Biomedical Engineering Reference
In-Depth Information
18.7 FUTURE DIRECTIONS
Thrombotic complications in the compatibility of biomaterials have been greatly addressed by
application of anticoagulant coatings. Work over the last quarter century has led to a new class
of “heparinoid” resulting from the natural marriage of AT with its clinical activator heparin by
a covalent linkage of the two molecules. Recent work using nonenzymatic glycation has fi nally
allowed a mechanism for selection of the optimum plasma AT and the most potent heparin for a
linkage without obtrusive human chemical intervention. Vigorous structure-function and mecha-
nistic studies have given a fairly well-defi ned product for progression to
in vivo
fl uid-phase studies
and, fi nally, investigation of a range of ATH surface coatings.
In order to launch ATH fl uid phase and surface-bound biomaterials into clinical use, a num-
ber of issues st a nd out t hat must be add ressed. One si mple aspect is t he production of pha r maceu-
tical grade compound. This is theoretically straightforward. However, industrial scale-up under
General Laboratory Practice (GLP) conditions requires careful technology transfer and proper
selection criteria for the ATH starting materials. Recent work with some clinically approved
AT products is instructive regarding new discoveries that might be gained during this process.
Commercially obtained plasma-derived AT and a recombinant human AT produced in goats
were each used to generate ATH complexes. Biodistribution studies showed that while plasma
AT-containing ATH largely remained in the circulation during early time points, recombinant
ATH rapidly became associated with arterial and venous walls, presumably due to altered N-
linked glycosylation on the recombinant AT moiety.
312
Given that coagulation very commonly
starts at the site of vessel wall damage,
313
selective targeting of ATH by the AT glycans may be
an elegant mechanism for optimizing the conjugate's anticoagulant or antithrombotic function
in vivo
. Alternatively, presentation on biomaterial surfaces of ATH-containing AT with different
N-linked glycosylation may selectively affect favorable interactions between the coated bioma-
terial and either fl uid phase proteins or vascular tissue surfaces.
Finally, optimization of linkage technology for placing ATH complex onto biomaterials must
be completed. Just as coating methods impact the effectiveness of other anticoagulant materials
on blood-contacting device surfaces, ATH potency can best be exploited by the proper presenta-
tion upon biomaterials needing pacifi cation within procoagulant environments. Given the progress
made in the last 8 years, it seems feasible that coatings with covalent AT-heparin complexes can be
rapidly developed for the initial phases of clinical trials.
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