Biomedical Engineering Reference
In-Depth Information
Platelet Interactions
By far, prevention of thrombus formation has been the focus of researchers over the past
four decades. A variety of approaches have been tried, with very little success. Early
attempts focused on making the surface more hydrophilic, particularly with the use of
attached polyethylene glycol (PEG) molecules. Other approaches have included hydrogel
coatings and plasma treatment; most of these approaches have been reviewed by Sefton
and Gemmel (2004). Nevertheless, in spite of more than 30 years of research, the only suc-
cessful approach has been to use tethered heparin.
Heparin is a well-studied polysaccharide from the glycosaminoglycan family. It exerts
its anticoagulant activity via binding to antithrombin III. Heparin and its partially de-
polymerized form (low molecular weight heparin) are currently used for anticoagulation.
As mentioned earlier, heparinized coatings (strictly speaking, heparin immobilization
on surfaces) have enjoyed commercial success, specifically in blood oxygenators and dialy-
sis catheters. In both cases tethered heparin has been employed. We now briefly discuss
the various methods for attaching heparin chemically onto surfaces.
Because of the presence of several active functional groups in heparin, such as amine,
carboxyl, as well as hydroxyl groups, several chemical attachment options are available.
For example, for attachment to polyethylene, the following sequence has been proposed.
First, introduce carboxyl groups on PE using acrylic acid-enhanced plasma. Then react
this surface with bis 2-aminopropyl polyethylene glycol to attach PEG molecules on the PE
surface. Once this PEG molecule is attached, it can be used as a tether to attach heparin,
using the dangling amino group on the PEG molecules. The attachment of heparin via a
PEG tether allows for adjustment of the length of the tether unit (PEG) by simply using
PEGs of different molecular mass, whereas PEG itself can also act to repel adhesion pro-
teins on the surface.
As shown in Figure 10.5, heparin consists of a pentasaccharide sequence (Murugesan et
al., 2008) that is believed to be essential for binding to antithrombin (AT).
It is this unit that must not be changed as a result of any covalent attachment technique
that is used. The first such report of surface modification involved the use of a polyethy-
leneimine primer surface (Larsson et al., 1983). First, heparin with MW of about 12,000
was partially degraded in nitrous acid, and this introduced reactive aldehyde groups at
the terminal residues. The chosen biomaterial is then made to be negatively charged using
plasma or other chemical techniques. For example, polyethylene can be treated with sul-
furic acid and potassium permanganate to introduce sulfate groups. Then the negatively
charged surface is treated with polyethyleneimine to irreversibly adsorb the positively
CH
2
SO
-
COO
-
CH
2
SO
-
CH
2
SO
-
COO
-
OSO
-
OH
OH
OH
OH
O
O
O
O
O
NHSO
-
NHSO
-
OSO
-
NHSO
-
OH
FIGURE 10.5
Chemical structure of the pentasaccharide sequence of heparin; this is considered the active sequence that
predominates in binding to AT.
