Formation of Chitosan-Based Hydrogels Network - Chitosan Based Hydrogels: Functions and Applications - page 177

4.1 Complex Tissue from Simple Molecules
The tissues of the human body contain significant extracellular space, into which extracel-
lular matrix (ECM) molecules are secreted by the cells to form a complex hydrogel network.
The ECM provides mechanical support for tissues, organizes cells into specific tissues, and
controls cell behavior. In other words, ECM is a dynamic structure that provides structural
and anchoring support to the cells to improve tissue architecture. It also contributes to
signaling, directing cell fate and function through cell-matrix interactions. In addition,
the ECM is constantly remodeled by cells during development, homeostasis, and wound
healing by balancing its synthesis and degradation by a variety of enzymes.
4.1.1 eCM Component Cross-linking
Generally, the natural ECM is mainly composed of two classes of macromolecules: poly-
saccharide chains of the class called glycosaminoglycans (GAGs), which are usually found
covalently linked to protein in the form of proteoglycans (PGs), and fibrous proteins,
including collagens, elastin, fibronectin, and laminin, which have both structural and
adhesive functions. The PG molecules form highly hydrated gels, in which the assembled
fibrous proteins are embedded and interact with cells through mechanical as well as
chemical signals [1,2].
The ECM proteins include structural fibrous proteins such as collagen and elastin and
cell-adhesive proteins such as fibrolectin and laminin. Collagen, the most abundant pro-
tein in mammals, provides tensile strength to the ECM, while other proteins, such as elas-
tin, give the ECM its elasticity. Collagen comes in many different types. Type I collagen is
the most common fibrillar collagen found in skin, bone, and tendons, and type II collagen
possesses a similar fibrillar structure that provides tensile strength to the cartilage. Cells
bind to the ECM mainly through adhesive proteins such as laminin and fibronectin.
Laminin, which has a cross-shaped trimer structure containing a, b, and g chains, is the
major adhesive protein in basal lamina with binding sites for cell membrane receptors and
type IV collagen, heparan sulfate proteoglycan (HSPG), and entacin. Fibronectin, evolu-
tionarily related to fibrinogen, is another important adhesive protein in the ECM. Fibrinogen
is a V-shaped dimmer with several binding domains for mediating the connection between
the ECM and cell membrane, and binds a variety of proteins such as collagen and fibrin,
as well as cell-surface receptors such as integrins [3].
ECM proteins are embedded in highly negatively charged, polysaccharide-rich, gelati-
nous ground substances, called glycans, including GAGs and PGs. GAGs are linear poly-
mers of repeated disaccharide derivative with two types: nonsulfated, such as hyaluronic
acid (HA), and sulfated, such as chondroitin, dermatan, heparin, and keratin sulfates.
Sulfated GAGs can assemble on serine-rich proteins to form PGs, such as aggrecan and
HSPG. Both GAGs and PGs swell in the aqueous spaces between protein fibrils to form
hydrogel, taking compressive stresses, limiting tissue collapse under pressure. Glycans
also allow tissues to diffuse nutrients and provide the reservoir for signaling molecules
such as growth factors (GFs) [4].
4.1.2 Performance of Cross-linking Network
As mentioned above, ECM components undergo self-assembly as well as cell-directed
assembly to form complex 3D organized hydrogel networks. Cell receptors bind both