Ionic modulation of interpenetrating network formation, structure and recovery in low-polymeric, supramolecular hyaluronic acid based-hydrogel

Theformation of interpenetrating polymer networks (IPNs) in polysaccharide-based hydrogels is influenced by ion valency and coordination chemistry. In this work, hyaluronic acid (HA) and kappa-carrageenan (κ-CG) were combined at low polymer concentrations suitable for injectable hydrogel applications and enriched with monovalent (K+), divalent (Ca2+), and trivalent (Al3+) ions to investigate ion-specific contributions to network formation,structure and recovery. FTIR spectroscopy showed that K+ did not produce detectable sulfate or carboxylate shifts, consistent with a predominantly physical mixture and the absence of IPN formation. Ca2+ induced concentration-dependent shifts in both the amide/carboxylate region and the sulfate band, absent at a low concentration but reemerging at higher concentrations, consistent with local chain compaction, complexation of HA carboxylates and bridging between κ-CG helices, indicating promotion of a semi-interpenetrated network structure above a threshold concentration. Al3+ induced a distinct shoulder in the HA carboxylate region, confirming HA coordination and co-crosslinking with κ-CG, yielding a semi-IPN. Microrheology showed progressively stronger local confinement with increasing ion valency corroborating insights from spectroscopy, while recovery tests showed Ca2+ attained the highest recovery potential possibly due to more robust network formation, Al3+ systems displayed moderate recovery but over-screening at high concentrations resulted in network collapse, and K+ systems displayed poor recovery. Importantly, these ion-specific outcomes must be interpreted in the context of combined electrostatic screening effects, which contribute to charge neutralization and polymer chain association independent of coordination chemistry. Collectively, these findings highlight ion charge as critical design levers which may be leveraged in tailoring mechanical properties of interpenetrating network hydrogels for injectable applications.