Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Integrin binding to bioengineered hydrogel scaffolds is essential for tissue regrowth and regeneration, yet not all integrin binding can lead to tissue repair. Here, we show that through engineering hydrogel materials to promote alpha 3/alpha 5 beta 1 integrin binding, we can promote the formation of a space-filling and mature vasculature compared with hydrogel materials that promote alpha v beta 3 integrin binding. In vitro, alpha 3/alpha 5 beta 1 scafolds promoted endothelial cells to sprout and branch, forming organized extensive networks that eventually reached and anastomosed with neighbouring branches. In vivo, alpha 3/alpha 5 beta 1 scafolds delivering vascular endothelial growth factor (VEGF) promoted non-tortuous blood vessel formation and non-leaky blood vessels by 10 days post-stroke. In contrast, materials that promote alpha v beta 3 integrin binding promoted endothelial sprout clumping in vitro and leaky vessels in vivo. This work shows that precisely controlled integrin activation from a biomaterial can be harnessed to direct therapeutic vessel regeneration and reduce VEGF-induced vascular permeability in vivo.