Page 91 - Biomedical Engineering and Design Handbook Volume 2, Applications

70 MEDICAL DEVICE DESIGN

(Oesterle et al., 1998). Restenosis is not limited to stented lesions, but actually occurs at a higher rate
in lesions receiving PTCA only (Serruys et al., 1994) and is a significant contributor to stent place-
ment in previously treated lesions.
A large assortment of potential stent coatings and materials has been evaluated in an effort to reduce
the number of complications associated with stent implantation. Approaches have included both degrad-
able and nondegradable polymeric coatings for surface passivation and drug elution, coating with the
anticoagulant heparin to limit platelet activation, endothelial cell seeding to create a “natural” surface, and
using radioactive sources to inhibit cellular proliferation (Bertrand et al., 1998). Of these various
approaches, two deserve further mention: drug-eluting stents (DES) and vascular brachytherapy (VBT).
Drug-eluting stents (DES) developed as an approach to combat in-stent restenosis (Serruys
et al., 2006), a common problem plaguing traditional bare-metal stents (BMS). Potent antiproliferative
agents are incorporated into a substrate (often a polymer) and coated onto the stent to guarantee local
delivery of the drug (Serruys et al., 2006). Numerous clinical trials demonstrated the superior per-
formance of drug-eluting stents over bare-metal designs for limited follow-up periods (Morice et al.,
2002; Moses et al., 2003; Stone et al., 2004), and these devices gained widespread acceptance.
However, it was later determined that DES have a higher rate of very late stent thrombosis (defined
as occurring >1 year after the procedure) when compared to bare-metal designs (Windecker and
Meier, 2007). A recent review article evaluating the various potential causes of very late stage stent
thrombosis highlighted the fact that delayed development of an endothelial surface (which would
reduce procoagulant tendencies) and inflammatory reactions to the bare polymer could both con-
tribute to the risk of thrombosis (Van Belle et al., 2007). Although research into the root cause of
very late stent thrombosis continues, these findings bring home the message that one must consider
all ramifications of a particular treatment or modification; inhibiting cellular-proliferation limited
restenosis but may have set the stage for later thrombosis with an unhealed, inflammatory surface.
Radiation treatment of the vessel area receiving PTCA has been attempted with both gamma-
and beta-type radiation sources being delivered via catheter or radioactive stent to reduce cell
proliferation (Waksman, 1999). Beta irradiation of lesions treated with PTCA without concomitant
stent placement has been shown to reduce restenosis in a dose-dependent manner (Verin et al.,
2001). The use of a gamma radiation source has shown improved rates of clinical and angio-
graphic restenosis in patients treated for in-stent restenosis; unfortunately, the treatment was
associated with a higher rate of late thrombosis and subsequent heart attack (Leon et al., 2001).
Although the late incidence of thrombosis is likely due to the same prolonged denudation that
affects DES, the widespread acceptance of DES by the interventional community, combined with
a lack of access to vascular brachytherapy, has led to an almost complete cessation of radiation
treatment (Thomas, 2005).

3.3.5 Future Developments
Progress in stent technology will undoubtedly focus on reducing the incidence of restenosis and on
the improvement of stent outcomes in challenging vascular lesions. Treatment of restenosis in saphe-
nous vein grafts (SVGs) is a particular challenge as these conduits often exhibit diffuse atherosclerotic
disease and high complication rates when stented (Oesterle et al., 1998). Although initial enthusiasm
for the use of PTFE-coated stents (Baldus et al., 2000) for SVG lesions has waned in light of recent
data (Schachinger et al., 2003; Stankovic et al., 2003; Turco et al., 2006), both coated and drug-eluting
stents continue to be evaluated. Drug-eluting stents show promise for mitigating neointimal formation
and late-phase restenosis as high local concentrations of therapeutic and preventative agents may be
achieved. It is not difficult to envision a stent capable of minimizing vessel injury during deployment,
sealing the injured site when expanded, and releasing radiation, drugs, or other factors in a manner
responsive to the particular characteristics of the lesion involved. Wound-responsive “smart” stents
could result in improved patency rates even in difficult lesions where enhanced thrombotic deposition
or neointimal proliferation is likely to occur. Improved knowledge regarding the pathobiologic causes
of stent complications is required, as is additional insight into technical details such as elution rates,
radiation dosing, and other responsive features.