Biomedical Microdevices

, Volume 10, Issue 6, pp 869–882

Development and evaluation of microdevices for studying anisotropic biaxial cyclic stretch on cells

  • Wei Tan
  • Devon Scott
  • Dmitry Belchenko
  • H. Jerry Qi
  • Long Xiao


Mechanical effects on cells have received more and more attention in the studies of tissue engineering, cellular pathogenesis, and biomedical device design. Anisotropic biaxial cyclic stress, reminiscent of the in vivo cellular mechanical environment, may promise significant implications for biotechnology and human health. We have designed, fabricated and characterized a microdevice that imparts a variety of anisotropic biaxial cyclic strain gradients upon cells. The device is composed of an elastic membrane with microgroove patterns designed to associate cell orientation axes with biaxial strain vectors on the membrane and a Flexcell stretcher with timely controlled vacuum pressure. The stretcher generates strain profile of anisotropic biaxial microgradients on the membrane. Cell axes determined by the microgrooves are associated with the membrane strain profile to impose proper biaxial strains on cells. Using vascular smooth muscle cells as a cell model, we demonstrated that the strain anisotropy index of a cell was likely one of the determinant mechanical factors in cell structural and functional adaptations. The nuclear shape and cytoskeleton structure of smooth muscle cells were influenced by mechanical loading, but were not significantly affected by the strain anisotropy. However, cell proliferation has profound responses to strain anisotropy.


Anisotropic biaxial cyclic stretching Vascular smooth muscle cells Strain anisotropy 


  1. ABAQUS/Standard User’s Manual, Ver. 6.4, Vol.II. Hibbitt, Karlson & Sorensen, Inc. 2001Google Scholar
  2. G.H. Altman, R.L. Horan, I. Martin, J. Farhadi, P.R. Stark, V. Volloch et al., Cell differentiation by mechanical stress FASEB J. 16, 270–272 (2002)Google Scholar
  3. A.E. Baer, T.A. Laursen, F. Guilak, L.A. Setton, The micromechanical environment of intervertebral disc cells determined by a finite deformation, anisotropic, and biphasic finite element model J. Biomech. Eng. 125, 1–11 (2003), doi:10.1115/1.1532790 CrossRefGoogle Scholar
  4. T.D. Brown, Techniques for mechanical stimulation of cells in vitro: a review J. Biomech. 33, 3–14 (2000), doi:10.1016/S0021-9290(99)00177-3 CrossRefGoogle Scholar
  5. P. Camelliti, A.D. McCulloch, P. Kohl, Microstructured cocultures of cardiac myocytes and fibroblasts: a two-dimensional in vitro model of cardiac tissue Microsc. Microanal. 11, 249–259 (2005), doi:10.1017/S1431927605050506 CrossRefGoogle Scholar
  6. P. Camelliti, J.O. Gallagher, P. Kohl, A.D. McCulloch, Micropatterned cell cultures on elastic membranes as an in vitro model of myocardium Nat. Protocols 1, 1379–1391 (2006). doi:10.1038/nprot.2006.203 CrossRefGoogle Scholar
  7. M. Cayouette, M. Raff, The orientation of cell division influences cell-fate choice in the developing mammalian retina Development 130, 2329–2339 (2003), doi:10.1242/dev.00446 CrossRefGoogle Scholar
  8. C. Clark, T. Burkholder, J. Frangos, Uniaxial strain system to investigate strain rate regulation in vitro Rev. Sci. Instrum. 72, 2415–2422 (2001). doi:10.1063/1.1362440 CrossRefGoogle Scholar
  9. N. Dard, S. Louvet, A. Santa-Maria, J. Aghion, M. Martin, P. Mangeat et al., In vivo functional analysis of ezrin during mouse blastocyst formation Dev. Biol. 233, 161–173 (2001), doi:10.1006/dbio.2001.0192 CrossRefGoogle Scholar
  10. P.F. Davies, J.A. Spaan, R. Krams, Shear stress biology of the endothelium Ann. Biomed. Eng. 33, 1714–1718 (2005), doi:10.1007/s10439-005-8774-0 CrossRefGoogle Scholar
  11. M.T. Draney, F.R. Arko, M.T. Alley, M. Markl, R.J. Herfkens, N.J. Pelc et al., Quantification of vessel wall motion and cyclic strain using cine phase contrast MRI: in vivo validation in the porcine aorta Magn. Reson. Med 52, 286–295 (2004), doi:10.1002/mrm.20137 CrossRefGoogle Scholar
  12. G.A. Dunn, A.F. Brown, Alignment of fibroblasts on grooved surfaces described by a simple geometric transformation J. Cell Sci. 83, 313–340 (1986)Google Scholar
  13. E.L. Elson, Cellular mechanics as an indicator of cytoskeletal structure and function Annu. Rev. Biophys. Biophys. Chem. 17, 397–430 (1988), doi:10.1146/ CrossRefGoogle Scholar
  14. S.M. Emani, M.J. Ellis, L.R. Dibernardo, S. Colgrove, D.D. Glower, D.A. Taylor, Systolic contraction within aneurysmal rabbit myocardium following transplantation of autologous skeletal myoblasts J. Surg. Res. 135, 202–208 (2006), doi:10.1016/j.jss.2006.03.020 CrossRefGoogle Scholar
  15. N. Endlich, K. Endlich, Stretch, tension and adhesion—adaptive mechanisms of the actin cytoskeleton in podocytes Eur. J. Cell Biol. 85, 229–234 (2006), doi:10.1016/j.ejcb.2005.09.006 CrossRefGoogle Scholar
  16. J. Engel, J. Chen, N. Chen, S. Pandya, C. Liu, Development and characterization of an artificial hair cell based on polyurethane elastomer and force sensitive resistors. In Proceedings of the 4th IEEE International Conference on Sensors, Irvine, Calif, USA (2005)Google Scholar
  17. M.A. Gaballa, T.E. Raya, B.R. Simon, S. Goldman, Arterial mechanics in spontaneously hypertensive rats. Mechanical properties, hydraulic conductivity, and two-phase (solid/fluid) finite element models Circ. Res. 71, 145–158 (1992)Google Scholar
  18. J.A. Gilbert, P.S. Weinhold, A.J. Banes, G.W. Link, G.L. Jones, Strain profiles for circular cell culture plates containing flexible surfaces employed to mechanically deform cells in vitro J. Biomech. 27, 1169–1177 (1994), doi:10.1016/0021-9290(94)90057-4 CrossRefGoogle Scholar
  19. S.M. Gopalan, C. Flaim, S.N. Bhatia, M. Hoshijima, R. Knoell, K.R. Chien et al., Anisotropic stretch-induced hypertrophy in neonatal ventricular myocytes micropatterned on deformable elastomers Biotechnol. Bioeng. 81, 578–587 (2003), doi:10.1002/bit.10506 CrossRefGoogle Scholar
  20. F. Guilak, A. Ratcliffe, V.C. Mow, Chondrocyte deformation and local tissue strain in articular cartilage: a confocal microscopy study J. Orthop. Res. 13, 410–421 (1995), doi:10.1002/jor.1100130315 CrossRefGoogle Scholar
  21. J.H. Haga, Y.S. Li, S. Chien, Molecular basis of the effects of mechanical stretch on vascular smooth muscle cells J. Biomech. 40, 947–960 (2007), doi:10.1016/j.jbiomech.2006.04.011 CrossRefGoogle Scholar
  22. H. Hirata, H. Tatsumi, M. Sokabe, Dynamics of actin filaments during tension-dependent formation of actin bundles Biochim. Biophys. Acta 1770, 1115–1127 (2007)Google Scholar
  23. D.E. Ingber, Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology Circ. Res. 91, 877–887 (2002), doi:10.1161/01.RES.0000039537.73816.E5 CrossRefGoogle Scholar
  24. D.E. Ingber, Tensegrity II. How structural networks influence cellular information processing networks J. Cell Sci. 116, 1397–1408 (2003a), doi:10.1242/jcs.00360 CrossRefGoogle Scholar
  25. D.E. Ingber, Tensegrity I. Cell structure and hierarchical systems biology J. Cell Sci. 116, 1157–1173 (2003b), doi:10.1242/jcs.00359 CrossRefGoogle Scholar
  26. F. Ishida, H. Ogawa, T. Simizu, T. Kojima, W. Taki, Visualizing the dynamics of cerebral aneurysms with four-dimensional computed tomographic angiography Neurosurgery 57, 460–471 (2005)discussion 460–471, doi:10.1227/01.NEU.0000170540.17300.DD CrossRefGoogle Scholar
  27. B.F. Jones, M.E. Wall, R.L. Carroll, S. Washburn, A.J. Banes, Ligament cells stretch-adapted on a microgrooved substrate increase intercellular communication in response to a mechanical stimulus J. Biomech. 38, 1653–1664 (2005), doi:10.1016/j.jbiomech.2004.07.027 CrossRefGoogle Scholar
  28. H. Kenar, G.T. Kose, V. Hasirci, Tissue engineering of bone on micropatterned biodegradable polyester films Biomaterials 27, 885–895 (2006), doi:10.1016/j.biomaterials.2005.07.001 CrossRefGoogle Scholar
  29. T. Kozai, M. Eto, Z. Yang, H. Shimokawa, T.F. Luscher, Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rho-kinase pathway Cardiovasc. Res. 68, 475–482 (2005), doi:10.1016/j.cardiores.2005.07.002 CrossRefGoogle Scholar
  30. K. Kurpinski, J. Chu, C. Hashi, S. Li, Anisotropic mechanosensing by mesenchymal stem cells Proc. Natl. Acad. Sci. USA 103, 16095–16100 (2006a), doi:10.1073/pnas.0604182103 CrossRefGoogle Scholar
  31. K. Kurpinski, J. Park, R.G. Thakar, S. Li, Regulation of vascular smooth muscle cells and mesenchymal stem cells by mechanical strain Mol. Cell. Biomech. 3, 21–34 (2006b)Google Scholar
  32. J.S. Lee, C.M. Hale, P. Panorchan, S.B. Khatau, J.P. George, Y. Tseng et al., Nuclear lamin A/C deficiency induces defects in cell mechanics, polarization, and migration Biophys. J. 93, 2542–2552 (2007), doi:10.1529/biophysj.106.102426 CrossRefGoogle Scholar
  33. S. Lehoux, A. Tedgui, Cellular mechanics and gene expression in blood vessels J. Biomech. 36, 631–643 (2003), doi:10.1016/S0021-9290(02)00441-4 CrossRefGoogle Scholar
  34. Q. Li, Y. Muragaki, H. Ueno, A. Ooshima, Stretch-induced proliferation of cultured vascular smooth muscle cells and a possible involvement of local renin–angiotensin system and platelet-derived growth factor (PDGF) Hypertens. Res. 20, 217–223 (1997), doi:10.1291/hypres.20.217 CrossRefGoogle Scholar
  35. G.S. Lin, H.H. Hines, G. Grant, K. Taylor, C. Ryals, Automated quantification of myocardial ischemia and wall motion defects by use of cardiac SPECT polar mapping and 4-dimensional surface rendering J. Nucl. Med. Technol. 34, 3–17 (2006)Google Scholar
  36. W. Lötters, J.C. Olthuis, P.H. Veltink, P. Bergveld, The mechanical properties of the rubber elastic polymer polydimethylsiloxane for sensor applications J. Micromech. Microeng. 7, 145–147 (1997). doi:10.1088/0960-1317/7/3/017 CrossRefGoogle Scholar
  37. G.N. Maksym, L. Deng, N.J. Fairbank, C.A. Lall, S.C. Connolly, Beneficial and harmful effects of oscillatory mechanical strain on airway smooth muscle Can. J. Physiol. Pharmacol. 83, 913–922 (2005), doi:10.1139/y05-091 CrossRefGoogle Scholar
  38. M. Malina, T. Lanne, K. Ivancev, B. Lindblad, J. Brunkwall, Reduced pulsatile wall motion of abdominal aortic aneurysms after endovascular repair J. Vasc. Surg. 27, 624–631 (1998), doi:10.1016/S0741-5214(98)70226-5 CrossRefGoogle Scholar
  39. I.V. Maly, R.T. Lee, D.A. Lauffenburger, A model for mechanotransduction in cardiac muscle: effects of extracellular matrix deformation on autocrine signaling Ann. Biomed. Eng. 32, 1319–1335 (2004), doi:10.1114/B:ABME.0000042221.61633.23 CrossRefGoogle Scholar
  40. A.J. Maniotis, C.S. Chen, D.E. Ingber, Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure Proc. Natl. Acad. Sci. USA 94, 849–854 (1997), doi:10.1073/pnas.94.3.849 CrossRefGoogle Scholar
  41. N.L. McKnight, J.A. Frangos, Strain rate mechanotransduction in aligned human vascular smooth muscle cells Ann. Biomed. Eng. 31, 239–249 (2003), doi:10.1114/1.1543935 CrossRefGoogle Scholar
  42. M. Moretti, A. Prina-Mello, A.J. Reid, V. Barron, P.J. Prendergast, Endothelial cell alignment on cyclically-stretched silicone surfaces J. Mater. Sci. Mater. Med. 15, 1159–1164 (2004), doi:10.1023/B:JMSM.0000046400.18607.72 CrossRefGoogle Scholar
  43. D. Morrow, C. Sweeney, Y.A. Birney, S. Guha, N. Collins, P.M. Cummins et al., Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo Am. J. Physiol. Cell Physiol. 292, C488–C496 (2007), doi:10.1152/ajpcell.00337.2005 CrossRefGoogle Scholar
  44. A. Nicolas, B. Geiger, S.A. Safran, Cell mechanosensitivity controls the anisotropy of focal adhesions Proc. Natl. Acad. Sci. USA 101, 12520–12525 (2004), doi:10.1073/pnas.0403539101 CrossRefGoogle Scholar
  45. J.D. Pajerowski, K.N. Dahl, F.L. Zhong, P.J. Sammak, D.E. Discher, Physical plasticity of the nucleus in stem cell differentiation Proc. Natl. Acad. Sci. USA 104, 15619–15624 (2007), doi:10.1073/pnas.0702576104 CrossRefGoogle Scholar
  46. J.S. Park, J.S. Chu, C. Cheng, F. Chen, D. Chen, S. Li, Differential effects of equiaxial and uniaxial strain on mesenchymal stem cells Biotechnol. Bioeng. 88, 359–368 (2004), doi:10.1002/bit.20250 CrossRefGoogle Scholar
  47. E.A. Peeters, C.V. Bouten, C.W. Oomens, D.L. Bader, L.H. Snoeckx, F.P. Baaijens, Anisotropic, three-dimensional deformation of single attached cells under compression Ann. Biomed. Eng. 32, 1443–1452 (2004), doi:10.1114/B:ABME.0000042231.59230.72 CrossRefGoogle Scholar
  48. E.N. Pugacheva, F. Roegiers, E.A. Golemis, Interdependence of cell attachment and cell cycle signaling Curr. Opin. Cell Biol. 18, 507–515 (2006), doi:10.1016/ CrossRefGoogle Scholar
  49. M.N. Richard, J.F. Deniset, A.L. Kneesh, D. Blackwood, G.N. Pierce, Mechanical stretching stimulates smooth muscle cell growth, nuclear protein import, and nuclear pore expression through mitogen-activated protein kinase activation J. Biol. Chem. 282, 23081–23088 (2007), doi:10.1074/jbc.M703602200 CrossRefGoogle Scholar
  50. G.M. Riha, P.H. Lin, A.B. Lumsden, Q. Yao, C. Chen, Roles of hemodynamic forces in vascular cell differentiation Ann. Biomed. Eng. 33, 772–779 (2005), doi:10.1007/s10439-005-3310-9 CrossRefGoogle Scholar
  51. S. Sarkar, M. Dadhania, P. Rourke, T.A. Desai, J.Y. Wong, Vascular tissue engineering: microtextured scaffold templates to control organization of vascular smooth muscle cells and extracellular matrix Acta Biomater. 1, 93–100 (2005), doi:10.1016/j.actbio.2004.08.003 CrossRefGoogle Scholar
  52. M. Thery, M. Bornens, Cell shape and cell division Curr. Opin. Cell Biol. 18, 648–657 (2006), doi:10.1016/ CrossRefGoogle Scholar
  53. K. Van Vliet, G. Bao, S. Suresh, The biomechanics toolbox: experimental approaches for living cells and biomolecules Acta Mater. 51, 5881–5905 (2003). doi:10.1016/j.actamat.2003.09.001 CrossRefGoogle Scholar
  54. J.H. Wang, E.S. Grood, The strain magnitude and contact guidance determine orientation response of fibroblasts to cyclic substrate strains Connect. Tissue Res. 41, 29–36 (2000), doi:10.3109/03008200009005639 CrossRefGoogle Scholar
  55. J.H. Wang, G. Yang, Z. Li, W. Shen, Fibroblast responses to cyclic mechanical stretching depend on cell orientation to the stretching direction J. Biomech. 37, 573–576 (2004), doi:10.1016/j.jbiomech.2003.09.011 CrossRefGoogle Scholar
  56. Y. Zhang, J. Takagawa, R.E. Sievers, M.F. Khan, M.N. Viswanathan, M.L. Springer et al., Validation of the wall motion score and myocardial performance indexes as novel techniques to assess cardiac function in mice after myocardial infarction Am. J. Physiol. Heart Circ. Physiol. 292, H1187–H1192 (2007), doi:10.1152/ajpheart.00895.2006 CrossRefGoogle Scholar
  57. C. Zhu, G. Bao, N. Wang, Cell mechanics: mechanical response, cell adhesion, and molecular deformation Annu. Rev. Biomed. Eng. 2, 189–226 (2000), doi:10.1146/annurev.bioeng.2.1.189 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Wei Tan
    • 1
    • 2
  • Devon Scott
    • 1
  • Dmitry Belchenko
    • 1
  • H. Jerry Qi
    • 1
  • Long Xiao
    • 1
  1. 1.Department of Mechanical EngineeringUniversity of Colorado at BoulderBoulderUSA
  2. 2.Department of PediatricsUniversity of Colorado Health Science CenterDenverUSA

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