Biomedical Engineering Reference
In-Depth Information
Various biodegradable polymers have been employed as carrier coatings, including
collagen (Chen et al., 2005) with sirolimus and a PLGA grafted with polyvinyl alcohol
(Wested et al., 2006) to increase water uptake and, hence, degradation rate. The graft copoly-
mer did not increase degradation rate but appeared to give a slightly more linear release
rate of paclitaxel dissolved in the coating. The clinical significance of this linearity of rate
is unclear, however.
A different approach was to use a degradable polymer based on poly(salicylic acid) and
poly(adipic acid) (Jabara et al., 2008). This polymer degrades into salicylic and adipic acids,
which are deemed as acceptable degradation products. The in vitro degradation time is
4-6 weeks, and the pig study was carried out over 4 weeks. The stent coated with just the
polymer (PSA) did not reduce restenosis compared with BMS; however, incorporation of
sirolimus in the coating did. Nevertheless, a tendency of the PSA-coated stent to lower
inflammatory scores was noted. Whether suppression of the inflammatory response is
beneficial is not clear because there is a chance that this may delay the healing process
further. It was also not possible, from the study design, to determine whether acute throm-
bosis was reduced with the salicylate coating.
As of this writing, there is a bewildering range of coatings available for DES. Many
polymers may be coated either directly on the metal or on a parylene-coated metal sur-
face with reasonable adhesion and resistance to cracking under balloon expansion. What
appears to be lacking, however, is a range of new, more selective antiproliferation com-
pounds. The issue of endothelialization is still the key to the continued use of DES, and
although biodegradable coatings help in this regard (by ensuring complete release of
drug into tissue), the drugs themselves are hydrophobic and are not cleared rapidly from
tissue.
The search for alternatives to sirolimus (and limus compounds) and paclitaxel continues.
An early candidate was heparin, although this was more to reduce thrombosis than resteno-
sis. Combining an antiproliferative in a heparin-polymer yielded some interesting results
(Leea et al., 2007). In this case, heparin was hydrophobically modified using polyacrylic
acid and
N
-hydroxy succinimide. The resulting polymer was dissolved in cyclohexane. A
base coat of polyurethane was sprayed onto a stainless steel stent and then dipped in the
cyclohexane solution of the modified heparin. The resulting coating showed some anti-
platelet activity in vitro, confirming, to some degree, the retained bioactivity of heparin
(in spite of dissolution in an organic solvent). The drug used was echinomycin, a potent
anticancer drug, not known for its selectivity. The 30-day pig study indicated reduction
in stenosis for the 5% echinomycin loading in the coating, although this is evident more
through histological micrographs than any calculated % stenosis values. Disappointingly,
the stent with a top-coated heparin polymer alone (no echinomycin) appeared to not have
been used as one of the controls; hence, it is difficult to draw any conclusions regarding
minimization of thrombosis by the heparin.
An interesting compound that has been studied for its antiproliferative and antithrom-
botic effects is curcumin, obtained from turmeric, which belongs to the ginger family. The
curcumin is hydrophobic and dissolves in organic solvents. A solution with PLGA was
spray-coated to a home-made stainless steel stent (Pan et al., 2006). The resulting coating
appeared to be robust and withstood the balloon expansion of the stent quite well. In
vitro activated partial thromplastin time (APTT) studies showed an increased time for
the curcumin-containing samples approaching 45 to 50 s, although it is not clear that suf-
ficient curcumin would have been released in this period (and in the 3 min of prior incuba-
tion). An in vitro study (Nguyen et al., 2004) showed that PLLA films containing curcumin
inhibited SMC proliferation (but not attachment).
