Biomaterials for Cell-Based Therapeutic Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 244

Fig. 1 Schematic description of blood vessel formation through angiogenesis. Following
vascular endothelial growth factor (VEGF) stimulation, immature new blood vessels sprout from
existing vasculature lacking pericytes or smooth muscle cells. Stimulation via angiopoeitin 1
(Ang 1) and platelet derived growth factor (PDGF) promotes association of the neovessel with
pericytes and smooth muscle cells. The result is a new stable and mature blood vessel [ 30 ]
However, these molecular therapies are often plagued by limited outcomes. For
example, recreation of mature and functional blood vessels requires sequential
activation of multiple signaling factors; however, it is still a challenging task to
optimize the dose and duration of multiple drug molecules for revascularization [ 3 ].
In addition, the frequent and high dosage of angiogenic factors presents the potential
risks of promoting inflammation and also producing leaky and dysfunctional neo-
vessels [ 5 ].
To overcome these challenges encountered with molecular therapies for
revascularization, cells which can endogenously express multiple angiogenic
factors and also release them in response to external stimuli (e.g. hypoxia or
inflammatory factors) are increasingly studied as an alternative vascular medicine.
These cells include mesenchymal stem cells, endothelial progenitor cells, and
fibroblasts [ 1 ]. Alternatively, cells transfected with non-viral or viral genes
encoding angiogenic factors can produce exogenous angiogenic factors in a sus-
tained manner [ 5 ]. These cells are also advantageous to delivering multiple
angiogenic factors in a sustained manner.
In the beginning of cell therapies, it was common to locally transplant the cells via
intramuscular injection [ 6 ]. However, transplanted cells without any physical barriers
present the potential problem of initiating an immune response. Furthermore, cells
injected into a patient may lose their bioactivity and also scatter due to extracellular
chemical and mechanical factors at the transplantation sites. In order to enhance
bioactivity and viability of cells, and further regulate their function to produce
angiogenic factors, efforts are increasingly made to load cells into biomaterials with
varied forms including microporous scaffolds, fibrous scaffolds and hydrogels.