Hyaluronic acid-based hydrogels modulate neuroinflammation and extracellular matrix remodelling in multiple sclerosis: insights from a primary cortical cell model

Multiple sclerosis (MS) is the main neurodegenerative disorder among young adults. Cortical involvement in MS has emerged as an important determinant of disease progression. Although inflammation is recognized as a key feature, the mechanisms of cortical pathology are still poorly understood. The critical role of the extracellular matrix (ECM) in the development and homeostasis of the central nervous system (CNS) and hyaluronic acid (HA) in primis has been emphasized. HA synthesis increases during neuroinflammation in the cortex, mostly through hyaluronan synthase 2 (HAS2), generating an ECM scar on demyelinated axons. Here, we aimed to prove the potential role of an external source of HA in CNS inflammation, specifically in a complex in vitro model of neuroinflammation using primary cortical cells (PCC). We engineered and characterized a battery of cross-linked HA-based hydrogels and tested their impact on LPS-triggered inflammation in PCC. The performance of the tested HA scaffolds is promising for their potential use in vivo, exhibiting an appealing anti-inflammatory response. We also studied the effect of the crosslinked HA hydrogels on hyaluronan metabolism and catabolism markers, showing a significant decrease in HAS2 expression, which could have a critical impact on scar generation in demyelinated axons. Finally, we analyzed the effect of the degradation products of the HA constructs, shedding light on the unsolved debate about the potential dual effect of HA-based materials on the CNS depending on their molecular weight. Altogether, our results contribute to baseline knowledge regarding the use of HA-based materials in the context of CNS inflammatory disorders.