Biomaterials for Cell-Based Therapeutic Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 249

nanofiber mesh characterized in vitro, there has not been success in developing
mature and functional blood vessels aligned along the fiber orientation in vivo.
2.3 Hydrogel
Hydrogels are commonly formed from chemical and physical cross-linking reac-
tions between water soluble polymers [ 20 ]. These hydrogels have been increas-
ingly used for cell encapsulation and transplantation because of several
advantageous features including structural similarity to natural ECM and hydrated
environments. Recently, efforts are being extensively made to regulate phenotypic
activities of encapsulated cells with chemical and mechanical properties of
hydrogels in concert with soluble factors. In addition, cell-encapsulated hydrogels
can be injected into target sites, allowing for minimally invasive cell transplan-
tation. Furthermore, coupled with various microfabrication techniques, cell-
encapsulated hydrogels can be built into three dimensional constructs consisting of
multiple layers with pre-defined spatial organization [ 21 ]. These merits of
hydrogels have led to increasing exploration of the use of hydrogels in cell-based
vascularization therapies.
One popular approach is to encapsulate cells which can endogenously produce
multiple angiogenic factors. These cells were encapsulated into the hydrogel via
mild in situ cross-linking reactions. Cell-secreted angiogenic factors are released
from the hydrogel by diffusion. One example of such a system involves the
encapsulation of fibroblasts in alginate gel beads. The cells encapsulated in the gel
beads remained viable over the course of the study, as demonstrated by constant
metabolic activity. After 17 days of in vitro culture, VEGF secreted into the media
peaked at approximately 25 ng/mL. The cell-secreted VEGF was released from
the gel beads via diffusion. Endothelial cells cultured with media conditioned from
the alginate beads exhibited an increase in proliferation [ 22 ].
Recently, efforts are increasingly being made to control cellular production of
angiogenic factors by tuning chemical and mechanical properties of the hydrogels.
For example, using pendent polymer chains inserted between cross-linking junc-
tions, the mechanical stiffness of poly(ethylene glycol) diacrylate (PEGDA)
hydrogels was tailored without significantly altering gel permeability. Fibroblasts
encapsulated in the hydrogels with varying stiffness displayed that the growth
factor productions, specifically VEGF, become maximal when the elastic modulus
of the hydrogel was comparable to the elastic of fibrous tissue (i.e. 10-12 kPa)
(Fig. 6 )[ 23 ]. Additionally, incorporating photo cross-linkable alginate methacry-
lates into the PEGDA hydrogels resulted in an increase in both rigidity and per-
meability of the hydrogel, so that the various cell types could remain viable and
active to produce angiogenic factors in the 3D gel matrix [ 24 , 25 ]. These important
hydrogel properties can be controlled in a more sophisticated manner by assem-
bling hydrogels with various microfabrication techniques including stereolithog-
rahic assembly processes (Figs. 7 and 8 )[ 21 ].