Biomedical Engineering Reference
In-Depth Information
signals. Consequently, the biophysical properties of
ECMs influence various cell functions, including adhe-
sion and migration. Moreover, the fibrillar structure of
matrix components brings about adhesion ligand clus-
tering, which has been demonstrated to alter cell be-
havior. Structural ECM features, such as fibrils and
pores, are often of a size compatible with cellular pro-
cesses involved in migration, which may influence the
strategy by which cells migrate through ECMs.
Natural ECMs modulate tissue dynamics through
their ability to locally bind, store, and release soluble
bioactive ECM effectors such as growth factors to direct
them to the right place at the right time. When many
growth factors bind to ECM molecules through, for ex-
ample, electrostatic interactions to heparan sulfate pro-
teoglycans, it raises their local concentration to levels
appropriate for signaling, localizes their morphogenetic
activity, protects them from enzymatic degradation, and
in some cases may increase their biological activity by
optimizing receptor-ligand interactions. Growth factors
are required in only very tiny quantities to elicit a bi-
ological response.
The macromolecular components of natural ECMs are
degraded by cell-secreted and cell-activated proteases,
mainly by matrix metalloproteases (MMPs) and serine
proteases. This creates a dynamic reciprocal response,
with the ECM stimulating the cells within it and cellular
proteases remodeling the ECM and releasing bioactive
components from it.
With the discovery that ECM plays a role in the
conversion of myoblasts to myotubes and that structural
proteins such as collagen and GAGs are important in
salivary gland morphogenesis it became obvious that
ECM proteins serve many functions including the pro-
vision of structural support and tensile strength, attach-
ment sites for cell surface receptors, and as a reservoir for
signaling factors that modulate such diverse host pro-
cesses as angiogenesis and vasculogenesis, cell migration,
cell proliferation and orientation, inflammation, immune
responsiveness, and wound healing. Stated differently,
the ECM is a vital, dynamic, and indispensable compo-
nent of all tissues and organs and is a nature's scaffold for
tissue and organ morphogenesis, maintenance, and re-
construction following injury.
Until the mid-1960s the cell and its intracellular
contents, rather than ECM, was the focus of attention for
most cell biologists. However, ECM is much more than
a passive bystander in the events of tissue and organ
development and in the host response to injury. The
distinction between structural and functional proteins is
becoming increasingly blurred. Domain peptides of pro-
teins originally thought to have purely structural prop-
erties have been identified and found to have significant
and potent modulating effects upon cell behavior. For
example, the RGD (R: arginine; G: glycine; D: aspartic
acid) peptide that promotes adhesion of numerous cell
types was first identified in the fibronectin (FN) mole-
cule, a molecule originally described for its structural
properties. Several other peptides have since been
identified in ''dual function'' proteins including LN,
entactin, fibrinogen, types I and VI collagen, and vitro-
nectin. The discovery of cytokines, growth factors, and
potent functional proteins that reside within the ECM
characterized it as a virtual information highway between
cells. The concept of ''dynamic reciprocity'' between the
ECM and the intracellular cytoskeletal and nuclear ele-
ments has become widely accepted. The ECM is not
static. The composition and the structure of the ECM are
a function of location within tissues and organs, age of the
host, and the physiologic requirements of the particular
tissue. Organs rich in parenchymal cells, such as the
kidney, have relatively little ECM. In contrast, tissues
such as tendons and ligaments with primarily structural
functions have large amounts of ECM relative to their
cellular component. Submucosal and dermal forms of
ECM reside subjacent to structures that are rich in epi-
thelial cells (ECs) such as the mucosa of the small in-
testine and the epidermis of the skin. These forms of
ECM tend to be well vascularized, contain primarily type
I collagen and site-specific GAGs, and a wide variety of
growth factors.
Collagen types other than type I exist in naturally
occurring ECM, albeit in much lower quantities. These
alternative collagen types each provide distinct me-
chanical and physical properties to the ECM and con-
tribute to the utility of the intact ECM as a scaffold for
tissue repair. Type IV collagen is present within the
basement membrane of all vascular structures and is an
important ligand for endothelial cells, while type VII
collagen is an important component of the anchoring fi-
brils of keratinocytes to the underlying basement mem-
brane of the epidermis. Type VI collagen functions as
a ''connector'' of functional proteins and GAGs to larger
structural proteins such as type I collagen, helping to
provide a gel-like consistency to the ECM. Type III col-
lagen exists within selected submucosal ECMs, such as
the submucosal ECM of the urinary bladder, where less
rigid structure is demanded for appropriate function.
The relative concentrations and orientation of these
collagens to each other provide an optimal environment
for cell growth
in vivo.
This diversity of collagen within
a single material is partially responsible for the distinctive
biological activity of ECM scaffolds and is exemplary of
the difficulty in re-creating such a composite
in vitro,
although the translation of the ECM functions to the
therapeutic use of ECM as a scaffold for tissue engi-
neering applications has been attempted.
The ECM of the basement membrane that resides
immediately beneath ECs such as urothelial cells (UCs)
of the urinary bladder, endothelial cells of blood vessels,
