Formation of Chitosan-Based Hydrogels Network - Chitosan Based Hydrogels: Functions and Applications - page 178

soluble and tethered signaling cues from the ECM environment. In turn, these receptor-
ligand interactions trigger complex cascades of intracellular enzymatic reactions that
regulate gene and protein expression, and define the fate of a cell in a tissue. Simul-
taneously, cells send out signals to actively construct and degrade their microenviron-
ment. Thus, the ECM acts not only as a simple space filler and a mechanical scaffold
for the cells, but also as a bioactive and dynamic environment that mediates cellular
functions. Generally, the natural ECM has three basic biofunctions, including cell adhe-
sion, proteolytic degradation, and GF binding. Cell attachment to the ECM is an obvious
prerequisite for a number of important cell function processes, such as cell proliferation
and cell migration. The ECM provides cell adhesive domains for binding cell surface
receptors. There are various cell surface receptors, among which are integrins, selectins,
CD44, and syndecan. Integrins are the major family responsible for cell attachment to the
ECM; they bind to specific domains present in ECM proteins such as fibronectin, laminin,
and collagen. Through binding to these functional cell-binding domains, integrins play
central roles in tissue development, organization, and maintenance, by providing anchor-
age and triggering signals that direct cell function, cell cycle progression, and expression
of differentiated phenotypes. The proteolytic degradation of the natural ECM is an essen-
tial feature of a variety of biological processes, such as cell migration, tissue repair, and
remolding. Most ECM proteins, including collagen, fibrin, fibronectin, and laminin, have
specific cleavage sites for degradation by enzymes, such as matrix metalloproteinases,
plasmin, and elastase [3,4].
Moreover, GAGs play a critical role in assembling protein-protein complexes such as
GF-receptor or enzyme-inhibitor on the cell surface and in the ECM that are directly
involved in initiating cell signaling events or inhibiting biochemical pathways. Further-
more, extracellular GAGs can potentially sequester proteins and enzymes and present
them to the appropriate site for activation ( cf . Figure 4.1). Thus for a given high-affinity
GAG-protein interaction, the positioning of the protein-binding oligosaccharide motifs
along the GAG chain determines whether an active signaling complex is assembled on the
cell surface and/or an inactive complex is sequestered in the matrix. It should be noted that
high-affinity GAG-protein interactions are not the only biologically significant interac-
tions. GAGs have been shown to play important roles in maintaining morphogen gradi-
ents across a cell or tissue, which have been implicated in developmental processes.
Maintaining a gradient in the concentration of GFs or morphogens would involve graded
affinities between different GAG sequences with the given protein. Thus, the nature of
GAG-protein interactions coupled with their sequence diversity enables GAGs to “fine-
tune” or what can be viewed as an “analog modulation” of the activity of proteins [5].
On the other hand, hydrogels are comprised of cross-linked polymer networks that have
a high number of hydrophilic groups or domains. These networks have a high affinity for
water, but are prevented from dissolving due to the chemical or physical bonds formed
between the polymer chains. Water penetrates these networks causing swelling, giving
the hydrogel its form. Fully swollen hydrogels have some physical properties common to
living tissues, including a soft and rubbery consistency, and low interfacial tension with
water or biological fluids. The elastic nature of fully swollen or hydrated hydrogels has
been found to minimize irritation to the surrounding tissues after implantation. The low
interfacial tension between the hydrogel surface and body fluid minimizes protein adsorp-
tion and cell adhesion, which reduces the chances of a negative immune reaction. Because
the hydrogel's physiochemistry is similar to the native ECM, hydrogels can serve as dual-
propose devices, acting as a supporting material for cells during tissue regeneration as
well as delivering a drug payload [2,6,7].