Biomedical Engineering Reference
In-Depth Information
1.3
Adhesive Interactions in Cell and Host Responses to Biomaterials
Because of their essential roles in cell adhesion to ECM components, inte-
grins are critically involved in host and cellular responses to biomaterials.
For example, the platelet integrin
α
IIb
β
3
(GP IIb/IIIa) binds to several lig-
ands involved in platelet aggregation in hemostasis and thrombosis, such as
fibrinogen, von Willebrand factor, and fibronectin [8]. Furthermore, this re-
ceptor mediates initial events in the blood-activation cascade upon blood
contact with synthetic materials [22, 23]. Leukocyte-specific
β
2
integrins,
in particular
α
M
β
2
(Mac-1), mediate monocyte and macrophage adhesion
to various ligands, including fibrinogen, fibronectin, IgG, and complement
fragment iC3b, and these receptors play central roles in inflammatory re-
sponses in vivo [24, 25]. Binding of
α
M
β
2
integrin to fibrinogen P1 and P2
domains exposed upon adsorption to biomaterial surfaces controls recruit-
ment and accumulation of inflammatory cells on implanted devices [26].
This integrin is also involved in macrophage adhesion and fusion into giant
foreign-body cells [25, 26]. For numerous connective, muscular, neural, and
epithelial cell types,
β
1
integrins provide the dominant adhesion mechanism
to extracellular matrix ligands, including proteins adsorbed onto biomaterial
surfaces [27]. In addition to supporting adhesion, spreading, and migra-
tion, these receptors activate intracellular signaling pathways controlling gene
expression and protein activity that regulate cell proliferation and the expres-
sion of differentiated phenotypes.
Integrins mediate cellular interactions with biomaterials by binding to ad-
hesive extracellular ligands that can be (i) adsorbed from solution (e.g., pro-
tein adsorption from blood, plasma, or serum); (ii) secreted and deposited
onto the biomaterial surface by cells (for example, FN and COL-I deposi-
tion); and/or (iii) engineered at the interface (e.g., bioadhesive motifs such as
RGD incorporated onto synthetic supports) (Fig. 2). These interactions are of-
ten highly dynamic in nature, and the dominant adhesion mechanism may
change over time and for different cell types. For example, the dominant
adhesive ligand present on biomaterials when exposed to plasma is fibrino-
gen, while vitronectin is generally responsible for cell adhesion to surfaces
exposed to serum [28, 29]. These adhesive ligands may be displaced and re-
placed by other adhesive proteins in the surrounding medium. Additionally,
while cells may initially adhere to synthetic surfaces via proteins precoated
(e.g., FN treatment) or adsorbed from solution, many cell types rapidly de-
grade/reorganize this layer of adsorbed proteins and deposit their own ECM.
Furthermore, the integrin expression and activity profiles on a particular cell
can change over time. As mentioned above, most cells exhibit several inte-
grins specific for the same ligand, and the binding activity of these receptors
can be rapidly regulated via changes in integrin conformation. It is import-
ant to note that the integrin expression profile does not necessarily correlate
