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An engineered microenvironment couples angiogenesis and osteogenesis for bone regeneration (Banfi Lab)
In this manuscript we find that controlling the dose distribution of VEGF protein in an osteogenic graft is key to maintaining the physiological coupling of angiogenesis and osteogenesis that is required for effective bone regeneration.
The therapeutic regeneration of vascularized bone is an unsolved challenge in regenerative medicine. Vascular Endothelial Growth Factor (VEGF) is the master regulator of vascular growth and during bone development angiogenesis and osteogenesis are physiologically coupled by VEGF. However, VEGF also has the potential to paradoxically impair net bone formation when over-expressed therapeutically, by stimulating excessive resorption.
In collaboration with the Plastic and Reconstructive Surgery of Unispital Basel (Prof. Dirk J. Schaefer) and the Pritzker School of Molecular Engineering at the University of Chicago (Prof. Jeffrey A. Hubbell), here we found that controlling the distribution of VEGF dose in an osteogenic graft is key to recapitulate its physiological function. To this end we took advantage of an engineered version of VEGF (TG-VEGF), fused to a short sequence that allows its cross-linking into a fibrin hydrogel during its polymerization. Fibrin is the physiological matrix deposited after injury and provides an ideal support to tissue regeneration. Homogeneous distribution of VEGF protein could stimulate early vascularization of osteogenic grafts without interfering with subsequent bone formation, and significantly improved repair of critical-size bone defects.
These findings suggest an explanation for the apparent discrepancy between the biological functions of VEGF and the paradoxical effects of its therapeutic delivery. These results also bear translational relevance for the design of effective therapeutic strategies to engineer vascularized osteogenic grafts. Fibrin matrices decorated with engineered VEGF protein provide a highly tunable and clinically applicable platform to generate a controlled regenerative microenvironment, opening interesting possibilities for a versatile class of off-the-shelf materials.