Fine-tuning the mechanical and degradation properties of chemically crosslinked hyaluronic acid hydrogels through salt treatment

This study proposes a novel method to fine-tune hyaluronic acid (HA) hydrogel properties by incorporating salt into the HA solution prior to crosslinking. The salt is hypothesized to influence HA chain conformation and HA-HA interactions mainly through the Hofmeister effect and electrostatic interactions, thereby affecting HA degree of modification (DoM), degree of crosslinking (DoCr), and chain arrangement within the hydrogel network. These changes become fixed upon crosslinking, resulting in stable modifications persisting after salt removal. To verify this, HA solutions (5% w/v) were crosslinked with 1,4-butanediol diglycidal ether (BDDE) after adding a sodium salt from the Hofmeister series (sodium citrate, sodium sulfate, or sodium chloride; 0-0.67 M). Following crosslinking and salt removal, the hydrogels were characterized using NMR, swelling, rheological, and degradation tests. Results demonstrated that salt treatment influenced swelling ratio, mechanical properties, and degradation rates, with changes depending on salt type and concentration. NMR analysis confirmed that salts did not directly participate in crosslinking but affected DoM and DoCr. Changes in hydrogel properties were primarily driven by DoM alterations, with potential contributions from non-covalent interactions and modified HA chain arrangement. This salt treatment technique may enable designing hydrogels with unique properties not achievable by simple changes in crosslinker concentration.