Biomedical Engineering Reference
In-Depth Information
and xenogeneic biologic devices and can limit the effi cacy of cell transplant
and cell seeding strategies for tissue engineered devices.
The activation of complement is a key component of the innate immune
response which occurs either via the classical pathway mediated by antigen
or C1q binding to antigen, the alternative pathway mediated by activated
complement components binding directly to the foreign body surface, or
the mannose binding (MB)-lectin pathway. Biomaterials activate comple-
ment primarily via the classical and alternative pathway, and the degree of
complement activation appears to be dependent on the type of biomaterial
used. Complement activation assayed by C5a generation has been shown
to be signifi cantly greater in patients with implanted polyethylene tere-
phthalate (PET) compared to expanded polytetrafl uoroethylene (ePTFE)
by both the classical pathway and alternative pathway (Shepard et al. , 1984).
All complement pathways converge on the formation of C3 convertase
which catalyzes downstream cleavages and generation of C5a, C3b, C3a,
and other products, which have effector functions that include peptide
mediation of infl ammation, phagocyte and other leukocyte recruitment, and
opsonization (Chenoweth, 1987; Henderson and Chenoweth, 1987; Carroll,
2008) Thus the activation of complement can have signifi cant downstream
effects by propagating infl ammation, inducing anaphylactoid reactions, and
potentially promoting device thromboses (Gorbet and Sefton, 2004; Nilsson
et al. , 2007).
In response to complement activation and generated C5a, leukotriene
B4 (LTB4), platelet activating factor (PAF) and other chemokines, and
deposited fi brin coagulum, neutrophils are recruited early in infl amma-
tion and produce products of oxygen metabolism and proteases which
contribute to tissue and biomaterial injury. If an endothelium is present,
neutrophil integrin receptors and sulfated sialyl-Lewis receptors bind to
endothelial cell intercellular adhesion molecules (ICAM) and P- and
E-selectins. For this reason, the determination of the biocompatibility of a
particular biomaterial often refers to the ability of a material to induce
the expression of EC surface proteins such as PECAM-1, ELAM-1,
ICAM-1 and VCAM-1 (Granchi et al. , 1998). For example, the demon-
stration that pyrolytic carbon does not induce expression of these adhe-
sion proteins on ECs had suggested their potential utility as a coating for
PET synthetic prostheses (Cenni et al. , 1995). In vitro assays, however, do
not necessarily account for other factors present in vivo which modulate
EC and neutrophil interactions on the biomaterial surface. These include
products of platelet degranulation, complement activation, and macro-
phage activation, such as interleukin-1 (IL-1), tumor necrosis factor
(TNF), LTB4, PAF, and C5a which have been demonstrated to increase
adhesiveness between neutrophils and ECs, and likely serve to promote
leukocyte adherence to the endothelium either surrounding the device or
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