Biomech Model Mechanobiol (2013) 12:671–683 DOI 10.1007/s10237-012-0433-4 ORIGINAL PAPER Cyclic strain amplitude dictates the growth response of vascular smooth muscle cells in vitro: role in in-stent restenosis and inhibition with a sirolimus drug-eluting stent Alberto Colombo · Shaunta Guha · Joseph N. Mackle · Paul A. Cahill · Caitríona Lally Received: 1 March 2012 / Accepted: 16 August 2012 / Published online: 8 September 2012 © Springer-Verlag 2012 Abstract The putative effects of changes in mean strain and cyclic strain amplitude on vascular smooth muscle cell (vSMC) growth (proliferation and apoptosis) were exam- ined. Subsequently, a quantitative measure of vSMC growth was obtained to determine the prolonged effect of changes in mechanical burden following bare-metal stent (BMS) and sirolimus drug-eluting stent (DES) deployment in vitro. Bovine aortic vSMCs were exposed to prolonged cyclic strain using a Flexercell TM Tension system and a novel Syl- gard TM phantom vessel following stent implantation before the level of vSMC proliferation and apoptosis was assessed by FACS analysis, cell counting, and immunocytochemistry. Physiological cyclic strain (5 %) decreased vSMC prolifer- ation and increased apoptosis in a temporal manner. There was no significant difference in cell growth following expo- sure to varying mean strains with similar amplitude. In con- trast, exposure to varying strain amplitudes with similar mean strains resulted in significant differences in cell proliferation and apoptosis. In parallel studies, the level of vSMC prolif- eration and cell survival was significantly increased within low amplitude, high mean strain regions of a phantom ves- sel following BMS implantation when compared to regions of higher strain amplitude upstream and downstream of the stent, respectively. Moreover, the level of vSMC growth A. Colombo · C. Lally (B ) School of Mechanical and Manufacturing Engineering, Dublin City University, Dublin 9, Ireland e-mail: triona.lally@dcu.ie A. Colombo · S. Guha · J. N. Mackle · P. A. Cahill School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland P. A. Cahill · C. Lally Centre for Medical Engineering Research, Dublin City University, Dublin 9, Ireland within the stented region was significantly attenuated follow- ing implantation of a sirolimus-coated DES independent of significant changes in cell survival. Cyclic strain amplitude is an important regulator of vSMC growth capacity within a stent and is a target for inhibition using a sirolimus-coated DES. Keywords Vascular smooth muscle cells · Cyclic strain · Restenosis · Stents · Apoptosis · Proliferation 1 Introduction Angioplasty and stent implantation is the preferred choice for the treatment of most coronary arterial stenoses (Babapulle and Eisenberg 2002; Wessely 2010; Holmes and Williams 2008). Stenting improves both the initial and long-term out- come when compared to angioplasty alone, but it drives restenosis due to an overreaction of the wound healing response (Babapulle and Eisenberg 2002). In-stent restenosis is characterised by the sequence of inflammation, granula- tion, extracellular matrix remodelling, and vascular smooth muscle cell (vSMC) proliferation and migration leading to neointimal formation (Babapulle and Eisenberg 2002). Although stents are deployed to prevent elastic recoil and ves- sel collapse following balloon angioplasty, neointimal for- mation persists as a result of accumulation of native vSMC and mesenchymal stem cell (MSC) populations within the stent (Babapulle and Eisenberg 2002). Advances in drug- eluting stents (DES) have substantially reduced restenosis (Wessely 2010), but recently emerged drawbacks with drug- eluting stents (DESs), including a reported high incidence in late stent thrombosis (Pfisterer 2008), have caused a resur- gence in research into alternative stent designs to mini- mise restenosis. The number of bare-metal stent designs 123