Biomedical Engineering Reference
In-Depth Information
surface are easily foreseeable by attachment through the AT of ATH, as opposed to the diffi culty
of having multiple linkage points to heparin alone without potentially modifying groups within the
pentasaccharide sequence. With multiple bonds to the ATH coating, leaching is less likely. In case
of heparin coatings, it is precisely to avoid conjugation to the surface through the active sequences
that end-point attachments have been developed, which indeed give better blood compatibility.
Several biomaterials composed of synthetic polymers used commercially
in vivo
have been
coated with Chan et al. ATH using an array of chemical coating methods. Physical integrity, struc-
tural characteristics, and anticoagulant activities
in vitro
have been assessed. These are discussed
with reference to the type of biomaterial and linkage chemistry used.
Attachment of keto-amine-linked ATH to an endoluminal graft, composed of polycarbonate
with urethane extenders, has been achieved by direct covalent linkage.
296
The graft (Corethane)
provided by Corvita Corporation was made from a fi nely woven material that was attached, through
its weave to a stainless steel mesh that was fl exible for elasticity during insertion within the blood
vessel. Internal diameter of the graft was from 3 to 6 mm and wall thickness was
1 mm. Bonding
was through urethane nitrogen atoms using chemistry based on the radical-initiated polymerization
on poly(
N
-chloroamide) donor surfaces.
297
After modifi cation of N-atoms using NaOCl, oligomeric
chain growth of allyl glycidyl ether units was initiated by -N• radicals produced by concomitant
reaction of the graft
<
Cl groups with Na
2
S
2
O
4
or Fe(NH
4
)
2
(SO
4
)
2
·6H
2
O.
296
Previous work
has ascertained that oligomers tend to contain 1-4.6 allyl glycidyl ether monomer units per point
of attachment.
298,299
Once attachment of allyl glycidyl ethers was complete, endoluminal grafts
were washed and incubated with ATH for reaction of AT amino groups with the surface epoxide
groups.
296
Reviews indicate that surface-coating effi ciency depends on a range of parameters includ-
ing surface area and mode of drug linkage.
300
Previous work with polyurethane model surfaces by
Chan et al. has confi rmed high substitution of active allyl glycidyl ether by this method. Analysis
of ATH coating on the polycarbonate urethane was by staining the surface for protein or GAG,
followed by elution and quantifi cation of the bound stain.
296
In addition, hirudin (used as a bioma-
terial coating clinically)
301,302
and heparin were coated by the same method for comparison. Graft
densities were highest for ATH (
-
N
-
sixfold higher than heparin and 20-fold greater than hirudin)
but leaching was similar for all three anticoagulants (a likely result of the direct covalent linkage
modality).
296
As expected, the ability to directly inhibit thrombin
in vitro
was negligible for heparin
alone while both ATH and hirudin surfaces neutralized signifi cant amounts of thrombin. Binding
of labeled AT (a measure of pentasaccharide content) was nine times greater for ATH relative to
heparin-coated surfaces. Notable was the fact that the AT-affi nity binding for ATH-coated surfaces
was more enhanced over heparin coating than the ratio of surface-coating density for ATH versus
heparin, consistent with ATH's greater pentasaccharide content.
264
Overall, ATH gives decidedly
more effective degree of coverage and specifi c activity in this direct covalent attachment model.
Coating of Chan et al. ATH by covalent linkage to polymer base coats that were noncovalently
adsorbed prior to polymerization on the biomaterial surface was investigated in a number of
reports.
303-305
Polyurethane catheters, based on Carmeda technology (provided by Solomon Scientifi c),
were used as the coating substrate. Catheters were from a combination of two types of polyurethane
units
306
incorporated into polymer blocks and chain extenders prepared by 1:1 reaction of polyols
and small diisocyanate monomers.
306,307
Heparin-coated catheters (i.e., CBAS) from Solomon were
obtained for comparison in these studies. Polyurethane construction in the heparin-coated catheters
was similar to that of the uncoated polyurethane and heparin was coated by end-point attachment by
reduction of Schiff bases formed between anhydromannose aldehyde termini on partially HNO
2
-
depolymerized heparin and amine-rich polyurethane-urea dip coatings.
307,308
Application of ATH
coatings to the polyurethane catheters was done by the following protocol.
305
Catheters were dip-
coated in dichloromethane solutions of monomer mixtures (methyl methacrylate, ethylene glycol
dimethacrylate, diurethane dimethacrylate, and polyethylene oxide (PEO) methacrylate) and a ther-
mally labile initiator (azobisisobutyronitrile [AIBN]), followed by drying. ATH was premodifi ed
by reaction with NHS-PEO-acrylate to give ATH conjugates, a PEO spacer arm and polymerizable
∼
