Long‐term delivery of etanercept mediated via a thermosensitive hydrogel for efficient inhibition of wear debris‐induced inflammatory osteolysis

Abstract

AbstractPeriprosthetic wear debris‐induced aseptic loosening brings great pain to patients undergoing total joint arthroplasty. Tumor necrosis factor α (TNF‐α) is a pivotal cytokine involved in wear debris‐induced aseptic inflammation and subsequent osteolysis. Herein, we developed an injectable hydrogel system containing etanercept (ETN), a TNF‐α antagonist, to inhibit wear debris‐induced osteolysis. A set of thermosensitive poly(lactide‐co‐glycolide)‐b‐poly(ethylene glycol)‐b‐poly(lactide‐co‐glycolide) (PLGA–PEG–PLGA) copolymers with comparable molecular weights but different LA/GA molar ratios were synthesized by us, and their aqueous solutions presented sol‐to‐gel transitions along with the elevation of temperature. The LA/GA ratio not only impacted the phase transition temperature but also controlled the degradation rate of gel in vivo. The hydrogel with an appropriate in vivo degradation rate was employed to load and deliver ETN, and the drug introduction did not influence on its thermo‐induced gelation behavior. The loaded ETN was released from the gel depot in vitro in a sustained manner for up to 30 days. In a mouse bone‐implanted air pouch model, a single injection of the hydrogel formulation and subsequent sustained release of active ETN efficiently neutralized TNF‐α, resulting in significant suppression of titanium particles‐induced aseptic inflammation and subsequent osteolysis, and the effect was pronouncedly superior to that of an ETN solution.