HA has been widely studied and appreciated as a pro-angiogenic tool in tissue engineering because it can initiate and maintain angiogenesis. HMW HA promotes quiescence in endothelial cells, but oligomeric HA promotes their proliferation and migration; this effect is mediated directly through endothelial cells and ref 1 also indirectly by inducing inflammatory cells to secrete pro-angiogenic factors. HA relays these messages through CD44, RHAMM and TLR-4 receptors.26,41,42 Long polymers of HA bind to CD44 and interfere with any biological signal transduction; this inhibits endothelial cell proliferation that leads to arrest of angiogenesis. Oligomeric HA, in contrast, attaches to CD44 and promote proliferation of endothelial cells.

This molecule also enhances matrix metalloproteinase (MMP)-2 and -9 expression, promoting matrix degradation and progression of angiogenesis. MMPs also activate endogenous TGF-�� that in turn contributes to angiogenesis. Interactions of short chain HA with RHAMM lead to cytoskeletal changes and subsequent migration of endothelial cells that further contribute to the formation of new vessels.26 Growing human umbilical vein endothelial cells (HUVECs) on HA gels improved their proliferation. This augmentation was proportional to the concentration of HA and by using 1% HA gel cells maximally increased their proliferation over 2-fold in a 48 h interval. HA also protects HUVECs against apoptosis induced by serum deprivation. An HA gel enhanced angiogenesis, arteriogensis and improved ischemia in an experimental model of mice limb ischemia when it encapsulated HUVECs.

43 Implanting HA hydrogels in the brain has improved angiogenesis.44 HA is also important in maintaining vascular integrity.45 These data show HA has the potential to support the formation of a vasculature to allow generation and survival of engineered constructs in sizes required to replace the infarcted brain tissue. Some studies have bound oligomeric HA to culture surfaces and thereby induced endothelial cell proliferation and tube formation.46 An alternative approach would be to engineer HMW HA gels to persistently degrade and provide host tissue endothelial cells with a continuous source of pro-angiogenic oligomeric HA.47 Interaction of endothelial cells with a plain or unmodified HA gel is often not sufficient to make a patent vasculature.

Chemical engineering can help to further enhance angiogenesis in HA gels by introducing components of extracellular matrix (ECM) molecules Anacetrapib such as fibronectin48 or fibronectin-derived synthetic protein motifs.44 Other studies have shown HA gels that gradually release pro-angiogenic growth factors VEGF or bFGF have an improved angiogenesis.26 Hyaluronan and Neural Stem/Progenitor Cells There are many indications that HA influences neural stem/progenitor cells in neural tissue development and therefore HA is a suitable candidate to encapsulate NSPCs in neural tissue engineering.