77
the gestational sac revealed even lower O 2 levels in earlier stages of embryogenesis, where O 2 is only transported by simple diffusion [115]. Diffusion, as opposed
to convection, transports nutrients between cells very slowly. Before vasculogenesis begins, the maximum diameter that a spherical embryo can reach without having any anoxic cells was calculated to be 2 mm [29]. This value varies with the
embryo’s geometry and, most importantly, with the O 2 consumption of the animal
cells. The results of in vivo imaging of various animal embryos show that the maximum diameter remains below 1 mm, which agrees with the theoretically estimated
value [29, 230].
Vasculogenesis is crucial to facilitate cell proliferation and for the embryo to
grow larger. In mouse embryos, vasculogenesis commences after day 7, with the
differentiation of the mesoderm into angioblasts, which then assemble to form a
simple circulatory system consisting of a heart, dorsal aorta, and yolk sac by day 8
[56, 107]. Afterward, spatial increases are observed in O 2 levels throughout the
course of embryonic development [141]. These profound spatiotemporal O 2 level
changes in the embryo can be accepted as evidence for vascular formation during
embryogenesis. The large existing vasculature then sprouts and proliferates to supply O 2 and nutrients to cells located in poorly oxygenated regions. Hypoxia, considered the most critical factor controlling the angiogenesis process, works via
numerous protein-signaling pathways. The mechanism determining the directionality of angiogenesis and the complex networking of endothelial capillaries around
the tissues is manipulated by several other parameters, including hemodynamic
forces and cytokines; this mechanism will be discussed later in the chapter [150].
Once embryonic development is complete and sufficient concentrations of O 2 and
nutrients are supplied to the tissues, the oxygen gradient still persists in some tissues,
providing several benefits to specific cell types. In adults, O 2 distribution ranges
from 1 to 13 in normal tissues. Although the formation of blood vessels and capillary
networking is complete, some tissues still lack vasculature, such as the bone marrow
niche [91, 132, 175]. In such tissues, diffusion is the controlling mechanism for
nutrient transport, thus resulting in a wide range of O 2 distributions from the internal
hypoxic region to the external regions, which remains at physiological O 2 .
The discovery of circulating EPCs in blood vessels revealed that neovascularization in adults is directed not only by angiogenesis but also by the vasculogenesis
process, which depends on the renewal, mobility, recruitment, and differentiation of
EPCs [12, 13, 96, 219]. The bone marrow (BM) provides a host microenvironment
for a variety of cells, including hematopoietic stem cells (HSCs), mesenchymal
stem cells (MSCs), and EPCs. The development of EPCs occurs in the BM, which
has a unique structure that allows severe hypoxic regions to exist. Although the BM
is inaccessible for noninvasive oxygen measurements, both simulation studies and
qualitative measurements have demonstrated the existence of hypoxic regions.
Several theoretical models have been developed in order to simulate the distribution
of oxygen throughout the BM [41, 132, 133]. Chow et al. used homogeneous
Kroghian models to estimate oxygen levels in the BM [41]. Their simulations suggested that both HSCs and EPCs are exposed to low O 2 tensions in the BM. There
are various BM architectural organizations possible depending on parameters such
4 Hypoxia and Matrix Manipulation for Vascular Engineering
the gestational sac revealed even lower O 2 levels in earlier stages of embryogenesis, where O 2 is only transported by simple diffusion [115]. Diffusion, as opposed
to convection, transports nutrients between cells very slowly. Before vasculogenesis begins, the maximum diameter that a spherical embryo can reach without having any anoxic cells was calculated to be 2 mm [29]. This value varies with the
embryo’s geometry and, most importantly, with the O 2 consumption of the animal
cells. The results of in vivo imaging of various animal embryos show that the maximum diameter remains below 1 mm, which agrees with the theoretically estimated
value [29, 230].
Vasculogenesis is crucial to facilitate cell proliferation and for the embryo to
grow larger. In mouse embryos, vasculogenesis commences after day 7, with the
differentiation of the mesoderm into angioblasts, which then assemble to form a
simple circulatory system consisting of a heart, dorsal aorta, and yolk sac by day 8
[56, 107]. Afterward, spatial increases are observed in O 2 levels throughout the
course of embryonic development [141]. These profound spatiotemporal O 2 level
changes in the embryo can be accepted as evidence for vascular formation during
embryogenesis. The large existing vasculature then sprouts and proliferates to supply O 2 and nutrients to cells located in poorly oxygenated regions. Hypoxia, considered the most critical factor controlling the angiogenesis process, works via
numerous protein-signaling pathways. The mechanism determining the directionality of angiogenesis and the complex networking of endothelial capillaries around
the tissues is manipulated by several other parameters, including hemodynamic
forces and cytokines; this mechanism will be discussed later in the chapter [150].
Once embryonic development is complete and sufficient concentrations of O 2 and
nutrients are supplied to the tissues, the oxygen gradient still persists in some tissues,
providing several benefits to specific cell types. In adults, O 2 distribution ranges
from 1 to 13 in normal tissues. Although the formation of blood vessels and capillary
networking is complete, some tissues still lack vasculature, such as the bone marrow
niche [91, 132, 175]. In such tissues, diffusion is the controlling mechanism for
nutrient transport, thus resulting in a wide range of O 2 distributions from the internal
hypoxic region to the external regions, which remains at physiological O 2 .
The discovery of circulating EPCs in blood vessels revealed that neovascularization in adults is directed not only by angiogenesis but also by the vasculogenesis
process, which depends on the renewal, mobility, recruitment, and differentiation of
EPCs [12, 13, 96, 219]. The bone marrow (BM) provides a host microenvironment
for a variety of cells, including hematopoietic stem cells (HSCs), mesenchymal
stem cells (MSCs), and EPCs. The development of EPCs occurs in the BM, which
has a unique structure that allows severe hypoxic regions to exist. Although the BM
is inaccessible for noninvasive oxygen measurements, both simulation studies and
qualitative measurements have demonstrated the existence of hypoxic regions.
Several theoretical models have been developed in order to simulate the distribution
of oxygen throughout the BM [41, 132, 133]. Chow et al. used homogeneous
Kroghian models to estimate oxygen levels in the BM [41]. Their simulations suggested that both HSCs and EPCs are exposed to low O 2 tensions in the BM. There
are various BM architectural organizations possible depending on parameters such
4 Hypoxia and Matrix Manipulation for Vascular Engineering