Table 2.
Collagen–growth factor (GF) release systems: summary of their growth factor retention ability and their main benefit.
| Mechanism of GF loading | GF system used | GF remaining in system | In vivo and in vitro effect | Other findings | References |
|---|---|---|---|---|---|
| Direct loading (No cross-linking or other modifications) | bFGF | 50% after 7 d | N/A | The affinity of bFGF to collagen was examined and compared with other GFs. | [177] |
| 15–30% after 7 d | N/A | Collagen was found to function as a bFGF reservoir in vivo | [178] | ||
| 40–80% after 70 h | N/A | Collagen was found to function as a bFGF reservoir in vivo and in vitro. | [178] | ||
| 45% after 7 d | Dual release of HGF and bFGF from collagen enhanced blood vessel formation. | N/A | [108] | ||
| HGF | 30% after 7 d | N/A | The affinity of HGF to collagen was examined and compared with other GFs. | [177] | |
| 35% after 7 d | Dual release of HGF and bFGF from collagen enhanced blood vessel formation. | [108] | |||
| PDGF-BB | 30% after 7 d | N/A | The affinity of PDGF-BB to collagen was examined and compared with other GFs. | [177] | |
| VEGF | <15% after 7 d | N/A | The affinity of VEGF to collagen was examined and compared with other GFs. | [177] | |
| IGF-1 | <5% after 7 d | N/A | The affinity of IGF-1 to collagen was examined and compared with other GFs. | [177] | |
| HB-EGF | <5% after 7 d | N/A | The affinity of H -EGF to collagen was examined and compared with other GFs. | [177] | |
| rh-BMP2 | N/A | N/A | Certain isotypes of rh-BMP2 have a pH- and salt-dependent increase in affinity for collagen. | [179] | |
| Chemical cross-linking | VEGF bound to collagen using EDAC | 50–70% depending on cross-linking concentration compared with <10% for the non- cross-linked system at time point 0 h. | Increase in viability, invasion and assembly of endothelial cells into the collagen hydrogel compared with the no VEGF and soluble VEGF groups. | N/A | [193] |
| EGF PEGylated with PEG-NHS and bound to collagen | N/A | Cell proliferation of cross-linked EGF using PEG-NHS was lower compared with the non- cross-linked condition due to PEG sterically hindering cells of attaching to the EGF properly. | Cell proliferation was highly dependent on the site of EGF PEGylation. PEGylation at the N-terminus showed the best, albeit still lower than non- cross-linked EGF, and PEGylation at Lysine 48 the worst biological response in vitro. | [194] | |
| EGF cross-linked using riboflavin | 96–98% after 120 h | Cytokeratin (CK) 3/12 – an important corneal epithelial cell differentiation marker – was upregulated and tight junction were observed between adjacent cells. | No significant difference was observed between the immobilized EGF and the soluble EGF group in terms of differentiation | [195] | |
| Electrostatic and other protein–protein interactions | rhFGF-2 interacting with heparan sulfate bound to collagen |
60% in hydrogels with heparan sulfate and 20% without after 21 d | The collagen-HS-bFGF complex showed extensive angiogenesis throughout the hydrogels in vivo, which was not the case in the collagen-bFGF and collagen-HS hydrogels. | N/A | [197] |
| EGF interacting with hyaluronan bound to collagen | N/A | Aided in keratinocyte migration in a scratch assay as well as EGF-signaling and HGF expression of fibroblast, which affect keratinocyte differentiation. HA-EGF containing hydrogels also resulted in more effective wound healing compared with the no-EGF group. | Sulfated hyaluronan increased EGF binding to collagen compared with heparan sulfate and hyaluronan | [198] | |
| bFGF bound to heparinized collagen | 60% in hydrogels with heparan suldate and 20% without after 250 h | N/A | N/A | [199] | |
| EGF expressed with a collagen binding domain (CBD) bound to collagen | N/A | Gene expression analysis also revealed that neural stem cells in the EGF-CBD-Collagen expressed significantly more stem cell, neuron, astrocyte and oligodendrocyte associated markers compared with unbound EGF. Cell proliferation was also increased in the former. | N/A | [175] | |
| VEG121 merged with Fibronectin Collagen Binding Domain (FNCBD) bound to collagen | N/A | FNCBD-VEGF121 showed a similar bioactivity to soluble VEGF121 but significantly increased the expression of VEGFR-2, a receptor for VEGF – on endothelial progenitor cells (EPCs). In vivo experiments showed that the novel chimeric growth factor could induce EPC mobilization locally without having a system effect on the cell type. | N/A | [200] | |
| Other carrier Systems | Collagen microgels containing rhBMP-2. | 80% BMP-2 retained after 14 d | [123,201,202] | ||
| EDAC-NHS cross-linked Collagen microgels containing rhVEGF |
rhVEGF was released in 8 days in collagenase and in 4 weeks in cell medium. | HUVEC cultures that show capillary formation after 21 days, comparable with a control with VEGF in solution. | N/A | [203] | |
| Magnetic GFs | N/A | The study showed that scaffolds supported cell adhesion and proliferation. | Magnetic nanoparticles did not leak out of the scaffold over time. | [204] | |
| VEGF and PDGF-BB immobilized using the TrAP system | <1 ng/ml release with TrAP over 49 h compared with 3 ng/ml without TrAP | TrAP-PDGF-BB functionalised coverslips resulted in increased cell proliferation compared with soluble PDGF-BB in 2D. There was no significant difference between collagen hydrogels loaded with PDGF-BB and TrAP-PDGF-BB decorated collagen hydrogels in 3D | N/A | [205] |