Injectable Dynamically Crosslinked Zwitterionic Hydrogels as a Viscosupplement for Osteoarthritis Treatment.

While hyaluronic acid-based viscosupplements have been widely used clinically for osteoarthritis treatment, their rapid in vivo degradation and variable biological interactions have led to inconsistent patient outcomes. Herein, we report the use of a dynamically crosslinked hydrazone-based zwitterionic hydrogel based on mixing hydrazide (ZH) and aldehyde (ZA) or ketone (ZK)-functionalized precursor polymers as an alternative to hyaluronic acid-based viscosupplements. Upon coinjection via a double-barrel syringe, the water-like precursor polymer solutions gel within ∼0.5-3 min. Relative to a leading hyaluronic acid-based product (Synvisc®), the dynamic zwitterionic hydrogels showed 10-50× higher compressive moduli, beneficial to mechanically support the joint while at the same time exhibiting a 5-9× higher reduction in the coefficient of friction at walking frequencies against an alumina surface over 400 cycles and a >25% lower coefficient of friction against ex vivo cartilage samples, all while also being easy to inject given the low initial viscosity of the precursor polymers. The hydrogel was noncytotoxic and showed minimal inflammatory responses when injected in vivo, with the ZA formulations persisting for >90 days postinjection compared to only days for conventional HA-based viscosupplements. Overall, zwitterionic dynamic hydrogels provide a combination of mechanical support, lubricity, and in vivo inertness/stability while being injectable, suggesting promise for clinical translation for osteoarthritis treatment.