Is molecular size a discriminating factor in hyaluronan interaction with human cells?

•A simple protocol to degrade hyaluronic acid, without structural change identity, is presented.•A close correlation between molecular size and biological response was evaluated and assessed.•The role of different HA in inflammatory response, using an in vitro simplified cellular skin model, was elucidated at transcriptional and protein level.•Receptor activation according to HA at different size, was investigated. Nowadays there is a great interest in investigating the effect of particular hyaluronan fragments in the biomedical field and in cosmeceutical applications. Literature has reported that very low molecular weight HA (Mw