Biomedical Engineering Reference
In-Depth Information
overcome resistance of surface-bound factors to inhibition,
in vivo
administration of such strong
anticoagulation is not viable because of hemorrhagic complications.
47
Bleeding side effects of UFH
have also hampered use of devices coated with heparin to prevent thrombosis. Leaching of surface-
bound heparin from vascular devices has led to unwanted circulation of anticoagulant as well as
loss of competency of surface coating.
48
Finally, since only about one-third of the starting UFH in
commercial products have anticoagulant activity due to a lack of high affi nity AT-activating binding
sites,
49
much of the surface area coated with heparin is devoid of anticoagulant activity.
Given the issues surrounding heparin's clinical use, there has been an impetus to devise improved
heparinoid derivatives to overcome these obstacles. One novel development is the creation of cov-
alent complexes of AT and heparin (ATH). Rationales behind the conception of covalent ATH
directly address UFH's major limitations. For example, if heparin is permanently linked to AT, the
GAG moiety cannot dissociate to transverse tissue layers or form unfavorable interactions leading
to loss from the circulation. Thus, covalent bonding to the serpin may result in an intravenous half-
life that is closer to that of AT. In addition to increased retention in the circulation, activity of ATH
will be maximal since the AT component will always be in its activated state because of ongoing
effects from the conjugated heparin chain. Thus, thrombin inhibition rates will be increased rela-
tive to those of the dissociable noncovalent AT-UFH complexes. Since contacts between AT and
heparin are maintained in ATH, a signifi cant portion of the heparin will be shielded from interac-
tions with plasma or cell surface proteins. This reduction in non-AT protein binding will engender
a more predictable anticoagulant response since nonproductive interactions with nonanticoagulant
proteins of varying concentrations are suppressed. A further consequence of reduced cell-receptor-
protein binding of the ATH is that bleeding side effects may be lessened. In concert with the relief
from many of UFH's sequelae with biological structures, the aforementioned properties and other
aspects of ATH lend to even more improvement over heparin for coating of biomaterial polymers.
Attachment of heparins to various commercial substrates on vascular devices is hampered by a lack
of functional groups on the GAG that are easily linkable in a consistent fashion. In order to generate
groups for immobilization, heparin is generally modifi ed in ways that are somewhat destructive of
its activity. Alternatively, ATH may be readily linked to surfaces of devices by utilizing the range
of amino acid R
-groups on the AT. Moreover, linkage through the AT guarantees that the critical
anticoagulant heparin chain will be directed away from the polymer surface to inhibit thrombin
generation in the blood fl ow. Further, all ATH molecules coated on the surface will be permanently
activated compared to surfaces with UFH in which only up to one-third of the molecules will be
active. Thus, the overall potential of the projected characteristics of ATH to alleviate UFH's limi-
tations encouraged the production of numerous covalent ATH complexes for study as a possible
anticoagulant agent.
The purpose of this chapter is to give a thorough presentation of the development of ATH
from its starting materials, with particular attention to its application as a biomaterial coating
that improves biocompatibility. This approach is intended to introduce the reader to structural
aspects and synthesis of AT, heparin, ATH, and ATH-containing surfaces, which will act as a
reference guide for production of devices that are non- or antithrombotic when in contact with
blood. AT structure-function will be described. Heparin structure and
in vivo
mechanisms will be
outlined with respect to the long-established use of this anticoagulant in thrombosis prophylaxis
and treatment. A general examination of ATH properties that directly address the major defi cien-
cies of UFH derivatives will be made as a framework for the design of conjugates that should give
the desired properties. Chemical and biological characteristics of ATH compounds that have been
produced will be explored from a chronological perspective to give a fl avor of the attempts toward
optimization of this molecule. This perspective may be useful in providing insights for further
improvements by future workers. Once development of the ATH conjugate has been discussed, the
processes for coating surfaces with ATH will be described and the resultant performance
in vitro
and
in vivo
will be listed. Finally, the chapter ends with a synopsis of possible future paths for this
new technology.
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