45
cells can form mature blood vessels that can maintain tissue viability over time. The
basic building blocks for blood vessel engineering are endothelial cells (ECs) and
supporting cells. Both cell types can be isolated from different sources or differentiated from different pluripotent stem cells. In most of the discussed studies, ECs and
supporting cells were co-cultured on different natural and synthetic biomaterials
harnessed to establish a natural 3D environment supportive of vascularization processes. Both matrix stiffness and boundary constraint affect cell-induced contractile
forces, which regulates cell-cell communication, vascular network structure, and
directionality. External forces, in the form of fluid shear stress and tensile forces,
induce vascular network formation and maturation and dictate vascular network
structure and directionality. Although the effect of mechanical stimulation on vascularization is clearly demonstrated, the origin of the biological triggers remains in
question. The impact of mechanical cues on vascularization can be explained by
direct communication, via EC mechanotransduction sensors [1], or by indirect cues
related to environmental changes such as neighbor cell responses, matrix deformation, and biochemical changes. A deeper understanding of the mechanisms through
which ECs are affected by mechanical stimulation in 3D matrices may be achieved
by correlating vascular morphogenesis with the levels of biosensors associated with
relevant known biomechanical pathways. In addition, while the vast majority of
studies focus on changes in vascular network morphology in response to mechanical
cues, technical hurdles limit research on other critical functional parameters key to
the success of engineered vessels, such as perfusability and barrier function.
Perfusable vascular networks enable generation of both luminal shear stress and
circumferential wall stress, both of which play critical roles in vascular mechanobiology [35]. Such physiologic stresses and strains exert vasoprotective actions, mediated by nitric oxide, and provide a homeostatic oxidative balance for further vascular
remodeling and maturation [35]. It is very important to clarify that the developmental stage of the vascular network largely impacts endothelial cell responses to
mechanical stimulation. For example, during vasculogenesis (when vascular networks are not fully established), ECs can respond to external shear stress by accelerating vascular network arrangement. This pro-angiogenic role of shear stress may
be critical in cases of injury, when the tissue is undergoing a wound healing process.
Conversely to anti-angiogenic role in vascular network remodeling, maturation and
quiescence processes occur under homeostasis conditions regulated by luminal
shear stress and circumferential wall stress.
Recently developed experimental approaches, based on evolving 3D microfabrication techniques, may open up new strategies for exploring the impact of biomechanical triggers on vascularization under more physiologically relevant conditions.
Moreover, the control and repeatability of patterning vascular and perivascular cells
in 3D engineered tissue will allow for a higher degree of regulation over the initial
organization of vascular structures and, therefore, will enable to study cell-cell and
cell-matrix mechanical interactions in more accurate and controlled systems. Such
high levels of accuracy will enhance computational estimations of local mechanical
cues, which can be validated by mechanical biosensor-based feedback signals.
Conclusively, integration of high-precision fabrication techniques with advanced
2 Mechanical Regulation of Vascularization in Three-Dimensional Engineered Tissues
cells can form mature blood vessels that can maintain tissue viability over time. The
basic building blocks for blood vessel engineering are endothelial cells (ECs) and
supporting cells. Both cell types can be isolated from different sources or differentiated from different pluripotent stem cells. In most of the discussed studies, ECs and
supporting cells were co-cultured on different natural and synthetic biomaterials
harnessed to establish a natural 3D environment supportive of vascularization processes. Both matrix stiffness and boundary constraint affect cell-induced contractile
forces, which regulates cell-cell communication, vascular network structure, and
directionality. External forces, in the form of fluid shear stress and tensile forces,
induce vascular network formation and maturation and dictate vascular network
structure and directionality. Although the effect of mechanical stimulation on vascularization is clearly demonstrated, the origin of the biological triggers remains in
question. The impact of mechanical cues on vascularization can be explained by
direct communication, via EC mechanotransduction sensors [1], or by indirect cues
related to environmental changes such as neighbor cell responses, matrix deformation, and biochemical changes. A deeper understanding of the mechanisms through
which ECs are affected by mechanical stimulation in 3D matrices may be achieved
by correlating vascular morphogenesis with the levels of biosensors associated with
relevant known biomechanical pathways. In addition, while the vast majority of
studies focus on changes in vascular network morphology in response to mechanical
cues, technical hurdles limit research on other critical functional parameters key to
the success of engineered vessels, such as perfusability and barrier function.
Perfusable vascular networks enable generation of both luminal shear stress and
circumferential wall stress, both of which play critical roles in vascular mechanobiology [35]. Such physiologic stresses and strains exert vasoprotective actions, mediated by nitric oxide, and provide a homeostatic oxidative balance for further vascular
remodeling and maturation [35]. It is very important to clarify that the developmental stage of the vascular network largely impacts endothelial cell responses to
mechanical stimulation. For example, during vasculogenesis (when vascular networks are not fully established), ECs can respond to external shear stress by accelerating vascular network arrangement. This pro-angiogenic role of shear stress may
be critical in cases of injury, when the tissue is undergoing a wound healing process.
Conversely to anti-angiogenic role in vascular network remodeling, maturation and
quiescence processes occur under homeostasis conditions regulated by luminal
shear stress and circumferential wall stress.
Recently developed experimental approaches, based on evolving 3D microfabrication techniques, may open up new strategies for exploring the impact of biomechanical triggers on vascularization under more physiologically relevant conditions.
Moreover, the control and repeatability of patterning vascular and perivascular cells
in 3D engineered tissue will allow for a higher degree of regulation over the initial
organization of vascular structures and, therefore, will enable to study cell-cell and
cell-matrix mechanical interactions in more accurate and controlled systems. Such
high levels of accuracy will enhance computational estimations of local mechanical
cues, which can be validated by mechanical biosensor-based feedback signals.
Conclusively, integration of high-precision fabrication techniques with advanced
2 Mechanical Regulation of Vascularization in Three-Dimensional Engineered Tissues