promote nerve repair and functional recovery in a rat model. J. Hand Surg. Am. 40(2):314–322, 2015.

    Article  PubMed  Google Scholar 

  10. Chao, P., H. Lu, C. Hung, S. Nicoll, and J. Bulinski. Effects of applied DC electric field on ligament fibroblast migration and wound healing. Connect Tissue Res. 48:188–197, 2007.

    Article  CAS  PubMed  Google Scholar 

  11. Collard, J., and M. Hinsenkamp. Cellular processes involved in human epidermal cells exposed to extremely low frequency electric fields. Cell. Signal. 27:889–898, 2015.

    Article  CAS  PubMed  Google Scholar 

  12. Dickinson, R. B., and R. T. Tranquillo. Optimal estimation of cell movement indices from the statistical analysis of cell tracking data. AlChe J. 39(12):1995–2010, 1993.

    Article  Google Scholar 

  13. Erickson, C. A., and R. Nuccitelli. Embryonic fibroblast motility and orientation can be influenced by physiological electric fields. J. Cell Biol. 98(1):296–307, 1984.

    Article  CAS  PubMed  Google Scholar 

  14. Fang, K. S., B. Farboud, R. Nuccitelli, and R. R. Isseroff. Migration of human keratinocytes in electric fields requires growth factors and extracellular calcium. J. Invest. Dermatol. 11:751–756, 1998.

    Article  Google Scholar 

  15. Farboud, B., R. Nuccitelli, I. R. Schwab, and R. R. Isseroff. DC electric fields induce rapid directional migration in human corneal epithelial cells. Exp. Eye Res. 70:667–673, 2000.

    Article  CAS  PubMed  Google Scholar 

  16. Feedar, J. A., L. C. Kloth, and G. D. Gentzkow. Chronic dermal ulcer healing enhanced with monophasic pulsed electrical stimulation. Phys. Ther. 71(9):639–649, 1991.

    Article  CAS  PubMed  Google Scholar 

  17. Funari, V. A., M. Winkler, J. Brown, S. D. Dimitrijevic, A. V. Ljubimov, and M. Saghizadeh. Differentially expressed wound healing-related microRNAs in the human diabetic cornea. PLoS ONE 8(12):e84425, 2013.

    Article  PubMed  PubMed Central  Google Scholar 

  18. George, S. P., H. Chen, J. C. Conrad, and S. Khurana. Regulation of directional cell migration by membrane-induced actin binding. J. Cell Sci. 126:312–326, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ghosh, K., X. Ren, G. Prestwich, and R. Clark. Fibronectin functional domains coupled to hyaluronan stimulate adult human dermal fibroblast responses critical for wound healing. Tissue Eng. 12:601–613, 1006.

    Article  Google Scholar 

  20. Grinnell, F. Fibronectin and wound healing. J. Cell. Biochem. 26(2):107–116, 1984.

    Article  CAS  PubMed  Google Scholar 

  21. Guo, A., B. Song, B. Reid, Y. Gu, J. Forrester, C. Jahoda, and M. Zhao. Effects of physiological electric fields on migration of human dermal fibroblasts. J. Invest. Dermatol. 130:2320–2327, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, M., M. Lee, B. Kwon, H. Seo, M. Koo, K. You, D. Kim, and J. Park. Control of neonatal human dermal fibroblast migration on poly(lactic-co-glycolic acid)-coated surfaces by electrotaxis. J. Tissue Eng. Regener. Med. 11:11–12, 2015.

    Article  Google Scholar 

  23. Kloth, L. C. Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. Adv. Wound Care 3(2):81–90, 2014.

    Article  Google Scholar 

  24. Lenselink, E. A. Role of fibronectin in normal wound healing. Int. Wound. J. 12:313–316, 2015.

    Article  PubMed  Google Scholar 

  25. Lin, F., X. Ren, Z. Pan, L. Macri, W. Zong, M. Tonnesen, M. Rafailovich, D. Bar-Sagi, and R. Clark. Fibronectin growth factor-binding domains are required for fibroblast survival. J. Invest. Dermatol. 131:84–98, 2011.

    Article  CAS  PubMed  Google Scholar 

  26. McCaig, C., A. Rajnicek, B. Song, and M. Zhao. Controlling cell behavior electrically: current views and future potential. Physiol. Rev. 85:943–978, 2005.

    Article  PubMed  Google Scholar 

  27. McClain, S., M. Simon, E. Jones, A. Nandi, J. Gailit, M. Tonnesen, D. Newman, and R. Clark. Mesenchymal cell activation is the rate-limiting step of granulation tissue induction. Am. J. Pathol. 149:1257–1270, 1996.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Meijering, E., O. Dzyubachyk, and I. Smal. Methods for cell and particle tracking. Methods Enzymol. 504:183–200, 2012.

    Article  PubMed  Google Scholar 

  29. Messerli, M., and D. Graham. Extracellular electrical fields direct wound healing and regeneration. Biol. Bull 221(1):79–92, 2011.

    Article  CAS  PubMed  Google Scholar 

  30. Mustoe, T. A., K. O’Shaughnessy, and O. Kloeters. Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast. Reconstr. Surg. 117(7 Suppl):35S–41S, 2006.

    Article  CAS  PubMed  Google Scholar 

  31. Natali, P. G., M. R. Nicotra, D. Filippo, and A. Bigotti. Expression of fibronectin, fibronectin isoforms and integrin receptors in melanocytic lesions. Br. J. Cancer 71(6):1243–1247, 1995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishimura, K. Y., R. R. Isseroff, and R. Nuccitelli. Human keratinocytes migrate to the negative pole in direct current electric fields comparable to those measured in mammalian wounds. J. Cell Sci. 109:199–207, 1996.

    CAS  PubMed  Google Scholar 

  33. Niu, X., M. Rouabhia, N. Chiffot, M. King, and Z. Zhang. An electrically conductive 3D scaffold based on a nonwoven web of poly(l-lactic acid) and conductive poly(3,4-ethylenedioxythiophene). J. Biomed. Mater. Res. Part A 103(8):2635–2644, 2015.

    Article  CAS  Google Scholar 

  34. Park, H., M. Rouabhia, D. Lavertu, and Z. Zhang. Electrical stimulation modulates the expression of multiple wound healing genes in primary human dermal fibroblasts. Tissue Eng. Part A 21(13–14):1982–1990, 2015.

    Article  CAS  PubMed  Google Scholar 

  35. Peters, E. J., L. A. Lavery, D. G. Armstrong, and J. G. Fleischli. Electric stimulation as an adjunct to heal diabetic foot ulcers: a randomized clinical trial. Arch. Phys. Med. Rehabil. 82(6):721–725, 2001.

    Article  CAS  PubMed  Google Scholar 

  36. Rasband, W. S. ImageJ, 1997–2016. http://imagej.nih.gov/ij/

  37. Rhoads, D. S., and J.-L. Guan. Analysis of directional cell migration on defined FN gradients: role of intracellular signaling molecules. Exp. Cell. Res. 313(18):3859–3867, 2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rouabhia, M., H. Park, S. Meng, H. Derbali, and Z. Zhang. Electrical stimluation promotes wound healing by enhancing dermal fibroblast activity and promoting myofibroblast transdifferentiation. PLoS ONE 8(8):e71660, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sebastian, A., F. Syeh, D. Perry, V. Balamurugan, J. Colthurst, I. Chaudhry, and A. Bayat. Acceleration of cutaneous healing by electrical stimulation: degeneral electrical waveform down-regulates inflammation, up-regulates angiogenesis and advances remodeling in temporal punch biopsies in a human volunteer study. Wound Repair Regen. 19(6):693–708, 2011.

    Article  PubMed  Google Scholar 

  40. Sen, C., G. Gordillo, S. Roy, R. Kirsner, L. Lambert, T. Hunt, F. Gottrup, G. Gurtner, and M. Longaker. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 17(6):763–771, 2009.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sheridan, D. M., R. R. Isseroff, and R. Nuccitelli. Imposition of a physiologic DC electric field alters the migratory response of human keratinocytes on extracelluar matrix molecules. J Invest. Dermatol. 106(4):642–646, 1996.

    Article  CAS  PubMed  Google Scholar 

  42. Sillman, A. L., D. M. Quang, B. Farboud, K. S. Fang, R. Nuccitelli, and R. R. Isseroff. Human dermal fibroblasts do not exhibit directional migration on collagen I in direct-current electric fields of physiological strength. Exp. Dermatol. 12(4):396–402, 2003.

    Article  CAS  PubMed  Google Scholar 

  43. Simpson, M. J., K. Y. Lo, and Y. S. Sun. Quantifying the roles of random motility and directed motility using advection-diffusion theory for a 3T3 fibroblast cell migration assay stimulated with an electric field. BMC Syst. Biol. 11(1):39, 2017.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tandon, N., C. Cannizzaro, P. H. Chao, R. Maidhof, A. Marsano, H. T. Au, M. Radisic, and G. Vunjak-Novakovic. Electrical stimulation systems for cardiac tissue engineering. Nat. Protoc. 4(2):155–173, 2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tarantino, N., J. Tinevez, E. F. Crowell, B. Boisson, R. Henriques, M. Mhlanga, F. Agou, A. Israel, and E. Laplantine. TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO-KK supramolecular structures. J. Cell Biol. 204(2):231–245, 2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ware, M. F., A. Wells, and D. A. Lauffenburger. Epidermal growth factor alters fibroblast migration speed and directional persistence reciprocally and in a matrix-dependent manner. J. Cell Sci. 111(Pt 16):2423–2432, 1998.

    CAS  PubMed  Google Scholar 

  47. Weiss, D., R. Kirsner, and W. Eaglestein. Electrical stimulation and wound healing. Arch. Dermatol. 126(2):222–225, 1990.

    Article  CAS  PubMed  Google Scholar 

  48. Wood, M., and R. K. Willits. Short-duraction, DC electrical stimulation increases chick embryo DRG neurite outgrowth. Bioelectromagnetics 27(4):328–331, 2006.

    Article  PubMed  Google Scholar 

  49. Zhao, M. Electrical fields in wound healing—an overriding signal that directs cell migration. Semin. Cell Dev. Biol. 20(6):674–682, 2009.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Funding for this work was provided through the Margaret F. Donovan Endowed Chair for Women in Engineering at The University of Akron. The authors would like to thank the Cornell University Statistical Consulting Unit for assistance with statistical analysis.

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  1. Sarah Snyder

    Present address: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

Authors and Affiliations

  1. Department of Biomedical Engineering, The University of Akron, Akron, OH, 44325-0302, USA

    Sarah Snyder, Carlisle DeJulius & Rebecca Kuntz Willits

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  1. Sarah Snyder
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Correspondence to Rebecca Kuntz Willits.

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Associate Editor Michael Gower oversaw the review of this article.

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Snyder, S., DeJulius, C. & Willits, R.K. Electrical Stimulation Increases Random Migration of Human Dermal Fibroblasts. Ann Biomed Eng 45, 2049–2060 (2017). https://doi.org/10.1007/s10439-017-1849-x

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  • DOI: https://doi.org/10.1007/s10439-017-1849-x

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