TABLE II.
Examples of growth factors delivery strategies for therapeutic angiogenesis.
| Delivery strategy | Growth factor | Methodology | Results |
|---|---|---|---|
| Physical encapsulation | FGF-2 | Light-induced crosslinkable chitosan hydrogels were loaded with bFGF | Encapsulation led to the sustained release of greater bFGF content through in vivo degradation; and achieved augmented wound healing and microvessel formation in diabetic mice121 |
| Microsphere and nanoparticle-mediated delivery | VEGF | PLGA microspheres encapsulating VEGF has been incorporated into dextran hydrogels to form composite hydrogels | |
| This hydrogel increased VEGF receptor Flk-1 approximately 20-fold and vascular differentiation of hESCs more than embryoid body cultures125 | |||
| Ionic complexation | SDF1-α | SDF1-α formed ionic complexation with anionic succinylated gelatin hydrogels | Ionic complexation led to increased GF retention, prolonged release and augmented angiogenesis after implantation129 |
| Immobilized GAG and GF-binding domain-mediated delivery | FGF-2 | FGF-2 was loaded into collagen matrices that covalently incorporates heparan sulfate, and matrices were implanted to rat | Heparan sulfate coupling increased binding capacity and retention of FGF-2 threefold and resulted in its sustained and prolonged FGF-2 release in vitro, and augmented neovascularization in vivo130 |
| Covalent conjugation/immobilization | Ephrin-A1 | Ephrin-A1 was covalently conjugated to PEGDA hydrogels | Covalent conjugation enhanced HUVEC adhesion, tubulogenesis; and stimulated stabilization by increased depositions of ECM proteins (laminin and collagen IV) in vitro and formed enlarged and highly branched microvasculature with higher vessel density and lower vessel diameter in vivo93 |
| Spatiotemporal delivery | VEGF | End-functionalized PEG hydrogels were cross-linked with MMP substrate covalently conjugated with thiol-containing the tripeptide Arg-Gly-Asp (RGD) and VEGF through Michael-type addition reaction | Hydrogel system enhanced MMP secretion by activating angiogenic cells such as HUVECs and VSMCs; and cleaved cross-linking MMP substrate. MMP-mediated degradation caused matrix-bound VEGF liberation, resulting in enhanced, long-term and controlled angiogenesis with mature microvasculature stabilized by SMCs131 |
| Simultaneous delivery of non-covalently conjugated multiple GFs | VEGF, Ang-1, SDF-1, IGF | GFs were co-immobilized in dextran hydrogels and the system was compared with the groups with fewer factors | Simultaneous delivery of 4 factors led to greater proangiogenic synergistic effect that resulted in functional microvasculature with increased number of larger and more mature blood vessel formation than hydrogels immobilized with individual GF132 |
| Simultaneous delivery of covalently conjugated multiple GFs | VEGF, Ang-1 | 3D collagen scaffolds were co-immobilized with VEGF and Ang-1 via EDC chemistry | Dual delivery led to more enhanced EC proliferation, attachment and tubulogenesis in vitro; and more mature and stable vessels and increased hemoglobin concentration indicating augmented angiogenesis with enhanced vessel density and proper connection to host circulation in CAM assay in vivo than their soluble controls and single GF immobilization groups that lack proper vascularization133 |
| Sequential delivery of multiple GFs | VEGF, PDGF, Ang-1, Ang-2 | Scaffolds formed from PLGA microspheres through gas foaming were loaded with VEGF, PDGF, Ang-1 and Ang-2 | Sequential delayed delivery of early and late angiogenic factors led to enhanced EC activity, pericyte detachment mediated-vessel disruption and new vessel sprouting by VEGF and Ang-2; and augmented microvessel remodeling, density, stabilization and maturation by PDGF and Ang-1 without inhibiting each other's activity compared to simultaneous delivery of all factors where late GFs inhibit the actions of early GFs135 |
| Spatiotemporal delivery of multiple GFs | VEGF, PDGF-BB | Bilayer PLGA scaffolds was loaded with only VEGF in one spatial zone and both VEGF and PDGF-BB in nearby zone for a sequential delivery | Spatiotemporal delivery resulted in the significant augmentation of maturity and vessel size135 |