Biomedical Engineering Reference
In-Depth Information
(Zhu et al., 2002; Zhu et al., 2003; Ma et al., 2005); and laminin (Chandy et al.,
2000).
(3) Incorporation of cell adhesion peptides and ligands
Cell adhesion, both in the body and on synthetic substrates, is mediated by
cell adhesion ligands interaction with cell-surface receptor. These cell adhesion
ligands can be oligopeptides, saccharides, or glycolipids (Alberts et al., 2002).
Immobilization of them could improve cell-surface interaction. Certain short
amino acid sequences appear to bind to receptors on cell surfaces and mediate cell
adhesion, for example, RGD in fibronectin (Massia and Hubbell, 1991; Hersel et
al., 2003; Gabriel et al., 2006; Larsen et al., 2006; Tugulu et al., 2007), YIGSR (Massia
and Hubbell, 1990; Jun and West, 2004) and IKVAV (Lin et al., 2006) in laminin, and
REDV (Hubbell et al., 1991; Hodde et al., 2002).
Micropatterning
Micropatterns printed on substrate were found to regulate/control EC adhesion and func-
tion (Christopher et al., 1998; Ito, 1999; Kumar et al., 2003; Gauvreau and Laroche, 2005;
Satomi et al., 2007; Yamamoto et al., 2007).
We have provided the above review of methods to illustrate the fact that this area of
research is quite an active one. However, it is fair to say that none of these approaches have
been proven to work for accelerating in situ endothelialization. As we have reviewed in
an earlier paper (Venkatraman et al., 2008), seeding of graft surfaces before implantation
appears to be the most clinically successful approach to date. For example, Williams et al.
(1985) found that it was necessary to precoat the vascular graft material (Dacron, PTFE)
with proteins, such as fibronectin, to enhance the stability of the attached ECs ex vivo. The
RGD peptide sequence found in these plasma proteins appears to enhance EC attachment
and stability, although it is not as selective as the REDV sequence. EC were taken from the
jugular or cephalic vein, and fibronectin-modified surfaces seeded with a seeding den-
sity of 3000 cells/cm
2
, requiring 9-10 days after seeding to achieve full surface coverage
ex vivo. Such ex vivo seeded grafts were found to perform much better than unseeded
grafts clinically, improving long-term patency rates (70% patency at 7 years comparable
to saphenous vein grafts) substantially (Meinhart et al., 1997). This approach is extremely
promising as an interim improvement while we await the completely tissue-engineered
graft.
Faster endothelialization of stents is also critical to its long-term acceptance. As men-
tioned above, DES delay endothelialization of the stent, resulting in prolonged therapy
with systemic antiplatelet agents (expensive and with possible adverse side effects such
as bleeding). To overcome this, one elegant technique is to anchor an antibody that cap-
tures floating endothelial progenitor cells (EPCs) from the bloodstream. In clinical trials,
the Genous® stent, which is not drug-eluting, was reported to have fared as well as the
paclitaxel-eluting stent. The e-HEALING clinical study is a multicenter, worldwide study
with 5000 enrolled patients treated with the Genous stent. The study protocol recommends
that patients receive 1 month of clopidogrel treatment after the procedure. The data from
3200 patients showed a TLR rate of 5%, a SAT rate of 0.4%, a late stent thrombosis (LST) rate
of 0.3%, and MACE rate of 8.5%. The data support the use of Genous as an alternative to
DES, in light of the relatively minimal dual antiplatelet therapy requirements of the stent,
according to company news reports.
