Biomedical Engineering Reference
In-Depth Information
18.6 SURFACE COATING WITH COVALENT
ANTITHROMBIN-HEPARIN COMPLEXES
18.6.1 C
HEMISTRY
AND
In Vitro
C
HARACTERIZATION
Pacifi cation of blood-contacting biomaterial surfaces with ATH complexes has only been reported
using the Chan et al. keto-amine adduct. In order to use ATH on devices used as blood conduits
ex vivo
or
in vivo
, chemistries had to be devised that took into consideration all the technical and
biochemical issues that have caused serious impediments for biomaterial application.
As with the clinical application of heparin, biomaterials in contact with blood have a whole
plethora of limitations from inappropriate activation of biomaterial surface-bound platelets and
polymorphonucleocytes,
289,290
effects on fl ow from surface-bound plasma proteins that recruit
increasing layers of cells, induction of blood or tissue cell infl ammatory response,
291
complement
activation,
292
and activation of coagulation. Historically, surface induction of coagulation has been
the most problematic issue and various coatings have been applied to make surfaces less thrombo-
genic. Many coatings have inherent problems such as nonhomogeneous surface coverage, leaching
of anticoagulant coating off the surface, or interactions with biological molecules that modify
the coated surface, leaving it inactive or even procoagulant. Engineering design of chemistries to
address the optimization of applying the desired agent onto the surface might be grouped into three
broad methodology categories. Anticoagulant molecules might be coated by simple noncovalent
adsorption, covalently bound to a polymer base coat that is itself not covalently linked to the device
surface, or covalently bound (through an intervening linkage molecule) to the surface being coated.
Noncovalent adsorption has the potential of maximal packing, which may more completely cover
the surface, but loss of coating by mild interactions with macromolecules or by changing conditions
in vivo
would always remain a concern. As a consequence, noncovalent adsorption coating of anti-
coagulant molecules has been generally discounted as a viable option. Bonding of the anticoagulant
molecule to a base polymer coating that is not covalently linked to the device surface can give good
substitution, but strong abrasions may still be able to pull off large sections of the coverage. To opti-
mize its prevention, careful selection must be made to use base coat monomers that have high affi n-
ity for the biomaterial, so as to get tight adhesion and dense covering before or at polymerization.
Although covalent linkage of the agent being coated to the biomaterial surface itself would be the
most secure, activation of the biomaterial for linkage can require harsh conditions that negatively
alter its properties and complete coverage may be less likely. Potentially, either of the latter two
coating methodologies may be more appropriate dependent on the biomaterial in question.
Coatings of covalent ATH may have theoretical aspects that might solve many problems associ-
ated with previous anticoagulant fi lms on biomaterials. As with heparan sulfate in proteoglycans
naturally found on the luminal side of vessels,
293
surface attachment of ATH would present the
anticoagulant heparin chain in the proper orientation to interact with the blood coagulant system.
Furthermore, the coating would already have an AT protein that may inhibit binding of further,
unwanted, proteins from the circulation. Both AT
294
and heparin
295
have antiinfl ammatory prop-
erties and little immune response may be anticipated given that AT, heparin, and the Amadori
rearrangement bonding are all natural products. In the case of Chan et al. ATH, the additional
catalytic potency from
1.5 pentasaccharides per heparin chain,
264
combined with the extremely
rapid direct noncatalytic inhibition rate,
141
should be vastly superior to coatings of unprocessed
commercial heparin or LMWH products. Thus, ATH combines the strengths of coatings of indirect
(heparin) and direct (hirudin) thrombin inhibitors. Technical advantages are cogent for coating with
ATH as opposed to many other anticoagulant agents. Unlike heparin alone, the AT in ATH affords
many more functional groups for bonding to agents linking the anticoagulant to the device poly-
mer surface. Apart from the numerous R-groups, human AT is endowed with many nucleophilic
-NH
2
groups from its 37 lysyl ε-aminos,
61
whereas heparin amino groups are scarce.
231
Related to
the preponderance of AT functional groups in ATH is the fact that multiple covalent bonds to the
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