89
interactions. Gels made from ECM components, engineered to have properties
resembling those of native tissues, have been widely explored as a tool to study the
molecular regulation underlying vascular development [49] and as a scaffold to
transplant vascular progenitor cells [15, 46, 164]. However, their manipulation for
vascular tissue engineering has been narrowly limited by their inherent chemical
and physical properties. Therefore, a great need exists to chemically modify these
ECM components [40, 130] or to utilize biomaterials to form scaffolds from hydrogels, which are xeno-free and instructive for vascular tissue engineering [152].
Hydrogels are cross-linked polymer networks which can store a large amount of
fluid and which have biophysical properties similar to many soft tissues [138].
Hydrogels can be engineered from natural biomaterials (including ECM components), artificial protein polymers, self-assembling peptides, and synthetic polymers
to form scaffolds which mimic the native ECM. For example, dextran and chitosan,
natural biomaterials with similar structures, do not possess any inherent cross-linking ability [214, 215]. However, a simple chemical modification, such as introducing double bonds into the repeating unit, allows the cross-linking of these
polysaccharides to form hydrogels. Alginate is another natural material which can
be physically cross-linked by adding cations (e.g., Ca
2+
or Mg
2+
) [80]. Another
approach utilizes a purely synthetic polymer, like polyethylene glycol (PEG) or
poly-[lactic-co- glycolic acid] (PLGA), whose physical and chemical properties can
be easily manipulated. A simple modification can turn PEG, a cell-resistant material, into an instructive scaffold designed to promote vascularization [58, 59, 166,
176]. Furthermore, the synthetic material of choice must be biodegradable and biocompatible, and such physical properties as pore size, degradation kinetics, and
matrix mechanical properties must be easily tunable to favor vascular morphogenesis. Bioactive molecules—like GFs, cell adhesion motifs such as arginine-glycineaspartic acid (RGD), and MMP-sensitive peptides—must be presented with correct
spatial and temporal distributions within the synthetic biomaterials. Next, we will
discuss several strategies for manipulating the chemical and physical properties of
synthetic biomaterials.
Cell Adhesion Regulates Neovascularization
In order to support vascular cells and instruct them to undergo vascular morphogenesis, synthetic biomaterials must first be able to provide cell adhesion. Instead of
incorporating ECM components to make such materials bioactive, certain synthetic
peptides important for vascular morphogenesis can be incorporated into these inert
synthetic materials. The most common template is the integrin-binding domain of
fibronectin, RGD [178], and the laminin-derived peptide IKVAV [203]. The first
crucial step in vascular morphogenesis occurs when vascular cells utilize integrin
receptors to sense their surrounding microenvironments. Integrins are transmembrane receptors which not only maintain cell adhesion to ECM but also control cell
proliferation, migration, differentiation, and cytoskeletal organization. Since blood
vessels must be able to assemble in diverse tissue environments (e.g., adult versus
4 Hypoxia and Matrix Manipulation for Vascular Engineering
interactions. Gels made from ECM components, engineered to have properties
resembling those of native tissues, have been widely explored as a tool to study the
molecular regulation underlying vascular development [49] and as a scaffold to
transplant vascular progenitor cells [15, 46, 164]. However, their manipulation for
vascular tissue engineering has been narrowly limited by their inherent chemical
and physical properties. Therefore, a great need exists to chemically modify these
ECM components [40, 130] or to utilize biomaterials to form scaffolds from hydrogels, which are xeno-free and instructive for vascular tissue engineering [152].
Hydrogels are cross-linked polymer networks which can store a large amount of
fluid and which have biophysical properties similar to many soft tissues [138].
Hydrogels can be engineered from natural biomaterials (including ECM components), artificial protein polymers, self-assembling peptides, and synthetic polymers
to form scaffolds which mimic the native ECM. For example, dextran and chitosan,
natural biomaterials with similar structures, do not possess any inherent cross-linking ability [214, 215]. However, a simple chemical modification, such as introducing double bonds into the repeating unit, allows the cross-linking of these
polysaccharides to form hydrogels. Alginate is another natural material which can
be physically cross-linked by adding cations (e.g., Ca
2+
or Mg
2+
) [80]. Another
approach utilizes a purely synthetic polymer, like polyethylene glycol (PEG) or
poly-[lactic-co- glycolic acid] (PLGA), whose physical and chemical properties can
be easily manipulated. A simple modification can turn PEG, a cell-resistant material, into an instructive scaffold designed to promote vascularization [58, 59, 166,
176]. Furthermore, the synthetic material of choice must be biodegradable and biocompatible, and such physical properties as pore size, degradation kinetics, and
matrix mechanical properties must be easily tunable to favor vascular morphogenesis. Bioactive molecules—like GFs, cell adhesion motifs such as arginine-glycineaspartic acid (RGD), and MMP-sensitive peptides—must be presented with correct
spatial and temporal distributions within the synthetic biomaterials. Next, we will
discuss several strategies for manipulating the chemical and physical properties of
synthetic biomaterials.
Cell Adhesion Regulates Neovascularization
In order to support vascular cells and instruct them to undergo vascular morphogenesis, synthetic biomaterials must first be able to provide cell adhesion. Instead of
incorporating ECM components to make such materials bioactive, certain synthetic
peptides important for vascular morphogenesis can be incorporated into these inert
synthetic materials. The most common template is the integrin-binding domain of
fibronectin, RGD [178], and the laminin-derived peptide IKVAV [203]. The first
crucial step in vascular morphogenesis occurs when vascular cells utilize integrin
receptors to sense their surrounding microenvironments. Integrins are transmembrane receptors which not only maintain cell adhesion to ECM but also control cell
proliferation, migration, differentiation, and cytoskeletal organization. Since blood
vessels must be able to assemble in diverse tissue environments (e.g., adult versus
4 Hypoxia and Matrix Manipulation for Vascular Engineering