Biomedical Engineering Reference
In-Depth Information
vascular permeability. There are four alternatively sliced
variants of 121, 165, 189, and 206 amino acid residues.
The receptors for VEGF are VEGFR-1 and VEGFR-2.
Homozygous mutants of the VEGF receptors led to lack
of vasculogenesis and death of mouse embryos on day 8,
indicating that VEGF receptors are essential for the
formation of a normal vasculature. The FGFs tend to be
potent yet relatively non-specific growth factors with
some angiogenic activity while the VEGF group trends to
be relatively more specific to angiogenesis but with rel-
ative endothelial cell-specific, yet weaker, endothelial
cell mitogenicity.
isoforms exist as disulfide-linked homodimers and he-
terodimers and differently bind homodimer and heter-
odimer combinations of two receptor tyrosine kinases,
PDGF-Ra and PDGF-Rb. The PDGF-AA is widely
expressed in fibroblasts, osteoblasts, platelets, macro-
phages, smooth muscle cells, endothelial cells, and
Langerhans cells. The PDGF-AA activity is ubiquitous,
but dependent on cell expression of PDGF-Ra. The
PDGF-AA plays key roles in protein synthesis, chemo-
taxis inhibition, embryonic neuron fiber development,
and bronchial lung development. The PDGF-AB dem-
onstrates mitogenic activity for vascular smooth muscle
cells (VSMCs) as well as stimulating angiogenesis in the
heart. Parallel to PDGF-AA and PDGF-BB expression,
PDGF-AB is important in a wide variety of cellular pro-
cesses of the immune, nervous, and cardiovascular sys-
tems. The PDGF-BB is mainly expressed in endothelial
cells and participates in angiogenesis and arterialization of
early organ, respiratory, and neuronal development. The
PDGF-BB is also observed in platelets, neurons, macro-
phages, and fetal fibroblasts. The PDGF-BB, via PDGF
Rb, is involved in cellular proliferation and TGF-like
activities. The PDGF-CC and PDGF-DD form a novel
subgroup of the PDGF family distinguished by structural
differences that include an N-terminal CUB domain.
Widely expressed in multiple embryonic and adult cell,
tissue, and organ types, PDGF-CC appears to be im-
portant for angiogenesis, cardiovasculature development,
and tumorigenesis.
7.2.7.1.4 TGF-b1
The TGF-b1 is the superfamily of growth and differen-
tiating factors of which BMP is a member. The MW of
TGF-b1 is 25 kDa. This protein is synthesized in plate-
lets and macrophages, as well as in some other cell types.
When released by platelet degranulation or actively se-
creted by macrophages, TGF-b1 acts as a paracrine
growth factor (i.e., growth factor secreted by one cell
exerting its effect on an adjacent second cell), affecting
mainly fibroblasts, marrow stem cells, and osteoblast
precursors. The TGF-b1 stimulates chemotaxis and
mitogenesis (increase in the cell populations of healing
cells) of osteoblast precursors, promotes differentiation
toward mature osteoblasts, stimulates deposition of
collagen matrix, and inhibits osteoclast formation and
bone resorption. Therefore, TGF-b represents a mecha-
nism for sustaining a long-term healing and bone re-
generation module.
7.2.7.2 Delivery of growth factors
The use of growth factors has not always been achieved
successfully in vivo. A major reason for this is the high
diffusibility and short half-life time of growth factors
in vivo to effectively retain their biological activities. Topi-
cal delivery of proteins remains in the site administered
for a limited duration because of protein diffusion, pro-
teolytic cleavage, and the early bioabsorption of carriers
when carriers such as fibrin glue are applied. Application
of growth factors in tissue engineering requires en-
hancement of their activities in vivo by means of ade-
quate delivery systems.
The delivery methods include bolus injection; release
of protein adsorbed directly on scaffold surfaces; in col-
lagen sponge or in porous coatings; constantly delivery via
osmotic pumps; and controlled release of protein trapped
in an absorbable polymer. There have been reported
numerous studies on the formulation of protein growth
factors within absorbable polymers for use as drug de-
livery vehicles. Although trapping in absorbable polymers
seems to yield formulations that can deliver active pro-
teins, there is ample literature demonstrating that or-
ganic solvents can have a negative effect on protein
association and function. By extension from normal
7.2.7.1.5 PDGF
The PDGF is a glycoprotein existing mostly as a dimer of
two chains of about equal size and MW (14-17 kDa). The
protein that seems to be the first growth factor present in
a wound is synthesized not only in platelet but also in
macrophages and endothelium. It initiates connective
tissue healing, including bone regeneration and repair. At
the time of injury PDGF emerges from degranulating
platelets and activates cell membrane receptors on target
cells. The most important specific activities of PDGF in-
clude mitogenesis, angiogenesis (endothelial mitoses into
functioning capillaries), and macrophage activation (de-
bridement of the wound site and a second-phase source of
growth factors for continued repair and bone formation).
The PDGF is also stored in the bone matrix and released
upon activation of osteoblasts, resulting in an increase of
new bone formation. The PDGF is a potent stimulator of
fibroblast cell migration, mitogenesis, proliferation, and
matrix synthesis important in wound healing.
The four PDGF isoforms (A, B, C, and D) are char-
acterized by a highly conserved eight-cysteine domain
termed the PDGF/VEGF homology domain. The PDGF
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