Release-Controlled Coatings - Biological and Biomedical Coatings - page 293

biolimus A9 (Grube et al., 2008 ). However, the second-generation Endeavor ZES stent uses
PC to achieve better biocompatibility.
The second perspective is modification of the existing drug regimens that suppress the
smooth muscle cell migration and proliferation in the first 3 months after implantation.
Two antiproliferative agents, paclitaxel (Honda et al., 2001; Liistro et al., 2002) and sirolimus
(Degertekin et al., 2002), have now been widely used in humans with promising results. Its
short cellular residence time (1 h), along with reversible antiproliferative activity, suggests
that it should be formulated in sustained-release dosage form (Alexis et al., 2004).
Owing to their lipophilic properties, both sirolimus and paclitaxel easily penetrate
cells leading to their retention in arterial tissue (Finn et al., 2005; Gummert et al., 1999;
Suzuki et al., 2001). Eluting drug in the first 3 months (Table 6.8) suppresses the growth
of smooth muscle cells and therefore reduces the rate of restenosis by approximately 80%.
Consequently, the use of DES has been swiftly embraced with market penetration of up to
90% in certain countries.
Given the ubiquitous expression of cell-cycle regulatory proteins, it is conceivable that
agents released from DES do not only affect proliferation and migration of VSMCs, but
also of endothelium. Indeed, sirolimus can inhibit endothelial cell proliferation (Steffel et
al., 2005) and migration (Matter et al., 2006) in vitro. Similarly, paclitaxel reduces endothe-
lial cell proliferation and migration through interaction with cell-cycle regulators and, at
least in part, through induction of apoptosis (Parry et al., 2005).
In animal models, the time course of reendothelialization after stent implantation varies
in different species. In pigs, the extent of reendothelialization is similar for DES and bare
metal stenting after 28 days (Suzuki et al., 2001). However, delayed endothelial healing
occurs in a rabbit iliac overlapping stent model after implantation of both sirolimus and
paclitaxel DES compared to bare metal (Finn et al., 2005). In humans, near complete reen-
dothelialization seems to occur after 3-4 months after bare metal stent implantation (Farb
et al., 2003), compared to delayed arterial healing and poor reendothelialization in DES
found at autopsy (Joner et al., 2006). Hence, there is clear evidence that the current genera-
tion of DES may significantly impair reendothelialization.
In an in vitro study of coronary arterial smooth muscle cells and endothelial cells, it was
found that sirolimus reversibly inhibited proliferation of both smooth muscle and endothe-
lial cells in nanomolar concentrations regardless of the duration of exposure (Parry et al.,
2005). In contrast, 2-day exposure of paclitaxel on smooth muscle cells was weak with, but
5 days elicited almost complete not reversible cellular inhibition in the low nanomolar
range.

TABLE 6.8
Drugs Released from Delivery System on Stents

LoadingEficiency
( μ g/cm 2 )

Percentageof
Release(%)

Lengthofthe
Period(Days) Stent Matrix Drug

CYPHER PEVA/PBMA Sirolimus 140 80 30

TAXUS SIBS Paclitaxel 100 10 90

XIENCE V Fluoropolymer Everolimus 100
Conor PLGA Paclitaxel 30
Note: PEVA, poly(ethylene-co-vinyl acetate); PBMA, poly( n -butyl methacrylate); SIBS, polystyrene- b -isobutylene-
b -styrene; PLGA, poly(lactide- co -glycolide).