In vitro, there has been remarkable success in forming new vessels using various microfluidic chambers to study the fundamentals of vasculogenesis. Additionally, the complex ECM structure consisting of proteins such as fibrin, fibronectin (FN), collagens, laminin and others serve not only as a mechanical scaffold for cell migration, proliferation and non-specific retention of GFs but create a dynamic environment able to bind GFs specifically, forming gradients and possibly releasing them on demand during proteolytic degradation, ,. A detailed role of secreted GFs and cytokines orchestrating this process has still not been fully elucidated, however a prominent role for the vascular endothelial GF (VEGF) family and their receptors and fibroblastic GF (FGF) has been repeatedly described. The presence of other cell types such as pericytes is important for vessel maturation. Angioblasts derived from bone marrow progenitor cells differentiate into endothelial cells and together with smooth muscle cells go on to form the vessel. As these processes are complex, a dynamic interaction between cells, growth factors (GFs) and extracellular matrix (ECM) components involves strict temporal and spatial regulation to allow both a nascent tube formation and vessel maturation. New vessels can be formed in two distinct ways: either via sprouting of existing vessels (angiogenesis), or development of de novo vessels from progenitor cells (vasculogenesis).

Detailed understanding of the process of vessel formation can provide a powerful tool to control vascularization in pathological conditions, and it can prove useful in tissue engineering and regenerative medicine where developing functional vascularized tissue is still a major challenge. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications.įully developed vascular networks are essential for cell growth and tissue formation as they aid nutrient and oxygen supply and removal of toxic metabolites. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. Importantly, the growth factor binding (FNIII 12-14) and integrin binding (FNIII 9-10) regions are simultaneously available on FN fibrils assembled on PEA.

Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling.

Synergy of serra review