Titanium Vascular Stents With Rationally-Designed Sub-Micrometer Scale Surface Patterning

Doctor of Philosophy, Graduate Program in Mechanical Engineering
University of California, Riverside, August 2014
Dr. Masaru P. Rao, Chairperson

Drug-eluting  stents  have  revolutionized  the  field  of  interventional  cardiology  by reducing  incidence  of  restenosis  through  local  delivery  of  drugs  that  inhibit  inflammation caused by implantation-induced injury. However, growing evidence suggests that this may also inhibit  reestablishment  of  the  endothelium,  thus  delaying  healing  and  increasing  potential  for thrombogenic  stimulus.  Herein,  we  discuss  progress  towards  realization  of  next-generation titanium (Ti) stents that seek to mitigate adverse physiological responses to stenting via rational design of stent surface topography at the micro-and sub-micrometer scale.

To better understand the effect of surface topography on cells, we evaluate the in vitro response  of  EA926  endothelial  cells  (EC)  to  variation  in  precisely-defined,  micrometer  to sub-micrometer scale groove-based topography, with groove widths ranging from 0.5 to 50 μm. Silicon (Si) and Ti materials are chosen for these studies due to their relevance for implantable microdevice applications, while grating-based patterns are chosen for their potential to induce elongated and aligned  cellular morphologies  reminiscent  of the native endothelium. We show significant  improvement  in  cellular  adhesion,  proliferation,  and  morphology  with  decreasing feature size on patterned Ti substrates. Moreover, we show similar, yet attenuated, trending on patterned Si substrates as compared to patterned Ti substrates. These results suggest promise for sub-micrometer topographic patterning to enhance endothelialization and neovascularisation for implantable microdevice applications.

We  also  discuss:  1)  advances  which  now  allow  patterning  of  features  in  Ti  substrates down  to  150  nm,  which  represents  the  smallest  features  achieved  to  date  using  our  novel  Ti deep  reactive  ion  etching  (Ti  DRIE)  technique;  2)  creation  and  evaluation  of  balloon-deployable, cylindrical, surface-patterned stents from micromachined planar Ti substrates; and 3)  integration  of  these  processes  to  produce  a  device  platform  that  allows,  for  the  first  time, evaluation  of  surface  patterning  in  more  physiologically  relevant  contexts,  e.g.  in  vitro  organ culture.  Using  elasto-plastic  finite  element  analysis,  we  also  explore  planar  stents  with  novel locking mechanisms intended to address radial stiffness deficiencies observed in earlier studies. Collectively, these efforts represent key steps towards our long-term goal of developing a new paradigm for stents in which rationally-designed surface patterning provides a physical means for complementing, or replacing, current pharmacological interventions.