105
4.3 Future Directions
Understanding the simultaneous effects of the ECM and O 2 tension on the processes
of angiogenesis/vasculogenesis will enable researchers to control these two factors
and thereby manipulate cellular responses in desired directions. Recent developments in many different fields of research, such as smart biomaterials and microfluidics, have made it possible to design and construct novel in vitro microenvironments
for cells. Smart biomaterials have been developed that can dynamically respond to
external stimuli, such as light [79], pH [174], temperature [216], and cytokines
[124]; these materials can truly mimic the complexity of a native ECM environment. The ability to control the physical and chemical properties of the gels at different spaces and times will provide better control over different stages of
angiogenesis. Light-sensitive hydrogels can be used to create biomaterials with distinct cross-linking densities to promote and inhibit cell spreading and migration
[121], which in turn can be used to pattern complex vascular networks. Since vascular morphogenesis is sensitive to tissue stiffness [52], orientation [23], and polarity [42, 149], researchers could also induce vascular assembly into a tube by creating
elasticity, GFs, adhesion peptide, and oxygen gradients along the 3D scaffold [144,
151, 228]. The development of photodegradable hydrogels, as well as the control of
cell-mediated degradation in synthetic hydrogels, whose mechanical and chemical
properties are controllable during the timescale of cellular development [123], has
enabled control of vascular assembly [89, 90]. On the other hand, creating smart
biomaterials that can shrink, swell, or degrade in response to oxygen tension would
also be desirable to prevent the formation of anoxic regions inside the gels. More
precise temporal control of O 2 gradients inside the constructs could also be beneficial to explain various phenomena taking place in the body, such as EPC regeneration in the BM and embryonic development, where the O 2 gradient plays a critical
role in differentiation and migration dynamics.
Figure 4.7 illustrates two proposed approaches for controlling oxygen distribution and ECM properties. One proposal for regulating O 2 gradients inside the gel
would be to incorporate microfluidic technology [66, 129, 163, 220]. Although this
approach provides better O 2 control over 3D microenvironments, the problem of
spatial variations in O 2 levels throughout the gel, due to the cells’ O 2 consumption,
must still be addressed. Advancements in microfluidic technology could enable spatial O 2 control over 3D microenvironments; for instance, the gel could be prepared
around a microtube, which would supply O 2 by flushing growth media containing a
desired amount of O 2 (Fig. 4.7a). Hence, different O 2 gradients could be generated
via the manipulation of O 2 concentrations in the outside environment and inside the
microtube.
Another method for controlling and improving O 2 transport in the gel would be to
microencapsulate O 2 carrier liquids, such as perfluorocarbons (PFCs). Due to their
high capacity to dissolve O 2 , PFCs have been used as a blood replacement to improve
O 2 delivery to tissues [112, 183]. Based on the high oxygen-carrying capacity of
PFCs, Radisic et al. [183] developed a PFC-perfused system to supply sufficient
4 Hypoxia and Matrix Manipulation for Vascular Engineering
4.3 Future Directions
Understanding the simultaneous effects of the ECM and O 2 tension on the processes
of angiogenesis/vasculogenesis will enable researchers to control these two factors
and thereby manipulate cellular responses in desired directions. Recent developments in many different fields of research, such as smart biomaterials and microfluidics, have made it possible to design and construct novel in vitro microenvironments
for cells. Smart biomaterials have been developed that can dynamically respond to
external stimuli, such as light [79], pH [174], temperature [216], and cytokines
[124]; these materials can truly mimic the complexity of a native ECM environment. The ability to control the physical and chemical properties of the gels at different spaces and times will provide better control over different stages of
angiogenesis. Light-sensitive hydrogels can be used to create biomaterials with distinct cross-linking densities to promote and inhibit cell spreading and migration
[121], which in turn can be used to pattern complex vascular networks. Since vascular morphogenesis is sensitive to tissue stiffness [52], orientation [23], and polarity [42, 149], researchers could also induce vascular assembly into a tube by creating
elasticity, GFs, adhesion peptide, and oxygen gradients along the 3D scaffold [144,
151, 228]. The development of photodegradable hydrogels, as well as the control of
cell-mediated degradation in synthetic hydrogels, whose mechanical and chemical
properties are controllable during the timescale of cellular development [123], has
enabled control of vascular assembly [89, 90]. On the other hand, creating smart
biomaterials that can shrink, swell, or degrade in response to oxygen tension would
also be desirable to prevent the formation of anoxic regions inside the gels. More
precise temporal control of O 2 gradients inside the constructs could also be beneficial to explain various phenomena taking place in the body, such as EPC regeneration in the BM and embryonic development, where the O 2 gradient plays a critical
role in differentiation and migration dynamics.
Figure 4.7 illustrates two proposed approaches for controlling oxygen distribution and ECM properties. One proposal for regulating O 2 gradients inside the gel
would be to incorporate microfluidic technology [66, 129, 163, 220]. Although this
approach provides better O 2 control over 3D microenvironments, the problem of
spatial variations in O 2 levels throughout the gel, due to the cells’ O 2 consumption,
must still be addressed. Advancements in microfluidic technology could enable spatial O 2 control over 3D microenvironments; for instance, the gel could be prepared
around a microtube, which would supply O 2 by flushing growth media containing a
desired amount of O 2 (Fig. 4.7a). Hence, different O 2 gradients could be generated
via the manipulation of O 2 concentrations in the outside environment and inside the
microtube.
Another method for controlling and improving O 2 transport in the gel would be to
microencapsulate O 2 carrier liquids, such as perfluorocarbons (PFCs). Due to their
high capacity to dissolve O 2 , PFCs have been used as a blood replacement to improve
O 2 delivery to tissues [112, 183]. Based on the high oxygen-carrying capacity of
PFCs, Radisic et al. [183] developed a PFC-perfused system to supply sufficient
4 Hypoxia and Matrix Manipulation for Vascular Engineering