Hierarchically Structured Biodegradable Microspheres Promote Therapeutic Angiogenesis

Promoting neovascularization is a prerequisite for many tissue engineering applications and the treatment of cardiovascular disease. Delivery of a pro-angiogenic stimulus via acellular materials offers several benefits over biological therapies but has been hampered by interaction of the implanted material with the innate immune response. However, macrophages, a key component of the innate immune response, release a plurality of soluble factors that can be harnessed to stimulate neovascularization and restore blood flow to damaged tissue. This study investigates the ability of biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres to restore tissue perfusion in a hind limb model of ischaemia. Microspheres exhibiting a hierarchical porous structure are associated with an increase in blood flow at day 21 post-implantation compared with solid microspheres composed of the same polymer. This corresponds with an increase in blood vessel density in the surrounding tissue. In vitro simulation of the foreign body response observed demonstrates M2-like macrophages incubated with the porous microspheres secreted increased amounts of vascular endothelial growth factor (VEGF) compared with M1-like macrophages providing a potential mechanism for the increased neovascularization. The results from this study demonstrate implantable biodegradable porous microspheres provide a novel approach for increasing neovascularization that could be exploited for therapeutic applications.