Ion-mediated crosslinking of hyaluronic acid into hydrogels without chemical modification

Hyaluronic acid (HA) is a biomedically relevant polymer widely explored as a component of hydrogels. The prevailing approaches for crosslinking HA into hydrogels require chemically modifying the polymer, which can increase processing steps and complicate biocompatibility. Herein, we demonstrate an alternative approach to crosslink HA that eliminates the need for chemical modifications by leveraging the interactions between metal cations and the negatively charged, ionizable functional groups on HA. We demonstrate that HA can be crosslinked with the bivalent metal cations Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Pd(II), and notably Mg(II). Using Mg(II) as a model, we show that ion-HA hydrogel rheological properties can be tuned by altering the HA molecular weight and concentrations of ion, NaOH and HA. Mg(II)-HA hydrogels showed the potential for self-healing and stimulus response. Our findings lay the groundwork for developing a new class of HA-based hydrogels for use in biomedical applications and beyond.