1). HMW HA is strongly negatively free copy charged and therefore absorbs up to 10�C10,000 times its weight water.23 It is generally a bio-inert molecule that acts to maintain a hydrated and porous environment, absorbs mechanical shock and regulates osmotic balance. HMW HA can also sequester and gradually release growth factors and other bioactive molecules to communicate a local biological influence over cells. HMW HA is specifically interesting from a tissue engineering standpoint as it can diminish the interaction of encapsulated cells with other cells and growth factors and therefore ��conceal�� them from local harmful signals; this is mainly done by modulating inflammatory response of macrophages.24 HMW HA can be degraded by enzymes, hyaluronidases, into oligomers that, unlike high molecular HA, are highly bioactive (see below).
HA degradation is facilitated in inflammation and injury by the production of reactive oxygen and nitrogen species.25 Figure 1. Scanning electron micrograph of HA hydrogel at (A) lower or (B) higher magnification. Reproduced with permission from ref. 77. Scale bar = (A) 50 ��m and (B) 20 ��m. HA is a reasonable choice to encapsulate cells for transplantation into the brain because it is naturally and abundantly found in the brain.26 HA has a role in the brain more than just space-filling, hydration and matrix provision. HA influences cell adhesion, migration, axon path-finding, brain regional specificity and therefore, it is actively involved in normal development of the brain.26,27 HA is increasingly deposited in the aged brain and diminishes oligodendrocyte precursor (OPC) maturation.
28 HA in the demyelinated plaques of multiple sclerosis prohibits OPC maturation and myelin repair.31 HA is a component of the perineuronal net that modulates mature cerebral neurons.29 HA is also involved in brain pathologies and diseases. HA promotes malignant glial cell adhesion, migration and metastasis in the brain.28 It also contributes to mossy fiber sprouting in the hippocampus that will eventually lead to temporal lobe epilepsy.27 HA is involved in immunomodulation, tissue injury and repair in the brain through the innate immune receptors toll-like receptors 2 and 4 (TLR2 and TLR4), signaling through the main inflammatory transcription factor NF��B, and tumor necrosis factor �� secretion.26,30 These phenomena are mediated through HA receptors, mainly CD44, RHAMM and TLR4.
Hence, HA affects a variety of physiologic and pathologic functions, which makes its application intriguing and challenging. HA gives different biological signals depending on the molecular weight Dacomitinib (see Table 2 for an overview). High molecular HA (> 500 kDa) that is normally found in the brain plays a structural role and silences inflammation, angiogenesis and neural differentiation.32-34 But in pathologies, such as brain ischemic stroke, HA is fragmented into 6- to 40-mers through the action of hyaluronidases and reactive oxygen or nitrogen species.