Biomaterials for Cell-Based Therapeutic Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 243

1 Introduction
Ischemia, characterized by the restriction of blood supply to various vital tissues
and organs, is the leading cause of tissue morbidity, and ultimately death across
the globe. There are a variety of causes of ischemia including acute injury,
atherosclerosis, hypertension, and embolism, among others. Early diagnosis and
subsequent surgical methods such as angioplasty or bypass grafting can prevent
ischemia [ 1 ]. These methods are useful in preventing ischemia or treating patients
in the early stages of ischemia. However, it is a challenging task to treat patients
who are in the advanced stages of ischemia, necessitating the development of a
method to treat such patients.
Efforts are separately being made to treat critical-sized wounds and tissue
defects, as a result of acute and chronic injuries and surgery, via tissue regener-
ation. It is well agreed that success in these tissue regenerative therapies relies on
the ability to facilitate the transportation of oxygen and nutrients to cells that are
either transplanted in or migrate into the tissue defects [ 2 ]. It is also important to
remove cellular metabolites and wastes from the tissue defects.
One promising approach that has emerged to treat ischemia and improve wound
healing and tissue regeneration is to regenerate micro-sized blood vessels by stim-
ulating angiogenesis in a controlled manner. Angiogenesis is characterized by the
sprouting of capillaries from pre-existing blood vessels (Fig. 1 ). This branching
process is active during development, self-healing, and tumorigenesis. Angiogenesis
is activated by the binding of various angiogenic cytokines and growth factors with
endothelial progenitor and precursor cells [ 3 ]. These soluble angiogenic factors
include vascular endothelial growth factor (VEGF), fibroblast-like growth factors
(FGFs), platelet derived growth factor (PDGF), and endothelin. The binding of
angiogenic factors stimulates cells to proliferate, migrate, and form endothelial
lumen, in concert with enzymatic degradation of interstitium driven by cell secreted
matrix metalloproteinases [ 3 ]. Subsequently, smooth muscle cells and pericytes are
mobilized to form mature blood vessels stabilized by smooth muscle layers and
pericyte layers. The soluble factors involved with the maturation include PDGF,
angiopoietin-1 (Ang1), and transforming growth factor (TGF)-b [ 3 ].
Supported by in-depth understanding of the role of individual angiogenic
cytokines and growth factors, these signaling factors have been tested in many pre-
clinical and clinical trials for revascularization [ 4 ]. Specifically, significant
advances in the recombinant techniques are expediting the use of these signaling
proteins with minimal concerns of host inflammation and pathogenic infection.
Single, dual, and multiple soluble factors are systemically or locally administered
to target tissue and stimulate revascularization. In addition, these soluble factors
are often encapsulated in nano-or micro-sized particles to extend their bioactivity
in physiological conditions [ 3 ]. Alternatively, these factors are loaded into a micro
porous scaffold or hydrogel typically used as a tissue engineering scaffold so that
the factors sustainably stimulate host and transplanted cells towards blood vessel
formation [ 5 ].